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Zare B, Monahan KJ. Guidelines for Familial Adenomatous Polyposis (FAP): challenges in defining clinical management for a rare disease. Fam Cancer 2025; 24:35. [PMID: 40192835 PMCID: PMC11976741 DOI: 10.1007/s10689-025-00462-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 03/29/2025] [Indexed: 04/10/2025]
Abstract
Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally. These recommendations reflect the diverse needs and capabilities of varying health systems worldwide, including thresholds for intervention and population health priorities. Whilst guidelines are closely aligned in many regards, there are areas of disparity. However, alongside discrepancies in guideline recommendations, common challenges also face professional bodies across the globe. Generation of a robust evidence-base in the environment of limited data is difficult in rare diseases such as FAP, underscored by the fact that expert consensus opinion underpins virtually all guidelines. The presence of a wide phenotypic spectrum in FAP and the other hereditary gastrointestinal polyposis syndromes, whilst now well recognised, further complicates the creation of universal recommendations. In this review we draw comparison between the various international guidelines for the management of FAP, using examples to focus on thematic areas of agreement and divergence. However, beyond this, we also wish to highlight the persisting evidence gaps in clinical management, and any areas of ongoing debate among clinicians, where we are yet to establish the optimal approach.
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Affiliation(s)
- Benjamin Zare
- Department of Surgery and Cancer, Imperial College London, London, UK
- The St Mark's Centre for Familial Intestinal Cancer, St Mark's: The National Bowel Hospital, Central Middlesex Hospital Site, Acton Lane, Park Royal, London, NW10 7NS, UK
| | - Kevin J Monahan
- St Mark's Centre for Familial Intestinal Cancer, St Mark's Hospital, London, UK.
- Department of Surgery and Cancer, Imperial College London, London, UK.
- The St Mark's Centre for Familial Intestinal Cancer, St Mark's: The National Bowel Hospital, Central Middlesex Hospital Site, Acton Lane, Park Royal, London, NW10 7NS, UK.
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Danieli PP, Hoang N, Selvanayagam T, Yang A, Breetvelt E, Tabbers M, Cohen C, Aelvoet AS, Trost B, Ward T, Semotiuk K, Durno C, Aronson M, Cohen Z, Dekker E, Vorstman J. Autistic traits in youth with familial adenomatous polyposis: A Dutch-Canadian case-control study. Am J Med Genet B Neuropsychiatr Genet 2024; 195:e32999. [PMID: 38967411 DOI: 10.1002/ajmg.b.32999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 05/25/2024] [Accepted: 06/10/2024] [Indexed: 07/06/2024]
Abstract
This study investigated the neurodevelopmental impact of pathogenic adenomatous polyposis coli (APC) gene variants in patients with familial adenomatous polyposis (FAP), a cancer predisposition syndrome. We hypothesized that certain pathogenic APC variants result in behavioral-cognitive challenges. We compared 66 FAP patients (cases) and 34 unaffected siblings (controls) to explore associations between APC variants and behavioral and cognitive challenges. Our findings indicate that FAP patients exhibited higher Social Responsiveness Scale (SRS) scores, suggesting a greater prevalence of autistic traits when compared to unaffected siblings (mean 53.8 vs. 47.4, Wilcoxon p = 0.018). The distribution of SRS scores in cases suggested a bimodal pattern, potentially linked to the location of the APC variant, with scores increasing from the 5' to 3' end of the gene (Pearson's r = 0.33, p = 0.022). While we observed a trend toward lower educational attainment in cases, this difference was not statistically significant. This study is the first to explore the connection between APC variant location and neurodevelopmental traits in FAP, expanding our understanding of the genotype-phenotype correlation. Our results emphasize the importance of clinical assessment for autistic traits in FAP patients, shedding light on the potential role of APC gene variants in these behavioral and cognitive challenges.
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Affiliation(s)
- Polina Perlman Danieli
- Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Ny Hoang
- Department of Genetic Counselling, The Hospital for Sick Children, Toronto, Ontario, Canada
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Thanuja Selvanayagam
- Department of Genetic Counselling, The Hospital for Sick Children, Toronto, Ontario, Canada
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Alvin Yang
- Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Elemi Breetvelt
- Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Merit Tabbers
- Department of Pediatrics, Emma Children's Hospital, Amsterdam, The Netherlands
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Emma Children's Hospital, Amsterdam Reproduction and Development and Amsterdam Gastroenterology Endocrinology Metabolism Research Institutes, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Christine Cohen
- Department of Gastroenterology and Hepatology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Arthur S Aelvoet
- Department of Gastroenterology and Hepatology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Brett Trost
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Thomas Ward
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Kara Semotiuk
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Carol Durno
- The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of Gastroenterology/Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Melyssa Aronson
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Zane Cohen
- The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Evelien Dekker
- Department of Gastroenterology and Hepatology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Jacob Vorstman
- Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Developmental Psychopathology, The Hospital for Sick Children, Toronto, Ontario, Canada
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Karstensen JG, Wewer MD, Bülow S, Hansen T, Højen H, Jelsig AM, Kuhlmann TP, Burisch J, Pommergaard HC. Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections - a nationwide Danish cohort study with long-term follow-up. Fam Cancer 2024; 23:607-615. [PMID: 39046601 PMCID: PMC11512927 DOI: 10.1007/s10689-024-00415-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 07/18/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND Familial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genotype-phenotype associations. METHODS All known FAP patients were included from the Danish Polyposis Register. FAP patients were defined as having more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the APC gene. Endoscopic procedures, histopathology, and genetics were evaluated. RESULTS Of 500 FAP patients, 70.6% underwent esophagogastroduodenoscopy (EGD) at least once. Of these, 59.2% presented with detectable duodenal adenomas. The most severe morphology was tubular in 62.7% patients, tubulovillous in 25.4%, and villous in 12.0%, while the most severe dysplasia was low-grade in 67.5% patients, high-grade in 25.4%, and 6.7% had adenocarcinoma. In 6.2% of FAP patients, duodenal resection was recommended, including 29% with duodenal adenocarcinoma. The risk of duodenal surgery was 1.31 per 1,000 person-years (median age: 53 years). The predominant reason for surgery was extensive polyposis (67.7%). Of the patients who underwent duodenal resection, a median of six (IQR: 4-8) EGDs were performed within five years prior to surgery, but 67.6% and 83.9% never underwent a duodenal polypectomy or endoscopic mucosa resection, respectively. Of note, seventeen of 500 patients (3.4%) developed duodenal adenocarcinoma, of which 47% were advanced at diagnosis. Genetic evaluations revealed various pathogenic variants in the APC gene, with no strong genotype-phenotype association. CONCLUSIONS The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. Nevertheless, the need for duodenal surgery persists and should together with endoscopic practice be monitored in national registers.
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Affiliation(s)
- J G Karstensen
- Danish Polyposis Register, Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre, Kettegaard Allé 30, DK-2650, Hvidovre, Denmark.
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
| | - M D Wewer
- Danish Polyposis Register, Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre, Kettegaard Allé 30, DK-2650, Hvidovre, Denmark
- Gastrounit, medical division, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - S Bülow
- Danish Polyposis Register, Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre, Kettegaard Allé 30, DK-2650, Hvidovre, Denmark
| | - Tvo Hansen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Genetics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - H Højen
- Danish Polyposis Register, Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre, Kettegaard Allé 30, DK-2650, Hvidovre, Denmark
| | - A M Jelsig
- Department of Clinical Genetics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - T P Kuhlmann
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
| | - J Burisch
- Danish Polyposis Register, Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre, Kettegaard Allé 30, DK-2650, Hvidovre, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Gastrounit, medical division, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - H C Pommergaard
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Hepatic Malignancy Surgical Research Unit (HEPSURU), Department of Surgery and Transplantation, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
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Büki G, Antal G, Bene J. Rare Germline Variants in the Adenomatous Polyposis Coli Gene Associated with Dental and Osseous Anomalies. Int J Mol Sci 2024; 25:8189. [PMID: 39125758 PMCID: PMC11312143 DOI: 10.3390/ijms25158189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
APC is a tumor suppressor gene that exerts its effect through the regulation of the Wnt signaling pathway. Loss of function mutations of the gene are associated with familial adenomatous polyposis (FAP). Early diagnosis in FAP patients is essential to prevent the development of colorectal cancer. Extraintestinal manifestations often precede the formation of the polyposis; therefore, these manifestations may serve as a clinical indicator for the condition. The aim of this study was to assess genotype-phenotype associations between the location of APC mutations and various extraintestinal features, mainly focusing on osseous and dental anomalies. Analyses of our cases and the mutations available in the literature with these manifestations revealed that mutations in the N-terminal region (amino acids 1-~1000) of the protein are more frequently associated with only osseous anomalies, whereas dental manifestations are more prevalent in mutations in the middle region (amino acids 1000-~2100). In addition, supernumerary teeth were found to be the most common dental feature. Since dental abnormalities often precede intestinal polyposis, dentists have a crucial role in the early identification of patients at risk.
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Affiliation(s)
- Gergely Büki
- Department of Medical Genetics, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary;
| | - Gréta Antal
- Department of Dentistry, Oral and Maxillofacial Surgery, Clinical Center, Medical School, University of Pécs, 7623 Pécs, Hungary;
| | - Judit Bene
- Department of Medical Genetics, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary;
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Falsetti I, Palmini G, Iantomasi T, Brandi ML, Tonelli F. Mechanisms of Action of Phytoestrogens and Their Role in Familial Adenomatous Polyposis. Pharmaceutics 2024; 16:640. [PMID: 38794302 PMCID: PMC11125335 DOI: 10.3390/pharmaceutics16050640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 05/26/2024] Open
Abstract
Familial adenomatous polyposis (FAP) is a rare disease characterized by the development of adenomatous polyps in the colon and rectum already in adolescence. If left untreated, patients develop colorectal cancer (CRC) with a 100% probability. To date, the gold standard of FAP management is surgery, which is associated with morbidity and mortality. A chemopreventive agent capable of delaying, preventing and reversing the development of CRC has been sought. Several classes of drugs have been used but to date no chemopreventive drug has been found for the management of this disease. In recent years, the importance of estrogen receptors in FAP and CRC, particularly the β subtype, has emerged. Indeed, the expression of the latter is strongly reduced in adenomatous polyps and CRC and is inversely correlated with the aggressiveness of the disease. Since phytoestrogens have a high affinity for this receptor, they have been suggested for use as chemopreventive agents in FAP and CRC. A combination of phytoestrogens and insoluble fibres has proved particularly effective. In this review, the various mechanisms of action of phytoestrogens were analyzed and the effectiveness of using phytoestrogens as an effective chemopreventive strategy was discussed.
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Affiliation(s)
- Irene Falsetti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy; (I.F.); (T.I.)
| | - Gaia Palmini
- Fondazione Italiana Ricerca sulle Malattie dell’Osso (FIRMO Onlus), 50129 Florence, Italy; (G.P.); (M.L.B.)
| | - Teresa Iantomasi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy; (I.F.); (T.I.)
| | - Maria Luisa Brandi
- Fondazione Italiana Ricerca sulle Malattie dell’Osso (FIRMO Onlus), 50129 Florence, Italy; (G.P.); (M.L.B.)
| | - Francesco Tonelli
- Fondazione Italiana Ricerca sulle Malattie dell’Osso (FIRMO Onlus), 50129 Florence, Italy; (G.P.); (M.L.B.)
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Mangla A, Agarwal N, Schwartz G. Desmoid Tumors: Current Perspective and Treatment. Curr Treat Options Oncol 2024; 25:161-175. [PMID: 38270798 PMCID: PMC10873447 DOI: 10.1007/s11864-024-01177-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2024] [Indexed: 01/26/2024]
Abstract
OPINION STATEMENT Desmoid tumors are rare tumors with a tendency to infiltrate locally. The lack of a standard treatment approach makes choosing the most appropriate treatment for patients challenging. Most experts recommend watchful observation for asymptomatic patients as spontaneous regression of tumor is observed in up to 20% of patients. Upfront resection of the desmoid tumor has fallen out of favor due to high morbidity and high relapse rates associated with the tumor. Systemic therapy has evolved over several decades. Where chemotherapy, hormonal therapy, and non-steroidal anti-inflammatory drugs were used over the last several decades, tyrosine kinase inhibitors came to the forefront within the last decade. Most recently, gamma-secretase inhibitors have shown significant clinical benefit in patients with desmoid tumors, bringing forth an entirely new mechanistic approach. Several Wnt pathway inhibitors are also under development. Invasive approaches like cryoablation have also shown clinical benefit in patients with extra-abdominal desmoid tumors in recent years. The recent approval of nirogacestat has ushered in a new era of treatment for patients diagnosed with desmoid tumors. Several new molecules are expected to be approved over the coming years.
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Affiliation(s)
- Ankit Mangla
- University Hospitals Seidman Cancer Center, Cleveland, OH, USA.
- Case Comprehensive Cancer Center, Cleveland, OH, USA.
- Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Lakeside Suite#1200, Room 1243, Cleveland, OH, 44106, USA.
| | - Nikki Agarwal
- Cleveland Clinic Children's Hospitals, Cleveland, OH, USA
| | - Gary Schwartz
- University Hospitals Seidman Cancer Center, Cleveland, OH, USA
- Case Comprehensive Cancer Center, Cleveland, OH, USA
- Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Lakeside Suite#1200, Room 1243, Cleveland, OH, 44106, USA
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Moreno DA, Bonatelli M, Antoniazzi AP, de Paula FE, Leal LF, Garcia FADO, de Paula AE, Teixeira GR, Santana IVV, Saggioro F, Neder L, Valera ET, Scrideli CA, Stavale J, Malheiros SMF, Lima M, Hajj GNM, Garcia-Rivello H, Christiansen S, Nunes S, Gil-da-Costa MJ, Pinheiro J, Martins FD, Junior CA, Mançano BM, Reis RM. High frequency of WNT-activated medulloblastomas with CTNNB1 wild type suggests a higher proportion of hereditary cases in a Latin-Iberian population. Front Oncol 2023; 13:1237170. [PMID: 37746264 PMCID: PMC10513896 DOI: 10.3389/fonc.2023.1237170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 07/31/2023] [Indexed: 09/26/2023] Open
Abstract
Purpose Medulloblastomas are the most common primary malignant brain tumors in children. They are divided into molecular subgroups: WNT-activated, SHH-Activated, TP53 mutant or wild type, and non-WNT/non-SHH (Groups 3 and 4). WNT-activated medulloblastomas are usually caused by mutations in the CTNNB1 gene (85%-90%), and most remaining cases of CTNNB1 wild type are thought to be caused by germline mutations in APC. So far, the frequencies of CTNNB1 have been reported mainly in North American and European populations. The aim of this study was to report the frequency of CTNNB1 mutations in WNT-activated medulloblastomas in a Latin-Iberian population and correlate with their clinicopathological characteristics. Methods A total of 266 medulloblastomas from seven different institutions from Brazil (n=211), Portugal (n=38), and Argentina (n=17) were evaluated. Following RNA and DNA isolation from formalin-fixed, paraffin-embedded (FFPE) tumor tissues, the molecular classification and CTNNB1 mutation analysis were performed by nCounter and Sanger sequencing, respectively. Results WNT-activated medulloblastomas accounted for 15% (40/266) of the series. We observed that 73% of WNT-activated medulloblastomas harbored CTNNB1 mutations. CTNNB1 wild-type cases (27%) were more prevalent in female individuals and suggested to be associated with a worse outcome. Among the CTNNB1 wild-type cases, the available analysis of family history revealed two cases with familiar adenomatous polyposis, harboring APC germline variants. Conclusion We observed a lower incidence of CTNNB1 mutations in WNT-activated medulloblastomas in our Latin-Iberian cohort compared to frequencies previously described in other populations. Considering that CTNNB1 wild-type cases may exhibit APC germline mutations, our study suggests a higher incidence (~30%) of hereditary WNT-activated medulloblastomas in the Latin-Iberian population.
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Affiliation(s)
| | - Murilo Bonatelli
- Molecular Diagnosis Laboratory, Barretos Cancer Hospital, Barretos, Brazil
| | | | | | - Leticia Ferro Leal
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil
- Pathology Department, Barretos Cancer Hospital, Barretos, Brazil
| | | | | | - Gustavo Ramos Teixeira
- Barretos School of Health Sciences Dr. Paulo Prata, Barretos Cancer Hospital, Barretos, Brazil
- Pathology Department, Barretos Cancer Hospital, Barretos, Brazil
| | | | - Fabiano Saggioro
- Department of Pathology and Forensic Medicine, University of São Paulo, Ribeirão Preto, Brazil
| | - Luciano Neder
- Department of Pathology and Forensic Medicine, University of São Paulo, Ribeirão Preto, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Carlos Alberto Scrideli
- Department of Pediatrics of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - João Stavale
- Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | | | - Matheus Lima
- Oncology Department, AC Camargo Hospital, São Paulo, Brazil
| | | | | | - Silvia Christiansen
- Pathology Department, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Susana Nunes
- Pediatric Oncology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | | | - Jorge Pinheiro
- Department of Pathology, Centro Hospitalar Universitário São João, Porto, Portugal
| | | | | | | | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil
- Molecular Diagnosis Laboratory, Barretos Cancer Hospital, Barretos, Brazil
- ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
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Fukushi G, Yamada M, Kakugawa Y, Gotoh M, Tanabe N, Ushiama M, Watanabe T, Yamazaki T, Matsumoto M, Hirata M, Nakajima T, Sugano K, Yoshida T, Matsuda T, Igarashi Y, Saito Y. Genotype-phenotype correlation of small-intestinal polyps on small-bowel capsule endoscopy in familial adenomatous polyposis. Gastrointest Endosc 2023; 97:59-68.e7. [PMID: 36084716 DOI: 10.1016/j.gie.2022.08.042] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 08/18/2022] [Accepted: 08/30/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIMS In familial adenomatous polyposis (FAP), neoplastic lesions outside the colon have become increasingly important. The genotype-phenotype correlation has been established for duodenal polyps, and regular screening is recommended. However, this correlation remains unclear for small-intestinal lesions, except for reports on the relationship between their occurrence and Spigelman stage. Here, we used small-bowel capsule endoscopy (SBCE) to investigate the genotype-phenotype correlation of small-intestinal polyps in FAP. METHODS The genotype-phenotype correlation of small-intestinal polyps was investigated in patients with FAP who underwent SBCE, Esophagogastroduodenoscopy (EGD), and adenomatous polyposis coli (APC) gene analysis. Of 64 patients with FAP who underwent SBCE, 41 were included in the final analysis, 4 did not undergo a complete small intestine examination, and 19 did not undergo genetic analysis. RESULTS The prevalence (median number) of small-intestinal polyps by Spigelman stage was 26% (1.5), 0% (0), 44% (5), 60% (4), and 73% (25.5) for stages 0 to IV, respectively. Significantly more small-intestinal polyps were found in Spigelman stage III and IV groups than in the stage 0 group (P < .05). The APC variant was negative for 6 patients (15%), and the sites associated with more than 5 small-intestinal polyps were codons 278, 1062, 1114, 1281, 1307, 1314, and 1504. CONCLUSIONS In FAP patients, SBCE surveillance is potentially recommended for patients with pathogenic variants in the APC gene at codons 278 and 1062 to 1504 or with Spigelman stage III or higher.
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Affiliation(s)
- Gozo Fukushi
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan; Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan; Division of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan
| | - Masayoshi Yamada
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan; Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan
| | - Yasuo Kakugawa
- Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | - Masahiro Gotoh
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Noriko Tanabe
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan
| | - Mineko Ushiama
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan; Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Tomoko Watanabe
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan
| | | | - Minori Matsumoto
- Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | - Makoto Hirata
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan; Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takeshi Nakajima
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Kokichi Sugano
- Department of Genetic Medicine, Koundo Hospital, Sasaki Foundation, Tokyo, Japan
| | - Teruhiko Yoshida
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan; Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takahisa Matsuda
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan; Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan; Division of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan
| | - Yoshinori Igarashi
- Division of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
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Kamani T, Charkhchi P, Zahedi A, Akbari MR. Genetic susceptibility to hereditary non-medullary thyroid cancer. Hered Cancer Clin Pract 2022; 20:9. [PMID: 35255942 PMCID: PMC8900298 DOI: 10.1186/s13053-022-00215-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 02/21/2022] [Indexed: 11/10/2022] Open
Abstract
Non-medullary thyroid cancer (NMTC) is the most common type of thyroid cancer. With the increasing incidence of NMTC in recent years, the familial form of the disease has also become more common than previously reported, accounting for 5-15% of NMTC cases. Familial NMTC is further classified as non-syndromic and the less common syndromic FNMTC. Although syndromic NMTC has well-known genetic risk factors, the gene(s) responsible for the vast majority of non-syndromic FNMTC cases are yet to be identified. To date, several candidate genes have been identified as susceptibility genes in hereditary NMTC. This review summarizes genetic predisposition to non-medullary thyroid cancer and expands on the role of genetic variants in thyroid cancer tumorigenesis and the level of penetrance of NMTC-susceptibility genes.
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Affiliation(s)
- Tina Kamani
- Women's College Research Institute, University of Toronto, 76 Grenville St. Room 6421, Toronto, ON, M5S 1B2, Canada
| | - Parsa Charkhchi
- Women's College Research Institute, University of Toronto, 76 Grenville St. Room 6421, Toronto, ON, M5S 1B2, Canada
| | - Afshan Zahedi
- Women's College Research Institute, University of Toronto, 76 Grenville St. Room 6421, Toronto, ON, M5S 1B2, Canada
| | - Mohammad R Akbari
- Women's College Research Institute, University of Toronto, 76 Grenville St. Room 6421, Toronto, ON, M5S 1B2, Canada. .,Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada. .,Dalla Lana School of Public Health, University of Toronto, Toronto, ON, M5T 3M7, Canada.
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10
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Bonnet LA, Conway RM, Lim LA. Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) as a Screening Marker for Familial Adenomatous Polyposis (FAP): Systematic Literature Review and Screening Recommendations. Clin Ophthalmol 2022; 16:765-774. [PMID: 35321042 PMCID: PMC8934868 DOI: 10.2147/opth.s354761] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 02/08/2022] [Indexed: 12/27/2022] Open
Abstract
Purpose Familial adenomatous polyposis (FAP) has an almost 100% colorectal cancer risk warranting early detection in gene carriers. This study presents congenital hypertrophy of the retinal pigment epithelium (CHRPE) as a highly specific phenotypical marker for FAP that can be used in screening at-risk individuals. Screening recommendations including morphological subclassification were formulated with supporting literature. Methods A systematic literature review with a comprehensive search strategy was conducted using online databases. Manual searches of bibliographies and reference lists were also performed. Studies meeting inclusion criteria were graded with respect to their hierarchy of evidence and strength of recommendations according to the National Health and Medical Research Council (NHMRC) guidelines of Australia. Results Almost 4500 participants were analysed across 28 included studies. The mean specificity of CHRPE as a phenotypical screening marker of FAP was 89% (standard deviation (SD); 14) with a mean sensitivity of 79% (SD; 8). The mean prevalence of CHRPE amongst FAP participants; at-risk participants were found to be 76% (SD; 24) and 37% (SD; 21) respectively. Bilateralism and multiple lesion number ≥3 are features highly specific for FAP. Conclusion CHRPE was found to be a non-invasive, rapid, early phenotypical screening marker of FAP. Clinical recognition further allows increased gene analysis efficiency. The absence of CHRPE alone cannot exclude FAP. Our screening recommendations provide guidance to clinicians on evidence based CHRPE assessment. We would advocate inclusion of ocular examinations as part of a three-pronged approach, along with endoscopy and genetic testing, for efficient, timely FAP assessment in at-risk individuals.
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Affiliation(s)
- Louis Antoine Bonnet
- University of Sydney, Sydney, New South Wales, Australia
- Correspondence: Louis Antoine Bonnet, 83 Western Line, RD1, Whanganui, 4571, New Zealand, Tel +64 0273947946, Email
| | - R Max Conway
- University of Sydney, Sydney, New South Wales, Australia
| | - Li-Anne Lim
- University of Sydney, Sydney, New South Wales, Australia
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11
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Germline mutations of the adenomatous polyposis coli (APC) gene in Algerian familial adenomatous polyposis cohort: first report. Mol Biol Rep 2022; 49:3823-3837. [PMID: 35142982 DOI: 10.1007/s11033-022-07228-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/03/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND Familial adenomatous polyposis (known also as classical or severe FAP) is a rare autosomal dominant colorectal cancer predisposition syndrome, characterized by the presence of hundreds to thousands of adenomatous polyps in the colon and rectum from an early age. In the absence of prophylactic surgery, colorectal cancer (CRC) is the inevitable consequence of FAP. The vast majority of FAP is caused by germline mutations in the adenomatous polyposis coli (APC) tumor suppressor gene (5q21). To date, most of the germline mutations in classical FAP result in truncation of the APC protein and 60% are mainly located within exon 15. MATERIAL AND METHODS In this first nationwide study, we investigated the clinical and genetic features of 52 unrelated Algerian FAP families. We screened by PCR-direct sequencing the entire exon 15 of APC gene in 50 families and two families have been analyzed by NGS using a cancer panel of 30 hereditary cancer genes. RESULTS Among 52 FAP index cases, 36 had 100 or more than 100 polyps, 37 had strong family history of FAP, 5 developed desmoids tumors, 15 had extra colonic manifestations and 21 had colorectal cancer. We detected 13 distinct germline mutations in 17 FAP families. Interestingly, 4 novel APC germline pathogenic variants never described before have been identified in our study. CONCLUSIONS The accumulating knowledge about the prevalence and nature of APC variants in Algerian population will contribute in the near future to the implementation of genetic testing and counseling for FAP patients.
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12
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Boyraz B, Hung YP. Spindle Cell Tumors of the Pleura and the Peritoneum: Pathologic Diagnosis and Updates. APMIS 2021; 130:140-154. [PMID: 34942046 DOI: 10.1111/apm.13203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 09/23/2021] [Indexed: 11/30/2022]
Abstract
A diverse group of both benign and malignant spindle cell tumors can involve the pleura or the peritoneum. Due to their rarity and overlapping morphologic features, these tumors can pose considerable diagnostic difficulty in surgical pathology. As these tumors differ in their prognosis and clinical management, their correct pathologic diagnosis is critical. In addition to histologic assessment, select immunohistochemical and molecular tools can aid the distinction among these tumors. In this review, we consider some of the major histologic differential diagnosis of spindle cell tumors involving these serosal membranes. This list of tumors includes: solitary fibrous tumor, inflammatory myofibroblastic tumor, desmoid fibromatosis, synovial sarcoma, sarcomatoid carcinoma, spindle cell melanoma, dedifferentiated liposarcoma, epithelioid hemangioendothelioma, and sarcomatoid mesothelioma. We describe their salient clinicopathologic and genetic findings, with a review on some of the recent discoveries on their molecular pathogenesis.
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Affiliation(s)
- Baris Boyraz
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Yin P Hung
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
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13
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Abstract
Abstract
Background
Desmoid tumors/aggressive fibromatosis (DTs/AF) are cytological bland fibrous neoplasms originating from the musculoaponeurotic structures throughout the body. The exact cause still remains unknown, however, they may present sporadically or as a manifestation of a hereditary syndrome called familial adenomatous polyposis (FAP). Although they lack the capacity to establish metastases, DTs/AF may be devastated and occasionally fatal. As a result of the heterogeneity of DTs/AF, treatment needs to be individualized to improve local tumor control and maintain patients’ quality of life. Therefore, after a multidisciplinary approach, all treatment options should be discussed with patients. Where systemic chemotherapy has been shown to be unsuccessful with marked side effects in case of advanced DTs/AF, new therapeutic options are needed.
Methods
A Medline search was conducted and published articles in different studies from 2000 to the present were reviewed.
Conclusion
More research is needed to illustrate both the prognostic and predictive factors of the targeted therapy and the value of their combinations with or without other treatment modalities to get the best result for the treatment of advanced DTs/AF.
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14
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Magnetic Resonance Imaging, the Virtual Biopsy of Mesenteric Masses. J Comput Assist Tomogr 2021; 45:177-190. [PMID: 33512853 DOI: 10.1097/rct.0000000000001131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
ABSTRACT The mesentery may be affected by multiple disease processes. Magnetic resonance imaging aids as a virtual pathological biopsy tool in the assessment of mesenteric masses because of superior soft tissue contrast and characterization. In this comprehensive review, we describe in detail the magnetic resonance imaging features of some solid and cystic mesenteric masses, with an emphasis on lesion-specific signal characteristics on T1- and T2-weighted images, diffusion-weighted imaging, and enhancement features on the dynamic postcontrast phase that aid in narrowing the differential diagnosis.
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15
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Noh JH, Song EM, Ahn JY, Yang DH, Lee W, Hong J, Kim A, Na HK, Lee JH, Jung KW, Kim DH, Choi KD, Song HJ, Lee GH, Jung HY. Prevalence and endoscopic treatment outcomes of upper gastrointestinal neoplasms in familial adenomatous polyposis. Surg Endosc 2021; 36:1310-1319. [PMID: 33709227 DOI: 10.1007/s00464-021-08406-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 02/15/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although upper gastrointestinal (GI) neoplasms are not rare in patients with familial adenomatous polyposis (FAP), few studies have focused on them and the long-term outcomes of their treatment by endoscopy. Therefore, we aimed to investigate the prevalence and endoscopic treatment outcomes of upper GI neoplasms in patients with FAP. METHODS Among 215 patients diagnosed with FAP between January 1991 and December 2019, 208 who underwent esophagogastroduodenoscopy were eligible. The clinical features and endoscopic treatment outcomes of upper GI neoplasms were retrospectively investigated and analyzed. RESULTS Among the enrolled patients, 113 (54.3%) had one or more upper GI neoplasms: gastric adenoma (n = 34), gastric cancer (n = 7), nonampullary duodenal adenoma (n = 86), and ampullary adenoma (n = 53). Among patients with gastric neoplasms (n = 37), 24 (64.9%) underwent treatment (endoscopic treatment: 22, surgery: 2). No tumor-related mortality occurred during median follow-up of 106 months (interquartile range [IQR] 63-174). Endoscopic treatment was performed in 47 (54.7%) of 86 patients with nonampullary duodenal adenoma and in 32 (60.4%) of 53 patients with ampullary adenoma. No patient underwent surgery for duodenal neoplasms, and no tumor-related mortality occurred during median follow-up of 88 months (IQR 42-145). The proportion of patients with increased Spigelman stage at 2 years after the initial diagnosis or treatment was significantly higher in untreated group than in the group treated for duodenal neoplasms (27.3% vs. 0.0%, p = 0.001). CONCLUSION Endoscopic surveillance in FAP patients is important for the detection and treatment of upper GI neoplasms in early stage. In particular, endoscopic therapy for duodenal neoplasms can reduce the severity of duodenal polyposis.
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Affiliation(s)
- Jin Hee Noh
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun Mi Song
- Department of Gastroenterology, Ewha Womans University Medical Center, Seoul, Korea
| | - Ji Yong Ahn
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
| | - Dong-Hoon Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
| | - Woochang Lee
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jinyoung Hong
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Aram Kim
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hee Kyong Na
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong Hoon Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kee Wook Jung
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Do Hoon Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kee Don Choi
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ho June Song
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gin Hyug Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hwoon-Yong Jung
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Disciglio V, Forte G, Fasano C, Sanese P, Lepore Signorile M, De Marco K, Grossi V, Cariola F, Simone C. APC Splicing Mutations Leading to In-Frame Exon 12 or Exon 13 Skipping Are Rare Events in FAP Pathogenesis and Define the Clinical Outcome. Genes (Basel) 2021; 12:353. [PMID: 33670833 PMCID: PMC7997234 DOI: 10.3390/genes12030353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/22/2021] [Accepted: 02/22/2021] [Indexed: 11/16/2022] Open
Abstract
Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, nearly 2000 APC mutations have been described in FAP, most of which are predicted to result in truncated protein products. Mutations leading to aberrant APC splicing have rarely been reported. Here, we characterized a novel germline heterozygous splice donor site mutation in APC exon 12 (NM_000038.5: c.1621_1626+7del) leading to exon 12 skipping in an Italian family with the attenuated FAP (AFAP) phenotype. Moreover, we performed a literature meta-analysis of APC splicing mutations. We found that 119 unique APC splicing mutations, including the one described here, have been reported in FAP patients, 69 of which have been characterized at the mRNA level. Among these, only a small proportion (9/69) results in an in-frame protein, with four mutations causing skipping of exon 12 or 13 with loss of armadillo repeat 2 (ARM2) and 3 (ARM3), and five mutations leading to skipping of exon 5, 7, 8, or (partially) 9 with loss of regions not encompassing known functional domains. The APC splicing mutations causing skipping of exon 12 or 13 considered in this study cluster with the AFAP phenotype and reveal a potential molecular mechanism of pathogenesis in FAP disease.
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Affiliation(s)
- Vittoria Disciglio
- Medical Genetics, National Institute of Gastroenterology “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.F.); (C.F.); (P.S.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Giovanna Forte
- Medical Genetics, National Institute of Gastroenterology “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.F.); (C.F.); (P.S.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.F.); (C.F.); (P.S.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Paola Sanese
- Medical Genetics, National Institute of Gastroenterology “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.F.); (C.F.); (P.S.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.F.); (C.F.); (P.S.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Katia De Marco
- Medical Genetics, National Institute of Gastroenterology “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.F.); (C.F.); (P.S.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.F.); (C.F.); (P.S.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Filomena Cariola
- Medical Genetics, National Institute of Gastroenterology “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.F.); (C.F.); (P.S.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.F.); (C.F.); (P.S.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
- Department of Biomedical Sciences and Human Oncology (DIMO), Medical Genetics, University of Bari Aldo Moro, 70124 Bari, Italy
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Garza-Rodríguez ML, Treviño V, Pérez-Maya AA, Rodríguez-Gutiérrez HF, González-Escamilla M, Elizondo-Riojas MÁ, Ramírez-Correa GA, Vidal-Gutiérrez O, Burciaga-Flores CH, Pérez-Ibave DC. Identification of a Novel Pathogenic Rearrangement Variant of the APC Gene Associated with a Variable Spectrum of Familial Cancer. Diagnostics (Basel) 2021; 11:diagnostics11030411. [PMID: 33670908 PMCID: PMC7997431 DOI: 10.3390/diagnostics11030411] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/05/2021] [Accepted: 02/22/2021] [Indexed: 01/14/2023] Open
Abstract
Familial adenomatous polyposis (FAP) is an autosomal-dominant condition characterized by the presence of multiple colorectal adenomas, caused by germline variants in the adenomatous polyposis coli (APC) gene. More than 300 germline variants have been characterized. The detection of novel variants is important to understand the mechanisms of pathophysiology. We identified a novel pathogenic germline variant using next-generation sequencing (NGS) in a proband patient. The variant is a complex rearrangement (c.422+1123_532-577 del ins 423-1933_423-1687 inv) that generates a complete deletion of exon 5 of the APC gene. To study the variant in other family members, we designed an endpoint PCR method followed by Sanger sequencing. The variant was identified in the proband patient's mother, one daughter, her brother, two cousins, a niece, and a second nephew. In patients where the variant was identified, we found atypical clinical symptoms, including mandibular, ovarian, breast, pancreatic, and gastric cancer. Genetic counseling and cancer prevention strategies were provided for the family. According to the American College of Medical Genetics (ACMG) guidelines, this novel variant is considered a PVS1 variant (very strong evidence of pathogenicity), and it can be useful in association with clinical data for early surveillance and suitable treatment.
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Affiliation(s)
- María Lourdes Garza-Rodríguez
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
| | - Víctor Treviño
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Nuevo, León 64710, Mexico;
| | - Antonio Alí Pérez-Maya
- Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Nuevo, León 64460, Mexico;
| | - Hazyadee Frecia Rodríguez-Gutiérrez
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
| | - Moisés González-Escamilla
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
| | - Miguel Ángel Elizondo-Riojas
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
| | - Genaro A. Ramírez-Correa
- Department of Molecular Science, UT Health Rio Grande Valley, McAllen, TX 78502, USA;
- Department of Pediatrics, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Oscar Vidal-Gutiérrez
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
| | - Carlos Horacio Burciaga-Flores
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
- Correspondence: (C.H.B.-F.); or (D.C.P.-I.); Tel.: +52-(81)-83338111 (C.H.B.-F. & D.C.P.-I.)
| | - Diana Cristina Pérez-Ibave
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
- Correspondence: (C.H.B.-F.); or (D.C.P.-I.); Tel.: +52-(81)-83338111 (C.H.B.-F. & D.C.P.-I.)
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Kemp Bohan PM, Mankaney G, Vreeland TJ, Chick RC, Hale DF, Cindass JL, Hickerson AT, Ensley DC, Sohn V, Clifton GT, Peoples GE, Burke CA. Chemoprevention in familial adenomatous polyposis: past, present and future. Fam Cancer 2021; 20:23-33. [PMID: 32507936 PMCID: PMC7276278 DOI: 10.1007/s10689-020-00189-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/18/2020] [Indexed: 01/05/2023]
Abstract
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome characterized by colorectal adenomas and a near 100% lifetime risk of colorectal cancer (CRC). Prophylactic colectomy, usually by age 40, is the gold-standard therapy to mitigate this risk. However, colectomy is associated with morbidity and fails to prevent extra-colonic disease manifestations, including gastric polyposis, duodenal polyposis and cancer, thyroid cancer, and desmoid disease. Substantial research has investigated chemoprevention medications in an aim to prevent disease progression, postponing the need for colectomy and temporizing the development of extracolonic disease. An ideal chemoprevention agent should have a biologically plausible mechanism of action, be safe and easily tolerated over a prolonged treatment period, and produce a durable and clinically meaningful effect. To date, no chemoprevention agent tested has fulfilled these criteria. New agents targeting novel pathways in FAP are needed. Substantial preclinical literature exists linking the molecular target of rapamycin (mTOR) pathway to FAP. A single case report of rapamycin, an mTOR inhibitor, used as chemoprevention in FAP patients exists, but no formal clinical studies have been conducted. Here, we review the prior literature on chemoprevention in FAP, discuss the rationale for rapamycin in FAP, and outline a proposed clinical trial testing rapamycin as a chemoprevention agent in patients with FAP.
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Affiliation(s)
- Phillip M Kemp Bohan
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA.
| | - Gautam Mankaney
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH, USA
| | - Timothy J Vreeland
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Robert C Chick
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Diane F Hale
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Jessica L Cindass
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Annelies T Hickerson
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Daniel C Ensley
- Department of Urology, Brooke Army Medical Center, Ft. Sam Houston, TX, USA
| | - Vance Sohn
- Department of Surgery, Madigan Army Medical Center, Joint Base Lewis-McChord, Tacoma, WA, USA
| | - G Travis Clifton
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | | | - Carol A Burke
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH, USA
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Jiang TJ, Wang F, Wang YN, Hu JJ, Ding PR, Lin JZ, Pan ZZ, Chen G, Shao JY, Xu RH, Zhao Q, Wang F. Germline mutational profile of Chinese patients under 70 years old with colorectal cancer. Cancer Commun (Lond) 2020; 40:620-632. [PMID: 32914570 PMCID: PMC7668457 DOI: 10.1002/cac2.12093] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Inherited susceptibility accounts for nearly one-third of colorectal cancer (CRC) predispositions and has an 80%-100% lifetime risk of this disease. However, there are few data about germline mutations of hereditary CRC-related genes in Chinese patients with CRC. This study aimed to assess the prevalence of gene mutations related to cancer susceptibility among Chinese patients with CRC, differences between Chinese and Western patients, and the phenotype-genotype correlation. METHODS We retrospectively collected tumor samples from 526 patients with CRC under 70 years old who underwent hereditary CRC genetic testing. A series of bioinformatic analyses, as well as statistical comparisons, were performed. RESULTS We found that 77 patients (14.6%) harbored functional variants of the 12 genes. The mutation frequencies of the top 5 mutated genes were 6.5% for MutL homolog 1 (MLH1), 5.1% for MutS homolog 2 (MSH2), 1.0% for MSH6, 0.8% for PMS1 homolog 2 (PMS2), and 0.8% for APC regulator of the WNT signaling pathway (APC). Our data showed much higher rates of mutations of MSH6 and PMS2 genes among all mismatch repair (MMR) genes as compared with those in Western populations. Mutations in MLH1, MSH2, and MSH6 were found to be mutually exclusive. Patients with MLH1 or MSH2 mutations had higher frequencies of personal history of cancer (MLH1: 20.6% vs. 8.7%; MSH2: 25.9% vs. 8.6%) and family history of cancer than those without these mutations (MLH1: 73.5% vs. 48.4%; MSH2: 70.4% vs. 48.9%), and the lesions were more prone to occur on the right side of the colon than on the left side (MLH1: 73.5% vs. 29.3%; MSH2: 56.0% vs. 31.0%). The proportion of stage I/II disease was higher in patients with MLH1 mutations than in those without MLH1 mutations (70.6% vs. 50.7%), and the rate of polyps was higher in patients with APC mutations than in those with wild-type APC (75.0% vs. 17.4%). CONCLUSION These results provide a full-scale landscape of hereditary susceptibility over 12 related genes in CRC patients and suggest that a comprehensive multi-gene panel testing for hereditary CRC predisposition could be a helpful analysis in clinical practice.
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Affiliation(s)
- Teng-Jia Jiang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Fang Wang
- Department of Molecular Diagnosis, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Ying-Nan Wang
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Jia-Jia Hu
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Pei-Rong Ding
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Jun-Zhong Lin
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Zhi-Zhong Pan
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Gong Chen
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Jian-Yong Shao
- Department of Molecular Diagnosis, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Rui-Hua Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Qi Zhao
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Feng Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
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20
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A Comprehensive Approach to the Management of Benign and Malignant Ampullary Lesions: Management in Hereditary and Sporadic Settings. Curr Gastroenterol Rep 2020; 22:46. [PMID: 32654103 DOI: 10.1007/s11894-020-00784-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review was to examine the historical roots of endoscopic management of ampullary lesions and explore emerging data on improved techniques, technologies, and outcomes. Of specific interest was answering whether there exists a reasonable body of data to support one resection technique or strategy above others. RECENT FINDINGS Review of recent literature suggests the continued use of endoscopic ampullectomy is a safe and effective means of curative treatment of ampullary adenomas. Complications are relatively infrequent and complete endoscopic resection is possible in a majority of cases, with proper patient and lesion selection. Greater than 2 decades of experience with endoscopic ampullectomy have shown this to be a viable, well-tolerated, and highly effective means of treating ampullary adenomas. While few concrete guidelines exist to advise endoscopists on the ideal technique for resection, experience, patient selection, and prior planning can greatly influence the technical and clinical success of endoscopic ampullectomy.
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21
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Disciglio V, Fasano C, Cariola F, Forte G, Grossi V, Sanese P, Lepore Signorile M, Resta N, Lotesoriere C, Stella A, Lolli I, Simone C. Gastric polyposis and desmoid tumours as a new familial adenomatous polyposis clinical variant associated with APC mutation at the extreme 3'-end. J Med Genet 2020; 57:356-360. [PMID: 31591141 PMCID: PMC7231465 DOI: 10.1136/jmedgenet-2019-106299] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 09/04/2019] [Accepted: 09/07/2019] [Indexed: 01/23/2023]
Abstract
Germline mutations of the APC gene, which encodes a multidomain protein of 2843 amino acid residues, cause familial adenomatous polyposis (FAP). Three FAP clinical variants are correlated with the location of APC mutations: (1) classic FAP with profuse polyposis (>1000 adenomas), associated with mutations from codon 1250 to 1424; (2) attenuated FAP (<100 adenomas), associated with mutations at APC extremities (before codon 157 and after codon 1595); (3) classic FAP with intermediate colonic polyposis (100-1000 adenomas), associated with mutations located in the remaining part of APC In an effort to decipher the clinical phenotype associated with APC C-terminal germline truncating mutations in patients with FAP, after screening APC mutations in one family whose members (n=4) developed gastric polyposis, colon oligo-polyposis and desmoid tumours, we performed a literature meta-analysis of clinically characterised patients (n=97) harbouring truncating mutations in APC C-terminus. The APC distal mutations identified in this study cluster with a phenotype characterised by colon oligo-polyposis, diffuse gastric polyposis and desmoid tumours. In conclusion, we describe a novel FAP clinical variant, which we propose to refer to as Gastric Polyposis and Desmoid FAP, that may require tailored management.
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Affiliation(s)
- Vittoria Disciglio
- Medical Genetics, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Filomena Cariola
- Medical Genetics, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Giovanna Forte
- Medical Genetics, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Paola Sanese
- Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari "Aldo Moro", Bari, Italy
| | - Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Nicoletta Resta
- Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari "Aldo Moro", Bari, Italy
| | - Claudio Lotesoriere
- Department of Oncology, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Alessandro Stella
- Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari "Aldo Moro", Bari, Italy
| | - Ivan Lolli
- Department of Oncology, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
- Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari "Aldo Moro", Bari, Italy
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22
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Vitellaro M, Piozzi G, Signoroni S, Ricci MT, Ciniselli CM, Cardani A, Vecchi I, Mancini A, Magarotto A, Verderio P, Massimino M, Ferrari A, Biasoni D. Short-term and long-term outcomes after preventive surgery in adolescent patients with familial adenomatous polyposis. Pediatr Blood Cancer 2020; 67:e28110. [PMID: 31802619 DOI: 10.1002/pbc.28110] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/14/2019] [Accepted: 11/16/2019] [Indexed: 01/24/2023]
Abstract
BACKGROUND APC gene pathogenic variants are characterized by a lifetime risk of nearly 100% to develop a colorectal carcinoma. International guidelines suggest a prophylactic surgery in the second decade. METHODS A descriptive analysis was performed evaluating a surgical series of adolescent patients with familial adenomatous polyposis (FAP) enrolled in the prospectively maintained hereditary polyposis registry. RESULTS Thirty-eight adolescent patients (median age 16 years; range, 7-19) underwent laparoscopic prophylactic surgery. APC gene pathogenic variants were detected in all patients, and six patients were proband. No patients were converted to open surgery. Median postoperative stay was five days (4-16). Early postoperative complications were one dural puncture and one anastomotic leakage. Regarding late complications, we observed one patient having small bowel obstruction 56 months after surgery. Pathological reports showed one patient with pTis adenocarcinoma in two separate sites; 33 patients with low-grade dysplasia, four with high-grade dysplasia. One patient developed a desmoid tumor 37 months after surgery. After a median follow-up of 40.5 months, no patients died or had a second abdominal surgery because of cancer in rectal stump. CONCLUSIONS Rectal sparing surgery was the first choice in the major respect of patients' quality of life. Laparoscopic prophylactic surgery for FAP is well accepted from adolescents. It represents a safe option due to the low incidence of post-surgical desmoids and quick postoperative recovery.
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Affiliation(s)
- Marco Vitellaro
- Hereditary Digestive Tract Tumors Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Colorectal Surgery Section, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Guglielmo Piozzi
- Colorectal Surgery Section, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Stefano Signoroni
- Hereditary Digestive Tract Tumors Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Teresa Ricci
- Hereditary Digestive Tract Tumors Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Chiara Maura Ciniselli
- Bioinformatics and Biostatistics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Anna Cardani
- Department of Critical and Supportive Therapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Irene Vecchi
- Department of Critical and Supportive Therapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Andrea Mancini
- Diagnostic and Therapeutic Endoscopy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Andrea Magarotto
- Diagnostic and Therapeutic Endoscopy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo Verderio
- Bioinformatics and Biostatistics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maura Massimino
- Pediatric Oncology Section, Department of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Andrea Ferrari
- Pediatric Oncology Section, Department of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Davide Biasoni
- Pediatric Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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23
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Management of an Obese Patient with Familial Adenomatous Polyposis: Surgical Implication of Biliopancreatic Diversion and Total Colectomy. Obes Surg 2019; 29:3360-3362. [PMID: 31332616 DOI: 10.1007/s11695-019-04098-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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24
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Lo W, Zhu B, Sabesan A, Wu HH, Powers A, Sorber RA, Ravichandran S, Chen I, McDuffie LA, Quadri HS, Beane JD, Calzone K, Miettinen MM, Hewitt SM, Koh C, Heller T, Wacholder S, Rudloff U. Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC). J Med Genet 2019; 56:370-379. [PMID: 30745422 PMCID: PMC6716162 DOI: 10.1136/jmedgenet-2018-105361] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 12/11/2018] [Accepted: 01/03/2019] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC. METHODS One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age). RESULTS Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants. CONCLUSION Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.
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Affiliation(s)
- Winifred Lo
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Bin Zhu
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA
| | - Arvind Sabesan
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Ho-Hsiang Wu
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA
| | - Astin Powers
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Rebecca A Sorber
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Department of Surgery, indiana University School of Medicine, indianapolis, indiana, USA
| | - Sarangan Ravichandran
- Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Ina Chen
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Lucas A McDuffie
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Department of Surgery, indiana University School of Medicine, indianapolis, indiana, USA
| | - Humair S Quadri
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Department of Surgery, MedStar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Joal D Beane
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Department of Surgery, indiana University School of Medicine, indianapolis, indiana, USA
| | - Kathleen Calzone
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Markku M Miettinen
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Stephen M Hewitt
- Experimental Pathology Laboratory, National Cancer Institute, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Sholom Wacholder
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA
| | - Udo Rudloff
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Rare Tumor initiative, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
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25
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de Oliveira JC, Viana DV, Zanardo C, Santos EMM, de Paula AE, Palmero EI, Rossi BM. Genotype-phenotype correlation in 99 familial adenomatous polyposis patients: A prospective prevention protocol. Cancer Med 2019; 8:2114-2122. [PMID: 30897307 PMCID: PMC6536935 DOI: 10.1002/cam4.2098] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/05/2019] [Accepted: 02/27/2019] [Indexed: 12/29/2022] Open
Abstract
Background Familial adenomatous polyposis (FAP) is a syndrome caused by germline pathogenic variants in the tumor suppressor gene adenomatous polyposis coli (APC). Identification of APC pathogenic variants sites and the genotype‐phenotype correlation are important for characterizing, monitoring, and treating members of affected families. The aim of this study was to correlate genotype‐phenotype of Brazilian individuals carrying APC pathogenic germline variants and that have FAP. Methods The polyposis phenotype of 99 individuals from 35 families between July 2013 and December 2014 were prospectively evaluated based on the InSIGHT polyposis staging classification. Seven extra‐colonic manifestations were assessed and the clinical manifestations correlated with the APC genotype. Results The age of the study participants ranged from 12 to 67 years (median of 29 years). Twenty‐six APC pathogenic variants were identified. Fifty‐five cases harbored nonsense pathogenic variants (55.6%). Frameshift alterations were noted in 39 cases (39.4%). Aberrant splicing was noted in 1 case (1%). Rearrangements were observed in 3 cases (3%). An association between nonsense variants and rearrangement was noted in 1 case (1%). The genotype‐phenotype correlation analysis led the identification of classic FAP in 94 cases (94.9%). Profuse polyposis was identified in 5 cases (5.1%). Thirty‐six cases were diagnosed with cancer of which 29 cases (80.6%) were colorectal cancer, 1 case (2.7%) was brain cancer, 4 cases (11.2%) were papillary thyroid cancer, and 2 cases (5.5%) were stomach cancer. The extra‐colonic manifestations included 9 individuals with desmoids tumors, 10 with osteomas, and 9 with congenital hypertrophy of the retinal pigment epithelium. Conclusions The genotype‐phenotype correlation in Brazilian individuals with FAP revealed specific findings not previously reported for other cohorts, demonstrating the relevance of knowledge regarding the variable pathogenic variants and clinical presentation in different populations for adequate individual clinical management of patients harboring this medical condition.
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Affiliation(s)
| | - Danilo V Viana
- Oncogenetics Department, Barretos Cancer Hospital, Barretos, SP, Brazil
| | - Cleyton Zanardo
- Biostatistics Department, Barretos Cancer Hospital, Barretos, SP, Brazil
| | - Erika M M Santos
- Cancer Genetics, Oncology Department, Sírio Libanes Hospital, São Paulo, Brazil
| | - André E de Paula
- Center of Molecular Diagnosis, Barretos Cancer Hospital, Barretos, SP, Brazil.,Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
| | - Edenir I Palmero
- Center of Molecular Diagnosis, Barretos Cancer Hospital, Barretos, SP, Brazil.,Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.,Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, Barretos, SP, Brazil
| | - Benedito M Rossi
- Cancer Genetics, Oncology Department, Sírio Libanes Hospital, São Paulo, Brazil
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26
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Liu Q, Tan YQ. Advances in Identification of Susceptibility Gene Defects of Hereditary Colorectal Cancer. J Cancer 2019; 10:643-653. [PMID: 30719162 PMCID: PMC6360424 DOI: 10.7150/jca.28542] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 12/08/2018] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is a common malignant tumor of the digestive system worldwide, associated with hereditary genetic features. CRC with a Mendelian genetic predisposition accounts for approximately 5-10% of total CRC cases, mainly caused by a single germline mutation of a CRC susceptibility gene. The main subtypes of hereditary CRC are hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). With the rapid development of genetic testing methods, especially next-generation sequencing technology, multiple genes have now been confirmed to be pathogenic, including DNA repair or DNA mismatch repair genes such as APC, MLH1, and MSH2. Since familial CRC patients have poor clinical outcomes, timely clinical diagnosis and mutation screening of susceptibility genes will aid clinicians in establishing appropriate risk assessment and treatment interventions at a personal level. Here, we systematically summarize the susceptibility genes identified to date and the potential pathogenic mechanism of HNPCC and FAP development. Moreover, clinical recommendations for susceptibility gene screening, diagnosis, and treatment of HNPCC and FAP are discussed.
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Affiliation(s)
- Qiang Liu
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan cancer Hospital and The Affiliated Cancer of Xiangya School of Medicine, Central South University, Changsha, China.,Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China.,Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
| | - Yue-Qiu Tan
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China.,Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
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27
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Rudloff U. Gastric adenocarcinoma and proximal polyposis of the stomach: diagnosis and clinical perspectives. Clin Exp Gastroenterol 2018; 11:447-459. [PMID: 30584346 PMCID: PMC6284852 DOI: 10.2147/ceg.s163227] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a recently described, rare gastric polyposis syndrome. It is characterized by extensive involvement of the fundus and body of the stomach with fundic gland polyps sparing the antrum and lesser curvature, an autosomal dominant inheritance pattern with incomplete penetrance, and a significant predisposition for the development of gastric adenocarcinoma. Due to the recent discovery of APC promotor IB mutations (c.-191T>C, c.-192A>G, and c.-195A>C), which reduce binding of the transcription factor Yin Yang 1 (YY1) and transcriptional activity of the promotor, as its underlying genetic perturbation, GAPPS has been added to the growing molecular class of APC-associated disorders. Recent reports on family members afflicted by gastric polyposis due to GAPPS have described the development of metastatic cancer or the presence of invasive gastric adenocarcinoma in total gastrectomy specimens after variable periods of endoscopic surveillance emphasizing the need for an improved understanding of the to-date poorly characterized natural history of the syndrome. There are, however, currently no guidelines on screening, timing of prophylactic gastrectomy, or endoscopic surveillance for GAPPS available. In this review, we summarize the clinical, pathological, and genetic aspects of GAPPS as well as management approaches to this rare cancer predisposition syndrome, highlighting the need for early recognition, a multidisciplinary approach, and the creation of prospective family registries and consensus guidelines in the near future.
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Affiliation(s)
- Udo Rudloff
- Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA,
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28
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Sample DC, Samadder NJ, Pappas LM, Boucher KM, Samowitz WS, Berry T, Westover M, Nathan D, Kanth P, Byrne KR, Burt RW, Neklason DW. Variables affecting penetrance of gastric and duodenal phenotype in familial adenomatous polyposis patients. BMC Gastroenterol 2018; 18:115. [PMID: 30012100 PMCID: PMC6048881 DOI: 10.1186/s12876-018-0841-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 07/02/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Patients with familial adenomatous polyposis (FAP) frequently undergo colectomy to reduce the 70 to 90% lifetime risk of colorectal cancer. After risk-reducing colectomy, duodenal cancer and complications from duodenal surgeries are the main cause of morbidity. Our objective was to prospectively describe the duodenal and gastric polyp phenotype in a cohort of 150 FAP patients undergoing pre-screening for a chemoprevention trial and analyze variables that may affect recommendations for surveillance. METHODS Individuals with a diagnosis of FAP underwent prospective esophagogastroduodenoscopy using a uniform system of mapping of size and number of duodenal polyps for a 10 cm segment. Gastric polyps were recorded as the total number. RESULTS The distribution of the count and sum diameter of duodenal polyps were statistically different in two genotype groups, those with APC mutations associated with classic FAP had a greater count (median 17) and sum diameter of polyps (median 32 mm) than those with APC mutations associated with attenuated FAP (median count 4 and median sum diameter of 7 mm) (p < 0.0001). The number of gastric polyps did not differ based on genotype (p = 0.67) but advancing age correlated with severity of gastric polyposis (p = 0.019). Spigelman (modified) staging of II or greater was found in 88% of classic FAP patients and 48% attenuated FAP patients. Examples of severe and mild upper GI phenotype are observed in patients with identical APC mutations, showing that the APC mutation location is not absolutely predictive of an upper GI phenotype. CONCLUSIONS Most FAP patients have duodenal and gastric polyps which become more prevalent and advanced with age. Standard upper endoscopic surveillance is recommended based on personal history independent of APC mutation location. TRIAL REGISTRATION NCT 01187901 registered August 24, 2010, prospective to enrollment.
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Affiliation(s)
- Danielle C Sample
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112-5550, USA.,University of Utah School of Medicine, 175 North Medical Drive East, Salt Lake City, UT, 84132, USA
| | - N Jewel Samadder
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112-5550, USA.,Division of Gastroenterology, University of Utah, Salt Lake City, UT, USA.,Department of Clinical Genomics and Gastroenterology, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Lisa M Pappas
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112-5550, USA
| | - Kenneth M Boucher
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112-5550, USA.,Division of Epidemiology in the Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Wade S Samowitz
- Department of Pathology, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Room 3100, Salt Lake City, UT, 84103, USA
| | - Therese Berry
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112-5550, USA
| | - Michelle Westover
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112-5550, USA
| | - Deepika Nathan
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112-5550, USA.,University of California Irvine, 333 City Blvd W, St 800, Irvine, CA, 92868, USA
| | - Priyanka Kanth
- Division of Gastroenterology, University of Utah, Salt Lake City, UT, USA.,University of Utah School of Medicine, 30 N 1900 E, Salt Lake City, UT, 84132, USA
| | - Kathryn R Byrne
- Division of Gastroenterology, University of Utah, Salt Lake City, UT, USA.,University of Utah School of Medicine, 30 N 1900 E, Salt Lake City, UT, 84132, USA
| | - Randall W Burt
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112-5550, USA.,Division of Gastroenterology, University of Utah, Salt Lake City, UT, USA
| | - Deborah W Neklason
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112-5550, USA. .,Division of Epidemiology in the Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. .,Hereditary Gastrointestinal Cancer Registry, Huntsman Cancer Institute at University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112-5550, USA.
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29
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Neffa F, Garcia L, Della Valle A, Carusso F, Vergara C, Sanchez D, Sapone M, Silveyra N, Revello AL, Esperon P. Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance. J Gastrointest Oncol 2018; 9:553-559. [PMID: 29998021 DOI: 10.21037/jgo.2017.10.06] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant genetic condition, caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Desmoid tumors (DTs) are seen in 15% to 20% of FAP patients. Specific location of mutation serves as a guide to predict colonic and extra colonic manifestations and their aggressiveness. A severe FAP-phenotypic family was registered in a genetic counselling high-risk Uruguayan hereditary cancer clinic. Proband's DNA was analysed by NGS, detecting a pathogenic mutation in APC gene. All willing family members were counselled and encouraged to be tested. Here we report a kindred formed by 16 individuals with a very severe FAP phenotype. A two-base deletion mutation: c.4393_4394delAG in APC gene and a consequent premature stop codon was detected. DTs were diagnosed in 6 individuals, ranging from 2 to 25 years of age. The causes of death were diverse: gastric cancer, rectal cancer and desmoid tumor. The already described genotype-phenotype correlation has proved its worth in this family, as clinical features reflect the mutation location at 3' end of APC gene. The inheritable and lethal nature of the disease needs a tailored follow up approach in order to reduce mortality, optimize local tumor control, and preserve patients' quality of life.
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Affiliation(s)
- Florencia Neffa
- Grupo Colaborativo Uruguayo, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay
| | - Lucia Garcia
- Grupo Colaborativo Uruguayo, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay
| | - Adriana Della Valle
- Grupo Colaborativo Uruguayo, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay
| | - Florencia Carusso
- Grupo Colaborativo Uruguayo, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay
| | - Carolina Vergara
- Grupo Colaborativo Uruguayo, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay
| | | | - Marta Sapone
- Grupo Colaborativo Uruguayo, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay
| | | | | | - Patricia Esperon
- Grupo Colaborativo Uruguayo, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay.,Laboratorio de Genética Molecular Facultad de Química, Universidad de la República, Montevideo, Uruguay
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30
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Libertini M, Mitra I, van der Graaf WTA, Miah AB, Judson I, Jones RL, Thomas K, Moskovic E, Szucs Z, Benson C, Messiou C. Aggressive fibromatosis response to tamoxifen: lack of correlation between MRI and symptomatic response. Clin Sarcoma Res 2018; 8:13. [PMID: 29785261 PMCID: PMC5950191 DOI: 10.1186/s13569-018-0100-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 04/04/2018] [Indexed: 01/22/2023] Open
Abstract
Background One of the commonly used systemic agents for the treatment of aggressive fibromatosis is the anti-oestrogen drug tamoxifen. However, data on efficacy and optimum methods of response assessment are limited, consisting mainly of small case series and reports. Methods A retrospective database was used to identify consecutive patients diagnosed with aggressive fibromatosis (AF) and treated with tamoxifen plus/minus non-steroidal anti-inflammatory drugs at our tertiary referral centre between 2007 and 2014. MRI and symptom changes were recorded. Results Thirty-two patients (13 male 19 female, median age 41 years) were included. Median duration of treatment with tamoxifen was 316 days. Of 9 patients with progressive disease by RECIST 1.1 (28%): 4 patients experienced worsening symptoms; 3 patients had improved symptoms and 2 had no change in symptoms. Of 22 patients with stable disease (69%): 11 had no change in symptoms; 6 had improved symptoms and 5 patients had worsening symptoms. One patient achieved a partial response with improved symptoms. Conclusions No relationship was identified between symptomatic benefit and response by RECIST 1.1 on MRI. Prospective studies in AF should incorporate endpoints focusing on patient symptoms.
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Affiliation(s)
- M Libertini
- 1Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, UK
| | - I Mitra
- 1Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, UK.,2Department of Radiology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London, SW3 6JJ UK
| | - W T A van der Graaf
- 1Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, UK.,3Institute of Cancer Research, Sutton, UK
| | - A B Miah
- 1Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, UK.,3Institute of Cancer Research, Sutton, UK
| | - I Judson
- 1Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, UK.,3Institute of Cancer Research, Sutton, UK
| | - R L Jones
- 1Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, UK.,3Institute of Cancer Research, Sutton, UK
| | - K Thomas
- 2Department of Radiology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London, SW3 6JJ UK
| | - E Moskovic
- 1Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, UK.,3Institute of Cancer Research, Sutton, UK
| | - Z Szucs
- 1Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, UK
| | - C Benson
- 1Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, UK
| | - C Messiou
- 1Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, UK.,2Department of Radiology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London, SW3 6JJ UK.,3Institute of Cancer Research, Sutton, UK
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31
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Talseth-Palmer BA. The genetic basis of colonic adenomatous polyposis syndromes. Hered Cancer Clin Pract 2017; 15:5. [PMID: 28331556 PMCID: PMC5353802 DOI: 10.1186/s13053-017-0065-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 03/07/2017] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and familial adenomatous polyposis (FAP) accounts for approximately 1% of all CRCs. Adenomatous polyposis syndromes can be divided into; familial adenomatous polyposis (FAP) – classic FAP and attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), NTHL1-associated polyposis (NAP) and polymerase proofreading-associated polyposis (PPAP). The polyposis syndromes genetics and clinical manifestation of disease varies and cases with clinical diagnosis of FAP might molecularly show a different diagnosis. This review examines different aspects of the adenomatous polyposis syndromes genetics and clinical manifestation of disease; in addition the genotype-phenotype and modifier alleles of FAP will be discussed. New technology has made it possible to diagnose some of the APC mutation negative patients into their respective syndromes. There still remain many molecularly undiagnosed adenomatous polyposis patients indicating that there remain causative genes to be discovered and with today’s technology these are expected to be identified in the near future. The knowledge about the role of modifier alleles in FAP will contribute to improved pre-symptomatic diagnosis and treatment. New novel mutations will continually be discovered in genes already associated with disease and new genes will be discovered that are associated with adenomatous polyposis. The search for modifier alleles in FAP should be made a priority.
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Affiliation(s)
- Bente A Talseth-Palmer
- Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, 7491 Norway.,Clinic for Medicine, Møre og Romsdal Hospital Trust, Molde, Norway.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW Australia.,Hunter Medical Research Institute, Newcastle, NSW Australia.,Clinic for Medicine, Library, Molde Hospital, Parkvegen 84, Molde, 6407 Norway
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32
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Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol 2017; 35:1086-1095. [PMID: 28135145 DOI: 10.1200/jco.2016.71.0012] [Citation(s) in RCA: 362] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability [MSI], mismatch repair [MMR] deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results. All participants underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene. Results One hundred five (9.9%; 95% CI, 8.2% to 11.9%) of 1,058 participants carried one or more pathogenic mutations, including 33 (3.1%) with Lynch syndrome (LS). Twenty-eight (96.6%) of 29 available LS CRCs demonstrated abnormal MSI/MMR results. Seventy-four (7.0%) of 1,058 participants carried non-LS gene mutations, including 23 (2.2%) with mutations in high-penetrance genes (five APC, three biallelic MUTYH, 11 BRCA1/2, two PALB2, one CDKN2A, and one TP53), 15 of whom lacked clinical histories suggestive of their underlying mutation. Thirty-eight (3.6%) participants had moderate-penetrance CRC risk gene mutations (19 monoallelic MUTYH, 17 APC*I1307K, two CHEK2). Neither proband age at CRC diagnosis, family history of CRC, nor personal history of other cancers significantly predicted the presence of pathogenic mutations in non-LS genes. Conclusion Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC. MSI/MMR testing reliably identifies LS probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.
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Affiliation(s)
- Matthew B Yurgelun
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Matthew H Kulke
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Charles S Fuchs
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Brian A Allen
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Hajime Uno
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Jason L Hornick
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Chinedu I Ukaegbu
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Lauren K Brais
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Philip G McNamara
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Robert J Mayer
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Deborah Schrag
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Jeffrey A Meyerhardt
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Kimmie Ng
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - John Kidd
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Nanda Singh
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Anne-Renee Hartman
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Richard J Wenstrup
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
| | - Sapna Syngal
- Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT
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Schäfer M, Kadmon M, Schmidt W, Treiber I, Moog U, Sutter C, Stehr M. Neonatal Gardner Fibroma Leads to Detection of Familial Adenomatous Polyposis: Two Case Reports. European J Pediatr Surg Rep 2016; 4:17-21. [PMID: 28018803 PMCID: PMC5177561 DOI: 10.1055/s-0036-1582443] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 03/06/2016] [Indexed: 12/11/2022] Open
Abstract
Gardner fibromas (GFs) have only recently been described as poorly circumscribed tumor-like lesions, which are exceedingly rare in children. GFs are associated with APC gene mutations and therefore with familial adenomatous polyposis (FAP). So far there is only very limited literature on GF in the neonatal period. We present two children with GF diagnosed at birth and subsequent FAP with very different clinical courses. In one case, the disease led to extensive surgery of the thoracic wall and detection of FAP in the father with the need of immediate proctocolectomy. In the other patient (with a positive family history for FAP) the disease remained stable. Our cases indicate that the diagnosis of GF in the neonatal period requires the exclusion of FAP both in the child as well as the parents. Since the clinical behavior of GF cannot be predicted, continuous monitoring is mandatory. Depending on tumor site and growth, individual therapeutic options must be thoroughly considered. Surgical resection, if necessary, has to be inevitably total to prevent recurrence.
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Affiliation(s)
- Mattias Schäfer
- Department of Pediatric Surgery and Urology, Cnopfsche Kinderklinik, Nürnberg, Germany
| | - Martina Kadmon
- Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany
| | - Wolfgang Schmidt
- Department of Pediatrics, Section Pediatric Oncology, Cnopfsche Kinderklinik, Nürnberg, Germany
| | - Irmgard Treiber
- Department of General, Visceral, and Transplant Surgery, Universitätsklinikum Heidelberg, Germany
| | - Ute Moog
- Institute of Human Genetics, Universitätsklinikum Heidelberg, Germany
| | - Christian Sutter
- Institute of Human Genetics, Universitätsklinikum Heidelberg, Germany
| | - Maximilian Stehr
- Department of Pediatric Surgery and Urology, Cnopfsche Kinderklinik, Nürnberg, Germany
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Yang J, Liu QW, Li LW, Wang QZ, Hong M, Dong J. Familial adenomatous polyposis in China. Oncol Lett 2016; 12:4877-4882. [PMID: 28105195 DOI: 10.3892/ol.2016.5330] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 10/04/2016] [Indexed: 12/11/2022] Open
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant disease with a poor prognosis, and has been studied by clinicians and geneticists in China for the past three decades. It is estimated that FAP has an incidence of between 1 in 8,000 and 1 in 10,000 individuals, and accounts for 0.94% of colorectal cancer cases in China. Recent advances in the understanding of FAP suggest that the genotype of the patient may allow for early diagnosis and surveillance, and guide surgical and chemopreventive management. However, the genetic mechanisms of FAP vary between different countries. FAP in China has its own characteristics, and this may be due to ethnic and geographical genetic variation. In the present review the clinical manifestations and genetics of FAP in China are discussed, as well as the surgical strategies, chemotherapeutics and traditional Chinese medicines used in its treatment. Increased insight into the genetic and clinical features of FAP in the Chinese population may aid in the prevention and management of the disorder.
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Affiliation(s)
- Jun Yang
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Qing Wei Liu
- Department of Internal Medicine-Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Liang Wen Li
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Qiang Zhi Wang
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Min Hong
- Department of Internal Medicine-Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Jian Dong
- Department of Internal Medicine-Oncology, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650106, P.R. China
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Creuzé M, Afchain P, Munck A, Viala J, Bonnard A, Bertrand V. [Desmoid tumors in an adolescent girl with familial adenomatous polyposis]. Arch Pediatr 2016; 23:1141-1145. [PMID: 27692552 DOI: 10.1016/j.arcped.2016.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 07/04/2016] [Accepted: 08/25/2016] [Indexed: 10/20/2022]
Abstract
Desmoid tumors (DT) are rare and nonmetastasizing fibroblastic neoplasms, characterized by local invasiveness. They occur sporadically or arise in the context of familial adenomatous polyposis (FAP; 5-10% of cases). Most cases develop sporadically in young adults, but some cases also occur in children. We report the case of an adolescent girl with FAP and DT, and we discuss the therapeutic strategies. An adolescent girl with FAP underwent surgery at the age of 14 years with total proctocolectomy. She had a neo-mutation in the APC gene at codon 1068, which is not usually associated with DT. Three years later, she had painful defecations. Imaging showed two abdominal DT. After a multidisciplinary team meeting, the patient was refused for surgery, and medical treatment with antihormonal agents and nonsteroidal anti-inflammatory drugs was started. Imaging 18 months later showed DT stabilization, but the patient had difficulties to control chronic pains, which required morphine treatment, hypnotic sessions, and transcutaneous electric nerve stimulation. This case highlights the importance of DT screening in patients with FAP, mainly after surgery, regardless of their age and genetic mutation. Progress remains to be made in determining DT risk factors and in developing treatment. DT are still difficult to cure because of their potential for local invasion and local recurrence, and need to be managed by a multidisciplinary team.
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Affiliation(s)
- M Creuzé
- Service de pédiatrie, centre hospitalier Jacques-Monod, 29, avenue Pierre-Mendès, 76600 Le Havre, France
| | - P Afchain
- Service d'oncologie médecine interne, hôpital St-Antoine, 184, rue du Faubourg-St-Antoine, 75571 Paris cedex 12, France
| | - A Munck
- Service de gastroentérologie et nutrition pédiatrique, hôpital Robert-Debré, 7019 université Paris 7, Assistance publique-Hôpitaux de Paris, 48, boulevard Sérurier, 75935 Paris cedex 19, France
| | - J Viala
- Service de gastroentérologie et nutrition pédiatrique, hôpital Robert-Debré, 7019 université Paris 7, Assistance publique-Hôpitaux de Paris, 48, boulevard Sérurier, 75935 Paris cedex 19, France
| | - A Bonnard
- Service de chirurgie pédiatrique, hôpital Robert-Debré, 48, boulevard Sérurier, 75935 Paris cedex 19, France
| | - V Bertrand
- Service de pédiatrie, centre hospitalier Jacques-Monod, 29, avenue Pierre-Mendès, 76600 Le Havre, France.
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Abstract
Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome with considerable genetic and phenotypic heterogeneity, defined by the development of multiple adenomas throughout the colorectum. FAP is caused either by monoallelic mutations in the adenomatous polyposis coli gene APC, or by biallelic germline mutations of MUTYH, this latter usually presenting with milder phenotype. The aim of the present study was to characterize the genotype and phenotype of Hungarian FAP patients. Mutation screening of 87 unrelated probands from FAP families (21 of them presented as the attenuated variant of the disease, showing <100 polyps) was performed using DNA sequencing and multiplex ligation-dependent probe amplification. Twenty-four different pathogenic mutations in APC were identified in 65 patients (75 %), including nine cases (37.5 %) with large genomic alterations. Twelve of the point mutations were novel. In addition, APC-negative samples were also tested for MUTYH mutations and we were able to identify biallelic pathogenic mutations in 23 % of these cases (5/22). Correlations between the localization of APC mutations and the clinical manifestations of the disease were observed, cases with a mutation in the codon 1200-1400 region showing earlier age of disease onset (p < 0.003). There were only a few, but definitive dissimilarities between APC- and MUTYH-associated FAP in our cohort: the age at onset of polyposis was significantly delayed for biallelic MUTYH mutation carriers as compared to patients with an APC mutation. Our data represent the first comprehensive study delineating the mutation spectra of both APC and MUTYH in Hungarian FAP families, and underscore the overlap between the clinical characteristics of APC- and MUTYH-associated phenotypes, necessitating a more appropriate clinical characterization of FAP families.
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Quast DR, Schneider R, Burdzik E, Hoppe S, Möslein G. Long-term outcome of sporadic and FAP-associated desmoid tumors treated with high-dose selective estrogen receptor modulators and sulindac: a single-center long-term observational study in 134 patients. Fam Cancer 2016; 15:31-40. [PMID: 26275868 DOI: 10.1007/s10689-015-9830-z] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Aim of this study is to evaluate the outcome of long-term conservative treatment with sulindac and high-dose selective estrogen receptor modulators (SERMs) for sporadic and FAP-associated desmoid tumors. Desmoids are very rare tumors in the general population but occur frequently in FAP patients, being encountered in 23-38 %. Treatment of desmoids is still most controversial since response cannot be predicted and they are prone to develop recurrence. This study included all desmoid patients that were treated and followed at our institution and had completed at least 1 year of treatment. Response was defined as stable size or regression of desmoid size between two CT or MRI scans. A total of 134 patients were included. 64 (47.8 %) patients had a confirmed diagnosis of FAP, 69 (51.5 %) patients were sporadic. Overall 114 (85.1 %) patients showed regressive or stable desmoid size. Patients with previous history of multiple desmoid-related surgeries showed less-favorable response. The mean time to reach at least stable size was 14.9 (±9.1) months. After regression or stabilization, medication was tapered in 69 (60.5 %) of the treated patients with only one long-term recurrence after >10 years. The results of this study fortify the role of sulindac and high-dose SERMs as an effective and safe treatment for both, sporadic and FAP-associated desmoid tumors. While invasive treatment frequently results in high recurrence rates, high morbidity and high mortality, this conservative treatment is successful in most patients. The recurrence rate is negligible with no desmoid-related mortality in this large series. Therefore surgical resection, especially for mesenteric desmoids, should be deferred favoring this convincingly effective, well tolerated regimen.
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Affiliation(s)
- Daniel Robert Quast
- Klinik für Allgemeine Innere Medizin - Medizinische Klinik I, St. Josef-Hospital, Gudrunstr. 56, 44791, Bochum, Germany.
| | - Ralph Schneider
- Klinik für Hereditäre Tumorerkrankungen, HELIOS-Klinikum Wuppertal, Heusnerstr. 40, 42283, Wuppertal, Germany
| | - Emanuel Burdzik
- Klinik für Allgemein- und Viszeralchirurgie, Evangelisches Krankenhaus Bethesda zu Duisburg, Heerstraße 219, 47053, Duisburg, Germany
| | - Steffen Hoppe
- Klinik für Radiologie, HELIOS St. Josefs-Hospital Bochum-Linden, Axstr. 35, 44879, Bochum, Germany
| | - Gabriela Möslein
- Klinik für Hereditäre Tumorerkrankungen, HELIOS-Klinikum Wuppertal, Heusnerstr. 40, 42283, Wuppertal, Germany.
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Li W, Zhou Y, Li Q, Tong H, Lu W. Intestinal perforation during chemotherapeutic treatment of intra-abdominal desmoid tumor in patients with Gardner's syndrome: report of two cases. World J Surg Oncol 2016; 14:178. [PMID: 27377916 PMCID: PMC4932702 DOI: 10.1186/s12957-016-0935-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Indexed: 11/29/2022] Open
Abstract
Background A minority of intra-abdominal desmoid tumors is associated with Gardner’s syndrome in which desmoid tumors become an important cause of morbidity and mortality if they are surgically unresectable. Case presentation Here, we report two cases of intestinal perforation during chemotherapy in patients with Gardner’s syndrome-associated intra-abdominal desmoids. One female and one male patients who developed inoperable desmoids were given the chemotherapeutic regimen of doxorubicin plus dacarbazine, followed by meloxicam. Significant tumor regression was observed clinically. However, intestinal perforation happened in both patients. They were subjected to emergency surgery, follow-up management, and survived up to now. Conclusions The doxorubicin plus dacarbazine chemotherapy is an effective treatment for intra-abdominal demoid tumors in patients with Gardner’s syndrome. On the other hand, given severe adverse events might occur, clinicians should pay more attention that tumor quick regression may cause intestinal perforation in which urgent surgical intervention is necessary.
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Affiliation(s)
- Wei Li
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuhong Zhou
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Qian Li
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hanxing Tong
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weiqi Lu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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39
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Lung MS, Trainer AH, Campbell I, Lipton L. Familial colorectal cancer. Intern Med J 2016; 45:482-91. [PMID: 25955461 DOI: 10.1111/imj.12736] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 02/24/2015] [Indexed: 12/12/2022]
Abstract
Identifying individuals with a genetic predisposition to developing familial colorectal cancer (CRC) is crucial to the management of the affected individual and their family. In order to do so, the physician requires an understanding of the different gene mutations and clinical manifestations of familial CRC. This review summarises the genetics, clinical manifestations and management of the known familial CRC syndromes, specifically Lynch syndrome, familial adenomatous polyposis, MUTYH-associated neoplasia, juvenile polyposis syndrome and Peutz-Jeghers syndrome. An individual suspected of having a familial CRC with an underlying genetic predisposition should be referred to a familial cancer centre to enable pre-test counselling and appropriate follow up.
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Affiliation(s)
- M S Lung
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - A H Trainer
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - I Campbell
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - L Lipton
- Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Victoria, Australia
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40
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Zhang S, Qin H, Lv W, Luo S, Wang J, Fu C, Ma R, Shen Y, Chen S, Wu L. Novel and reported APC germline mutations in Chinese patients with familial adenomatous polyposis. Gene 2016; 577:187-92. [DOI: 10.1016/j.gene.2015.11.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 11/24/2015] [Indexed: 12/26/2022]
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41
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Muccino E, Gentile G, Mantero S, Marchesi M, Rancati A, Zoja R. The medico-legal observation of an aggressive urogenital fibromatosis with isolated development not related to any traumatic event. Forensic Sci Int 2016; 260:e1-e6. [PMID: 26786144 DOI: 10.1016/j.forsciint.2016.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 09/26/2015] [Accepted: 01/02/2016] [Indexed: 11/29/2022]
Abstract
Desmoid tumor is a fibroproliferative neoplasm with an intermediate malignancy and it can be localized in every bodily district: some locations are considered exceptional, like the urogenital localization. The Author point out a rare case of giant idiopathic scrotal fibromatosis that was found during an autopsy. A widower, that lived alone in poor hygienic conditions, was found dead in his house. The Judicial Authority ordered the autopsy, that was performed two days later at the Medico-Legal Section of Milan University. External examinations revealed only the considerable dimension of the scrotum (cm 24 × 41). The cause of death was fixed in a cardiac tamponade due to a natural heart laceration localized in correspondence of a transmural infarction. The toxicological exam resulted negative, while the histopathological and immunohistochemical analysis qualify the scrotal mass as a desmoids tumor. Due to the absence of predisposing conditions and of fibroproliferative infiltration in bladder and retroperitoneal space, the neoplasm was configured as an idiopathic desmoid tumor. The presented case gives the reason for the discussion concerning medico-legal aspects that are typical of rare neoplasms.
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Affiliation(s)
- Enrico Muccino
- Sezione di Medicina Legale e delle Assicurazioni-Dipartimento di Scienze Biomediche per la Salute- Università degli Studi di Milano, Via Luigi Mangiagalli 37, 20133 Milano MI, Italy
| | - Guendalina Gentile
- Sezione di Medicina Legale e delle Assicurazioni-Dipartimento di Scienze Biomediche per la Salute- Università degli Studi di Milano, Via Luigi Mangiagalli 37, 20133 Milano MI, Italy
| | - Stefano Mantero
- Centro Nazionale delle Ricerche-Istituto di Ricerca Genetica e Biomedica (IRGB)- Istituto Clinico Humanitas, Via Manzoni 113, 20089 Rozzano MI, Italy
| | - Matteo Marchesi
- Azienda Ospedaliera Papa Giovanni XXIII-Piazza OMS 1, 24127 Bergamo
| | - Alessandra Rancati
- Sezione di Medicina Legale e delle Assicurazioni-Dipartimento di Scienze Biomediche per la Salute- Università degli Studi di Milano, Via Luigi Mangiagalli 37, 20133 Milano MI, Italy
| | - Riccardo Zoja
- Sezione di Medicina Legale e delle Assicurazioni-Dipartimento di Scienze Biomediche per la Salute- Università degli Studi di Milano, Via Luigi Mangiagalli 37, 20133 Milano MI, Italy.
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Rengifo-Cam W, Jasperson KW, Burt RW, Samadder NJ. Familial Adenomatous Polyposis. INTESTINAL POLYPOSIS SYNDROMES 2016:173-195. [DOI: 10.1007/978-3-319-28103-2_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Hata K, Yamamoto Y, Kiyomatsu T, Tanaka T, Kazama S, Nozawa H, Kawai K, Tanaka J, Nishikawa T, Otani K, Yasuda K, Kishikawa J, Nagai Y, Anzai H, Shinagawa T, Arakawa K, Yamaguchi H, Ishihara S, Sunami E, Kitayama J, Watanabe T. Hereditary gastrointestinal cancer. Surg Today 2015; 46:1115-22. [PMID: 26676416 DOI: 10.1007/s00595-015-1283-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Accepted: 11/09/2015] [Indexed: 12/11/2022]
Abstract
Gastrointestinal (GI) cancer, including gastric and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer have a familial history, and several causative genes have been identified. Gene carriers with these hereditary GI syndromes often harbor several kinds of cancer at an early age, and genetic testing and specific surveillance may save their lives through early detection. Gastroenterologists and GI surgeons should be familiar with these syndromes, even though they are not always associated with a high penetrance of GI cancer. In this review, we provide an overview and discuss the diagnosis, genetic testing, and management of four major hereditary GI cancers: familial adenomatous polyposis, Lynch syndrome, hereditary diffuse gastric cancer, and Li-Fraumeni syndrome.
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Affiliation(s)
- Keisuke Hata
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yoko Yamamoto
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Tomomichi Kiyomatsu
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Toshiaki Tanaka
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Shinsuke Kazama
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hiroaki Nozawa
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kazushige Kawai
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Junichiro Tanaka
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Takeshi Nishikawa
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kensuke Otani
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Koji Yasuda
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Junko Kishikawa
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yuzo Nagai
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hiroyuki Anzai
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Takahide Shinagawa
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Keiichi Arakawa
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hironori Yamaguchi
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Soichiro Ishihara
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Eiji Sunami
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Joji Kitayama
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Toshiaki Watanabe
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
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Doyen J, Duranton-Tanneur V, Hostein I, Karanian-Philippe M, Chevreau C, Breibach F, Coutts M, Dadone B, Saint-Paul MC, Gugenheim J, Duffaud F, Pedeutour F. Spatio-temporal genetic heterogeneity of CTNNB1 mutations in sporadic desmoid type fibromatosis lesions. Virchows Arch 2015; 468:369-74. [PMID: 26666421 DOI: 10.1007/s00428-015-1883-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 10/13/2015] [Accepted: 11/17/2015] [Indexed: 01/10/2023]
Abstract
Desmoid type fibromatosis (DT) is a rare lesion of unclear pathogenesis that most often presents a mutation of the (β-catenin) gene. The natural history and clinical evolution are highly variable between patients and to date there is no consensus on optimal therapy. We report two cases of a patient with multiple DT lesions. Molecular investigations performed in both patients on multiple tumors at different anatomical sites revealed non-identical CTNNB1 mutations. The first patient was a 39-year-old man with a history of recurrent DT. In two of the DT lesions, three different mutations were found in codons 41 and 45, respectively. The lesions showed marked inflammatory features, characterized by IgG4 positive lymphoplasmacytic infiltrates and a foreign body reaction, which increased in intensity over time. The patient was eventually treated with a COX-2 inhibitor and the remaining mass was stabilized. In the two DT lesions of the second patient, CTNNB1 mutations S45P and T41A were found. The presence of different mutations in multiple focally recurrent sporadic DT lesions indicates that they do not have a clonal relationship. Our data suggest that a CTNNB1 mutation is a necessary event probably by providing a selective growth advantage. An IgG4 host antigen response is discussed as a potential predisposing factor for one of the patients.
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Affiliation(s)
- Jérôme Doyen
- Laboratory of Solid Tumours Genetics, Nice University Hospital, 28 Avenue de Valombrose, 06107, Nice, France. .,Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France. .,Department of Radiation Oncology, Antoine-Lacassagne Center, Nice, France.
| | - Valérie Duranton-Tanneur
- Laboratory of Solid Tumours Genetics, Nice University Hospital, 28 Avenue de Valombrose, 06107, Nice, France.,Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France
| | | | - Marie Karanian-Philippe
- Department of Biopathology, Institut Bergonié, Bordeaux, France.,INSERM U916, Bordeaux, France.,University of Bordeaux, Bordeaux, France
| | - Christine Chevreau
- Department of Medical Oncology, Institut Universitaire du Cancer Toulouse-Oncopôle, Toulouse, France
| | - Florence Breibach
- Department of Pathology, Institut Universitaire du Cancer Toulouse-Oncopôle, Toulouse, France
| | - Michael Coutts
- Central Laboratory of Pathology, Nice University Hospital, Nice, France.,Wells NHS Trust Maidstone Hospital Hermitage Lane, Maidstone, UK
| | - Bérengère Dadone
- Laboratory of Solid Tumours Genetics, Nice University Hospital, 28 Avenue de Valombrose, 06107, Nice, France.,Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France.,Central Laboratory of Pathology, Nice University Hospital, Nice, France
| | | | - Jean Gugenheim
- Department of Digestive Surgery and Center for Hepatic Transplantation, Nice University Hospital, Nice, France
| | - Florence Duffaud
- Medical Oncology Unit, CHU La Timone, Aix-Marseille University, Marseille, France
| | - Florence Pedeutour
- Laboratory of Solid Tumours Genetics, Nice University Hospital, 28 Avenue de Valombrose, 06107, Nice, France.,Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France
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Eser B, Yıldar M. Two different nucleotide substitutions of APC gene in a family with familial adenomatous polyposis. J Surg Case Rep 2015; 2015:rjv118. [PMID: 26416840 PMCID: PMC4584263 DOI: 10.1093/jscr/rjv118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome leading to colorectal cancer. This disease appears as a result of germline mutation in adenomatous polyposis coli (APC) gene. The aim of the present study is to report the association between two different nucleotide substitutions detected in a family with FAP. In the proband, p.His1172Gln (c.3516delT) was detected in exon 15 of the APC gene. Furthermore, p.His1172Gln (c.3516delT) and, in addition to this mutation, p.Met1413Val (c.4237 A > G) were detected in exon 15 in both daughters of the proband. However, we believe that single nucleotide change in codon 1413 may be a polymorphic variant and deletion T in codon 1172 of APC gene is associated with FAP, attenuated FAP and extracolonic FAP involvement. Along with common use of genetic tests in the clinical practice, genotype–phenotype correlation may be recognized better and useful for early diagnosis and prevention of familial cancer syndromes.
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Affiliation(s)
- Betul Eser
- Department of Medical Genetics, Balıkesir University Faculty of Medicine, Balıkesir, Turkey
| | - Murat Yıldar
- Department of General Surgery, Balıkesir University Faculty of Medicine, Balıkesir, Turkey
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Kumamoto K, Ishida H, Ohsawa T, Ishibashi K, Ushiama M, Yoshida T, Iwama T. Germline and somatic mutations of the APC gene in papillary thyroid carcinoma associated with familial adenomatous polyposis: Analysis of three cases and a review of the literature. Oncol Lett 2015; 10:2239-2243. [PMID: 26622826 DOI: 10.3892/ol.2015.3578] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 07/07/2015] [Indexed: 02/07/2023] Open
Abstract
Patients with familial adenomatous polyposis (FAP), which is caused by the dysfunction of the adenomatous polyposis coli (APC) protein, have the possibility of developing extracolonic manifestations, including thyroid cancer (TC), congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and gastric and duodenal adenomas. The pathogenesis of these disorders associated with FAP is considered to be affected by the site of the germline mutation on the APC gene as a genotype-phenotype correlation. Moreover, β-catenin binding sites consist of 20-amino acid repeats (20-AARs) in the APC protein, and they are essential for the development of colorectal adenomas and certain other extracolonic manifestations. The present study retrospectively analyzed the germline and somatic mutations of the APC gene in three papillary TC patients with FAP to analyze the association between the remaining number of 20-AARs and the development of TC. The mutation sites of two TCs did not include 20-AARs in each allele. In one patient, the remaining number of 20-AARs was two in the germline mutation and zero in the somatic mutation. Together with the data on 13 FAP-associated thyroid cancerous lesions in 3 FAP patients reported previously, the majority of the remaining numbers of 20-AARs was zero in the TC patients with FAP (13/16; 81.3%). Consequently, the APC/β-catenin signaling pathway may be strongly involved with the pathogenesis of TC with FAP. Further accumulation of FAP patients with TC will be required to confirm the molecular pathogenesis of TC.
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Affiliation(s)
- Kensuke Kumamoto
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
| | - Tomonori Ohsawa
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
| | - Keiichiro Ishibashi
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
| | - Mineko Ushiama
- Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Teruhiko Yoshida
- Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Takeo Iwama
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
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Slowik V, Attard T, Dai H, Shah R, Septer S. Desmoid tumors complicating Familial Adenomatous Polyposis: a meta-analysis mutation spectrum of affected individuals. BMC Gastroenterol 2015; 15:84. [PMID: 26179480 PMCID: PMC4504176 DOI: 10.1186/s12876-015-0306-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 06/23/2015] [Indexed: 01/09/2023] Open
Abstract
Background Desmoid tumors are a group of benign, invasive, solid tumors that are relatively rare in the general population, but can occur in up to 21 % of patients with Familial Adenomatous Polyposis (FAP). They can be difficult to treat and have high rates of recurrence even after resection. Our goal with this study was to identify the genetic mutations that put certain patients with FAP at high risk for desmoid tumors and could be future targets for research. Methods We performed a search in Pubmed, Ovid Medline and Embase to identify subjects with desmoid tumors and FAP. As a reference group for APC mutations in the unselected FAP population, we used the UMD-APC database referenced in the Orphanet portal which includes APC mutation data on 2040 individuals with FAP. Results Mutations were able to be broken down into 7 regions based on previously published data. Mutations in the APC gene from codons 1310 to 2011 were the most common region encompassing 48 % of published desmoid cases and 40 % of the reference population. It had a slightly elevated odds ratio of 1.4 that was statistically significant along with codon region 543-713 that had an odds ratio of 2.0. Using a combination of p-value and CI, the remaining 5 regions did not meet statistical significance as either the p >0.05 or the CI included 1.0. The most common point mutation found was codon 1309 (13.1 %), but it was also the most commonly found mutation in our reference population (12.9 %) and had an odds ratio of 1.0. Conclusions There is an increased risk for desmoid tumors in individuals with APC mutations between codons 543-713 and 1310-2011 when compared to a reference population. These patients may benefit from further study to develop surveillance protocols that could improve outcomes. Electronic supplementary material The online version of this article (doi:10.1186/s12876-015-0306-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Voytek Slowik
- Section of Pediatric Gastroenterology, Children's Mercy Hospital, Kansas City, MO, USA.
| | - Thomas Attard
- Section of Pediatric Gastroenterology, Children's Mercy Hospital, Kansas City, MO, USA.
| | - Hongying Dai
- Department of Medical Research, Children's Mercy Hospital, Kansas City, MO, USA.
| | - Raj Shah
- University of Missouri Kansas City - School of Medicine, Kansas City, MO, USA.
| | - Seth Septer
- Section of Pediatric Gastroenterology, Children's Mercy Hospital, Kansas City, MO, USA.
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Ikenoue T, Yamaguchi K, Komura M, Imoto S, Yamaguchi R, Shimizu E, Kasuya S, Shibuya T, Hatakeyama S, Miyano S, Furukawa Y. Attenuated familial adenomatous polyposis with desmoids caused by an APC mutation. Hum Genome Var 2015; 2:15011. [PMID: 27081525 PMCID: PMC4785566 DOI: 10.1038/hgv.2015.11] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 01/13/2015] [Accepted: 01/13/2015] [Indexed: 11/12/2022] Open
Abstract
We present here a case of attenuated familial adenomatous polyposis (AFAP) with a family history of desmoids and thyroid tumors. This patient had no colonic polyps but did have multiple desmoids. Genetic analysis identified a 4-bp deletion in codon 2644 (c.7932_7935delTTAT: p.Tyr2645LysfsX14) of the adenomatous polyposis coli (APC) gene. In cases with limited numbers of colonic polyps and desmoids, AFAP may be caused by a mutation in the 3′ region of APC.
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Affiliation(s)
- Tsuneo Ikenoue
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Kiyoshi Yamaguchi
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Mitsuhiro Komura
- Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Seiya Imoto
- Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Rui Yamaguchi
- Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Eigo Shimizu
- Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Shinichi Kasuya
- Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Tetsuo Shibuya
- Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Seira Hatakeyama
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Satoru Miyano
- Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yoichi Furukawa
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
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Esplin ED, Snyder MP. Genomic era diagnosis and management of hereditary and sporadic colon cancer. World J Clin Oncol 2014; 5:1036-1047. [PMID: 25493239 PMCID: PMC4259930 DOI: 10.5306/wjco.v5.i5.1036] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 03/21/2014] [Accepted: 05/16/2014] [Indexed: 02/06/2023] Open
Abstract
The morbidity and mortality attributable to heritable and sporadic carcinomas of the colon are substantial and affect children and adults alike. Despite current colonoscopy screening recommendations colorectal adenocarcinoma (CRC) still accounts for almost 140000 cancer cases yearly. Familial adenomatous polyposis (FAP) is a colon cancer predisposition due to alterations in the adenomatous polyposis coli gene, which is mutated in most CRC. Since the beginning of the genomic era next-generation sequencing analyses of CRC continue to improve our understanding of the genetics of tumorigenesis and promise to expand our ability to identify and treat this disease. Advances in genome sequence analysis have facilitated the molecular diagnosis of individuals with FAP, which enables initiation of appropriate monitoring and timely intervention. Genome sequencing also has potential clinical impact for individuals with sporadic forms of CRC, providing means for molecular diagnosis of CRC tumor type, data guiding selection of tumor targeted therapies, and pharmacogenomic profiles specifying patient specific drug tolerances. There is even a potential role for genomic sequencing in surveillance for recurrence, and early detection, of CRC. We review strategies for diagnostic assessment and management of FAP and sporadic CRC in the current genomic era, with emphasis on the current, and potential for future, impact of genome sequencing on the clinical care of these conditions.
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Cobianchi L, Ravetta V, Viera FT, Filisetti C, Siri B, Segalini E, Maestri M, Dominioni T, Alessiani M, Rossi S, Dionigi P. The challenge of extraabdominal desmoid tumour management in patients with Gardner's syndrome: radiofrequency ablation, a promising option. World J Surg Oncol 2014; 12:361. [PMID: 25429890 PMCID: PMC4258061 DOI: 10.1186/1477-7819-12-361] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 11/06/2014] [Indexed: 11/20/2022] Open
Abstract
Desmoid tumours are benign, myofibroblastic stromal neoplasms common in Gardner’s syndrome, which is a subtype of familial adenomatous polyposis characterized by colonic polyps, osteomas, thyroid cancer, epidermoid cysts, fibromas and sebaceous cysts. The primary treatment is surgery, followed by adjuvant radiotherapy, but the local recurrence rate is high, and wide resection can result in debilitating loss of function. We report the case of a 39-year-old man with Gardner’s syndrome who had already undergone a total prophylactic colectomy. He developed desmoid tumours localized in the mesenteric root, abdominal wall and dorsal region, which were treated from 2003 through 2013 with several surgical procedures and percutaneous radiofrequency ablation. In 2008 and 2013, RFA was applied under ultrasonographic guidance to two desmoid tumours localized in the dorsal thoracic wall. The outcomes were low-grade pain and one case of superficial skin necrosis, but so far there has been no recurrence of desmoid tumours in these locations. Surgical resection remains the first-line therapy for patients with desmoid tumours, but wide resection may lead to a poor quality of life. Radiofrequency ablation is less invasive and expensive and is a possible therapeutic option for desmoid tumours in patients with Gardner’s syndrome.
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Affiliation(s)
- Lorenzo Cobianchi
- General Surgery 1, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, 27100 Pavia, Italy.
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