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Johansen AM, Forsythe SD, McGrath CT, Barker G, Jimenez H, Paluri RK, Pasche BC. TGFβ in Pancreas and Colorectal Cancer: Opportunities to Overcome Therapeutic Resistance. Clin Cancer Res 2024; 30:3676-3687. [PMID: 38916900 PMCID: PMC11371528 DOI: 10.1158/1078-0432.ccr-24-0468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/16/2024] [Accepted: 05/30/2024] [Indexed: 06/26/2024]
Abstract
TGFβ is a pleiotropic signaling pathway that plays a pivotal role in regulating a multitude of cellular functions. TGFβ has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFβ is upregulated in colorectal cancer and pancreatic cancer, altering the tumor microenvironment and immune system and promoting a mesenchymal state. The upregulation of TGFβ in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFβ expression have led to reduced therapeutic resistance when combined with chemotherapy and immunotherapy. Here, we review the current TGFβ inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFβ combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFβ signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.
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Affiliation(s)
- Allan M. Johansen
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082, USA
| | - Steven D. Forsythe
- Neuroendocrine Therapy Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Callum T. McGrath
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082, USA
| | - Grayson Barker
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082, USA
| | - Hugo Jimenez
- Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
| | - Ravi K. Paluri
- Section of Hematology/Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082. USA
| | - Boris C. Pasche
- Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
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2
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Mahmood K, Thomas M, Qu C, Hsu L, Buchanan DD, Peters U. Elucidating the Risk of Colorectal Cancer for Variants in Hereditary Colorectal Cancer Genes. Gastroenterology 2023; 165:1070-1076.e3. [PMID: 37453563 PMCID: PMC10866455 DOI: 10.1053/j.gastro.2023.06.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 06/07/2023] [Accepted: 06/27/2023] [Indexed: 07/18/2023]
Affiliation(s)
- Khalid Mahmood
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Center for Cancer Research, Victorian Comprehensive Cancer Center, Parkville, Victoria, Australia; Melbourne Bioinformatics, The University of Melbourne, Parkville, Victoria, Australia
| | - Minta Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington; Department of Biostatistics, University of Washington, Seattle, Washington.
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Center for Cancer Research, Victorian Comprehensive Cancer Center, Parkville, Victoria, Australia; Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington.
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Broekema MF, Redeker EJW, Uiterwaal MT, van Hest LP. A novel pathogenic frameshift variant in AXIN2 in a man with polyposis and hypodontia. Hered Cancer Clin Pract 2023; 21:16. [PMID: 37626374 PMCID: PMC10464116 DOI: 10.1186/s13053-023-00260-6] [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: 07/02/2023] [Accepted: 08/05/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND WNT signaling is pivotal in embryogenesis and tissue homeostasis. Aberrant WNT signaling, due to mutations in components of this pathway, contributes to the development and progression of human cancers, including colorectal cancer. AXIN2, encoded by the AXIN2 gene, is a key negative regulator and target of the canonical WNT signaling pathway. Germline mutations in AXIN2 are associated with absence of permanent teeth (hypo- and oligodontia) and predisposition to gastrointestinal polyps and cancer. The limited number of patients makes an accurate genotype-phenotype analysis currently challenging. CASE PRESENTATION We present the case of a 55-year-old male with colorectal polyposis and hypodontia. Genetic testing confirmed a novel frameshift germline mutation in exon 8 of the AXIN2 gene. In addition, we provide an updated overview of germline AXIN2 mutations reported in literature. CONCLUSIONS Although the number of missing teeth is less severe in our patient than in some previously reported cases, our findings provide additional evidence that missing teeth and gastrointestinal neoplasia are associated with rare pathogenic AXIN2 germline mutations.
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Affiliation(s)
- M F Broekema
- Department of Human Genetics, Amsterdam UMC, Academic Medical Center, Amsterdam, The Netherlands.
| | - E J W Redeker
- Department of Human Genetics, Amsterdam UMC, Academic Medical Center, Amsterdam, The Netherlands
| | - M T Uiterwaal
- Department of Gastroenterology, Spaarne Hospital, Hoofddorp, The Netherlands
| | - L P van Hest
- Department of Human Genetics, Amsterdam UMC, Academic Medical Center, Amsterdam, The Netherlands
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4
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Enko D, Schaflinger E, Müller DJ. [Clinical Application Examples of a Next-Generation Sequencing based Multi-Genepanel Analysis]. Dtsch Med Wochenschr 2023; 148:695-702. [PMID: 37216946 DOI: 10.1055/a-2033-5329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
This review provides an overview of clinically useful applications of a next-generation sequencing (NGS)-based multi-gene panel testing strategy in the areas of oncology, hereditary tumor syndromes, and hematology. In the case of solid tumors (e.g. lung carcinoma, colon-rectal carcinoma), the detection of somatic mutations contributes not only to a better diagnostic but also therapeutic stratification of those affected. The increasing genetic complexity of hereditary tumor syndromes (e.g. breast and ovarian carcinoma, lynch syndrome/polyposis) requires a multi-gene panel analysis of germline mutations in affected families. Another useful indication for a multi-gene panel diagnostics and prognosis assessment are acute and chronic myeloid diseases. The criteria of the WHO-classification and the European LeukemiaNet-prognosis system for acute myeloid leukemia can only be met by a multi-gene panel test strategy.
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Affiliation(s)
- Dietmar Enko
- Medizinische Universität Graz Klinisches Institut für Medizinische und Chemische Labordiagnostik, Graz, Austria
| | - Erich Schaflinger
- Institut für Humangenetik, Medizinische Universität Graz, Neue Stiftingtalstraße 2, 8010 Graz, Austria
| | - Daniel J Müller
- Klinisches Institut für Pharmakogenetische Wissenschaft, Cambell Family Mental Health Research Institute, Zentrum für Suchtkrankheit und psychische Gesundheit, College Street 250, Toronto, ON M5T 1R8, Toronto, Kanada
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5
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Leclerc J, Beaumont M, Vibert R, Pinson S, Vermaut C, Flament C, Lovecchio T, Delattre L, Demay C, Coulet F, Guillerm E, Hamzaoui N, Benusiglio PR, Brahimi A, Cornelis F, Delhomelle H, Fert-Ferrer S, Fournier BPJ, Hovnanian A, Legrand C, Lortholary A, Malka D, Petit F, Saurin JC, Lejeune S, Colas C, Buisine MP. AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer. Genes Chromosomes Cancer 2023; 62:210-222. [PMID: 36502525 PMCID: PMC10107344 DOI: 10.1002/gcc.23112] [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: 09/26/2022] [Revised: 11/23/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022] Open
Abstract
Only a few patients with germline AXIN2 variants and colorectal adenomatous polyposis or cancer have been described, raising questions about the actual contribution of this gene to colorectal cancer (CRC) susceptibility. To assess the clinical relevance for AXIN2 testing in patients suspected of genetic predisposition to CRC, we collected clinical and molecular data from the French Oncogenetics laboratories analyzing AXIN2 in this context. Between 2004 and June 2020, 10 different pathogenic/likely pathogenic AXIN2 variants were identified in 11 unrelated individuals. Eight variants were from a consecutive series of 3322 patients, which represents a frequency of 0.24%. However, loss-of-function AXIN2 variants were strongly associated with genetic predisposition to CRC as compared with controls (odds ratio: 11.89, 95% confidence interval: 5.103-28.93). Most of the variants were predicted to produce an AXIN2 protein devoid of the SMAD3-binding and DIX domains, but preserving the β-catenin-binding domain. Ninety-one percent of the AXIN2 variant carriers who underwent colonoscopy had adenomatous polyposis. Forty percent of the variant carriers developed colorectal or/and other digestive cancer. Multiple tooth agenesis was present in at least 60% of them. Our report provides further evidence for a role of AXIN2 in CRC susceptibility, arguing for AXIN2 testing in patients with colorectal adenomatous polyposis or cancer.
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Affiliation(s)
- Julie Leclerc
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.,Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Marie Beaumont
- Laboratoire de Génétique Moléculaire et Génomique, CHU Rennes, Rennes, France
| | - Roseline Vibert
- UF d'Oncogénétique Clinique, Département de Génétique et Institut Universitaire de Cancérologie, Hôpitaux Pitié-Salpêtrière et Saint-Antoine, AP-HP. Sorbonne Université, Paris, France
| | - Stéphane Pinson
- Human Genetics Department, Hospices Civils de Lyon, Lyon, France
| | - Catherine Vermaut
- Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Cathy Flament
- Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Tonio Lovecchio
- Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Lucie Delattre
- Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Christophe Demay
- Bioinformatics Unit, Molecular Biology Facility, Lille University Hospital, Lille, France
| | - Florence Coulet
- Sorbonne University, INSERM, Saint-Antoine Research Center, Microsatellites instability and Cancer, CRSA, Genetics Department, AP-HP, Hôpital Pitié Salpêtrière, Sorbonne University, Paris, France
| | - Erell Guillerm
- Sorbonne University, INSERM, Saint-Antoine Research Center, Microsatellites instability and Cancer, CRSA, Genetics Department, AP-HP, Hôpital Pitié Salpêtrière, Sorbonne University, Paris, France
| | - Nadim Hamzaoui
- Service de Génétique et Biologie Moléculaires, Hôpital Cochin, AP-HP Centre, Université de Paris, and INSERM UMR_S1016, Institut Cochin, Université de Paris, Paris, France
| | - Patrick R Benusiglio
- UF d'Oncogénétique Clinique, Département de Génétique et Institut Universitaire de Cancérologie, Hôpitaux Pitié-Salpêtrière et Saint-Antoine, AP-HP. Sorbonne Université, Paris, France
| | | | - François Cornelis
- Department of Genetics-Oncogénétics-Prevention, Clermont-Ferrand Hospital, Clermont-Auvergne University, Clermont Ferrand, France
| | - Hélène Delhomelle
- Department of Genetics, Curie Institute, Paris Sciences & Lettres Research University, Paris, France
| | | | - Benjamin P J Fournier
- Centre de Recherche des Cordeliers, University of Paris, Sorbonne University, INSERM UMRS 1138 - Molecular Oral Pathophysiology, Paris, France.,Dental Faculty Garanciere, Oral Biology Department, Centre of Reference for Oral and Dental Rare Diseases, AP-HP, University of Paris, Paris, France
| | - Alain Hovnanian
- INSERM UMR 1163 - Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France.,University of Paris, Paris, France.,Department of Genetics, Necker Hospital for sick children, AP-HP, Paris, France
| | - Clémentine Legrand
- Service de Génétique, Génomique et Procréation, CHU Grenoble Alpes, Grenoble, France
| | - Alain Lortholary
- Centre Catherine de Sienne, hôpital privé du Confluent, Nantes, France
| | - David Malka
- Department of Cancer Medicine, Gustave Roussy, Paris-Saclay University, INSERM UMR 1279 - Unité Dynamique des Cellules Tumorales, Villejuif, France
| | - Florence Petit
- Clinique de Génétique, CHU Lille, Lille, France.,Univ. Lille, EA7364 - RADEME, CHU Lille, Lille, France
| | | | | | - Chrystelle Colas
- Department of Genetics, Curie Institute, Paris Sciences & Lettres Research University, Paris, France
| | - Marie-Pierre Buisine
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.,Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
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Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test? Int J Mol Sci 2023; 24:ijms24032137. [PMID: 36768460 PMCID: PMC9916931 DOI: 10.3390/ijms24032137] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/25/2023] Open
Abstract
Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li-Fraumeni syndrome (TP53 gene), MUTYH-associated polyposis (MUTYH gene), Peutz-Jeghers syndrome (STK11 gene), Cowden syndrome (PTEN gene), and juvenile polyposis syndrome (BMPR1A and SMAD4 genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1. In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.
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Rosner G, Petel-Galil Y, Laish I, Levi Z, Kariv R, Strul H, Gilad O, Gluck N. Adenomatous Polyposis Phenotype in BMPR1A and SMAD4 Variant Carriers. Clin Transl Gastroenterol 2022; 13:e00527. [PMID: 36049049 PMCID: PMC9624493 DOI: 10.14309/ctg.0000000000000527] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/10/2022] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION Variants in SMAD4 or BMPR1A cause juvenile polyposis syndrome, a rare autosomal dominant condition characterized by multiple gastrointestinal hamartomatous polyps. A phenotype of attenuated adenomatous polyposis without hamartomatous polyps is rare. METHODS We describe a retrospective cohort of individuals with SMAD4 or BMPR1A heterozygous germline variants, having ≥10 cumulative colorectal adenomas and/or colorectal cancer without hamartomatous polyps. All individuals had multigene panel and duplication/deletion analysis to exclude other genetic syndromes. RESULTS The study cohort included 8 individuals. The pathogenic potential of the variants was analyzed. Variants detected included 4 missense variants, 1 nonsense variant, 1 splice site variant, and 2 genomic deletions. Features of pathogenicity were present in most variants, and cosegregation of the variant with polyposis or colorectal cancer was obtained in 7 of the 8 families. Three of 8 individuals had colorectal cancer (age less than 50 years) in addition to the polyposis phenotype. Two individuals had extraintestinal neoplasms (pancreas and ampulla of Vater). DISCUSSION The clinical phenotype of SMAD4 and BMPR1A variants may infrequently extend beyond the classical juvenile polyposis syndrome phenotype. Applying multigene panel analysis of hereditary cancer-related genes in individuals with unexplained polyposis can provide syndrome-based clinical surveillance for carriers and their family members.
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Affiliation(s)
- Guy Rosner
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Petel-Galil
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ido Laish
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Gastroenterology Institute, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Zohar Levi
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Gastroenterology, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
| | - Revital Kariv
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hana Strul
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ophir Gilad
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nathan Gluck
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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8
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Zhang XW, Jia ZH, Zhao LP, Wu YS, Cui MH, Jia Y, Xu TM. MutL homolog 1 germline mutation c.(453+1_454-1)_(545+1_546-1)del identified in lynch syndrome: A case report and review of literature. World J Clin Cases 2022; 10:7105-7115. [PMID: 36051147 PMCID: PMC9297429 DOI: 10.12998/wjcc.v10.i20.7105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 02/04/2022] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Lynch syndrome (LS) is an autosomal dominant hereditary disorder because of germline mutations in DNA mismatch repair genes, such as MutL homolog 1 (MLH1), PMS1 homolog 2, MutS homolog 2, and MutS homolog 6. Gene mutations could make individuals and their families more susceptible to experiencing various malignant tumors. In Chinese, MLH1 germline mutation c.(453+1_454-1)_(545+1_546-1)del-related LS has been infrequently reported. Therefore, we report a rare LS patient with colorectal and endometrioid adenocarcinoma and describe her pedigree characteristics. CASE SUMMARY A 57-year-old female patient complained of irregular postmenopausal vaginal bleeding for 6 mo. She was diagnosed with LS, colonic malignancy, endometrioid adenocarcinoma, secondary fallopian tube malignancy, and intermyometrial leiomyomas. Then, she was treated by abdominal hysterectomy, bilateral oviduct oophorectomy, and sentinel lymph node resection. Genetic testing was performed using next-generation sequencing technology to detect the causative genetic mutations. Moreover, all her family members were offered a free genetic test, but no one accepted it. CONCLUSION No tumor relapse or metastasis was found in the patient during the 30-mo follow-up period. The genetic panel sequencing showed a novel pathogenic germline mutation in MLH1, c.(453+1_454-1)_(545+1_546-1)del, for LS. Moreover, cancer genetic counseling and testing are still in the initial development state in China, and maybe face numerous challenges in the further.
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Affiliation(s)
- Xi-Wen Zhang
- Department of Gynecology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Zan-Hui Jia
- Department of Gynecology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Li-Ping Zhao
- Department of Gynecology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Yi-Shi Wu
- Department of Gynecology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Man-Hua Cui
- Department of Gynecology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Yan Jia
- Department of Gynecology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Tian-Min Xu
- Department of Gynecology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
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9
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Sanoba SA, Koeppe ES, Jacobs MF, Stoffel EM. Outcomes of retesting in patients with previously uninformative cancer genetics evaluations. Fam Cancer 2022; 21:375-385. [PMID: 34545504 PMCID: PMC8934750 DOI: 10.1007/s10689-021-00276-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 09/12/2021] [Indexed: 11/24/2022]
Abstract
Advances in cancer genetics have increased germline pathogenic/likely pathogenic variant (PV/LPV) detection rates. More data is needed to inform which patients with previously uninformative results could benefit most from retesting, especially beyond breast/ovarian cancer populations. Here, we describe retesting outcomes and predictors of PV/LPVs in a cohort of patients unselected by cancer diagnosis. Retrospective chart reviews were conducted for patients at a cancer genetics clinic between 1998 and 2019 who underwent genetic testing (GT) on ≥ 2 dates with ≥ 1 year between tests, with no PV/LPVs on first-line GT. Demographics, retesting indications, and GT details were reviewed to evaluate predictive factors of PV/LPV identification. 139 patients underwent retesting, of whom 24 (17.3%) had a PV/LPV, encompassing 15 genes. 14 PV/LPV carriers (58.3%) only returned for retesting after personal or familial history changes (typically new cancer diagnoses), while 10 (41.7%) retested due to updated GT availability. No specific GT method was most likely to identify PV/LPVs and no specific clinical factors were predictive of a PV/LPV. The identified PV/LPVs were consistent with patients' personal or family histories, but were discordant with the initial referral indication for GT. For 16 (66.7%) PV/LPV carriers, the genetic diagnosis changed clinical management. This study adds to the limited body of literature on retesting outcomes beyond first-line BRCA analysis alone and confirms the utility of multigene panel testing. Retesting certain affected individuals when updated GT is available could result in earlier PV/LPV identification, significantly impacting screening recommendations and potentially reducing cancer-related morbidity and mortality.
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Affiliation(s)
- Shenin A Sanoba
- The Pancreatic Cancer Center, NYU Langone Health, New York, NY, USA.
| | - Erika S Koeppe
- Michigan Medicine Cancer Genetics Clinic, Ann Arbor, MI, USA
| | | | - Elena M Stoffel
- Michigan Medicine Cancer Genetics Clinic, Ann Arbor, MI, USA
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10
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Jensen JM, Skakkebæk A, Gaustadness M, Sommerlund M, Gjørup H, Ljungmann K, Lautrup CK, Sunde L. Familial colorectal cancer and tooth agenesis caused by an AXIN2 variant: how do we detect families with rare cancer predisposition syndromes? Fam Cancer 2022; 21:325-332. [PMID: 34637023 DOI: 10.1007/s10689-021-00280-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 10/03/2021] [Indexed: 11/29/2022]
Abstract
We present a three-generation family with an AXIN2 variant and a family history of colorectal cancer (CRC), colon polyps and tooth agenesis. A likely pathogenic variant was detected in the AXIN2 gene (c.1994dup; p.(Asn666Glnfs*41)). This variant has previously been associated with tooth agenesis and polyposis, only. In this case report we describe eight carriers with tooth agenesis and variable clinical findings, including polyps and CRC. Our case provides additional knowledge to the sparse data on genotype-phenotype association related to AXIN2 associated cancer syndrome. Further, our case highlights the importance of analysing an extended CRC and oligodontia/ectodermal dysplasia gene panel including AXIN2 but also raises awareness and discussion about appropriate surveillance program.
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Affiliation(s)
- Janni M Jensen
- Department of Clinical Genetics, Aalborg University Hospital, Ladegaardsgade 5,5, 9000, Aalborg, Denmark.
| | - Anne Skakkebæk
- Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
| | - Mette Gaustadness
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Mette Sommerlund
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Hans Gjørup
- Department of Oral and Maxillofacial Surgery, Resource Centre for Oral Health in Rare Medical Conditions, Aarhus University Hospital, Aarhus, Denmark
| | - Ken Ljungmann
- Department of Surgery, Aarhus University Hospital, Aarhus, Denmark
- Institute of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Charlotte K Lautrup
- Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
| | - Lone Sunde
- Department of Clinical Genetics, Aalborg University Hospital, Ladegaardsgade 5,5, 9000, Aalborg, Denmark
- Institute of Biomedicine, Aarhus University, Aarhus, Denmark
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11
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Murphy A, Solomons J, Risby P, Gabriel J, Bedenham T, Johnson M, Atkinson N, Bailey AA, Bird‐Lieberman E, Leedham SJ, East JE, Biswas S. Germline variant testing in serrated polyposis syndrome. J Gastroenterol Hepatol 2022; 37:861-869. [PMID: 35128723 PMCID: PMC9305167 DOI: 10.1111/jgh.15791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 12/13/2021] [Accepted: 01/12/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Serrated polyposis syndrome (SPS) is now known to be the commonest polyposis syndrome. Previous analyses for germline variants have shown no consistent positive findings. To exclude other polyposis syndromes, 2019 British Society of Gastroenterology (BSG) guidelines advise gene panel testing if the patient is under 50 years, there are multiple affected individuals within a family, or there is dysplasia within any of the polyps. METHODS A database of SPS patients was established at the Oxford University Hospitals NHS Foundation Trust. Patients were referred for genetic assessment based on personal and family history and patient preference. The majority were tested for a hereditary colorectal cancer panel including MUTYH, APC, PTEN, SMAD4, BMPR1A, STK11, NTLH1, POLD1, POLE, GREM1 (40-kb duplication), PMS2, and Lynch syndrome mismatch repair genes. RESULTS One hundred and seventy-three patients were diagnosed with SPS based on World Health Organization 2019 criteria between February 2010 and December 2020. The mean age of diagnosis was 54.2 ± 16.8 years. Seventy-three patients underwent genetic testing and 15/73 (20.5%) were found to have germline variants, of which 7/73 (9.6%) had a pathogenic variant (MUTYH n = 2, SMAD4 n = 1, CHEK2 n = 2, POLD1 n = 1, and RNF43 n = 1). Only 60% (9/15) of these patients would have been recommended for gene panel testing according to current BSG guidelines. CONCLUSIONS A total of 20.5% of SPS patients tested were affected by heterozygous germline variants, including previously unreported associations with CHEK2 and POLD1. This led to a change in management in seven patients (9.6%). Current recommendations may miss SPS associated with germline variants, which is more common than previously anticipated.
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Affiliation(s)
- Aisling Murphy
- Translational Gastroenterology Unit, Oxford NIHR Biomedical Research CentreUniversity of OxfordOxfordUK
| | - Joyce Solomons
- Oxford Centre for Genomic Medicine, Nuffield Orthopaedic CentreOxford University Hospitals NHS Foundation TrustOxfordUK
| | - Peter Risby
- Oxford Centre for Genomic Medicine, Nuffield Orthopaedic CentreOxford University Hospitals NHS Foundation TrustOxfordUK
| | - Jessica Gabriel
- Oxford Regional Genetics Laboratories, Churchill HospitalOxford University Hospitals NHS Foundation TrustOxfordUK
| | - Tina Bedenham
- Oxford Regional Genetics Laboratories, Churchill HospitalOxford University Hospitals NHS Foundation TrustOxfordUK
| | - Michael Johnson
- Translational Gastroenterology Unit, Oxford NIHR Biomedical Research CentreUniversity of OxfordOxfordUK
| | - Nathan Atkinson
- New Zealand Familial Gastrointestinal Cancer RegistryAuckland City HospitalAucklandNew Zealand
| | - Adam A Bailey
- Translational Gastroenterology Unit, Oxford NIHR Biomedical Research CentreUniversity of OxfordOxfordUK
| | - Elizabeth Bird‐Lieberman
- Translational Gastroenterology Unit, Oxford NIHR Biomedical Research CentreUniversity of OxfordOxfordUK
| | - Simon J Leedham
- Translational Gastroenterology Unit, Oxford NIHR Biomedical Research CentreUniversity of OxfordOxfordUK,Intestinal Stem Cell Biology Lab, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - James E East
- Translational Gastroenterology Unit, Oxford NIHR Biomedical Research CentreUniversity of OxfordOxfordUK
| | - Sujata Biswas
- Translational Gastroenterology Unit, Oxford NIHR Biomedical Research CentreUniversity of OxfordOxfordUK,Gastroenterology DepartmentBuckinghamshire Healthcare NHS TrustUK
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12
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Kaissarian NM, Meyer D, Kimchi-Sarfaty C. Synonymous Variants: Necessary Nuance in our Understanding of Cancer Drivers and Treatment Outcomes. J Natl Cancer Inst 2022; 114:1072-1094. [PMID: 35477782 PMCID: PMC9360466 DOI: 10.1093/jnci/djac090] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/24/2022] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
Once called "silent mutations" and assumed to have no effect on protein structure and function, synonymous variants are now recognized to be drivers for some cancers. There have been significant advances in our understanding of the numerous mechanisms by which synonymous single nucleotide variants (sSNVs) can affect protein structure and function by affecting pre-mRNA splicing, mRNA expression, stability, folding, miRNA binding, translation kinetics, and co-translational folding. This review highlights the need for considering sSNVs in cancer biology to gain a better understanding of the genetic determinants of human cancers and to improve their diagnosis and treatment. We surveyed the literature for reports of sSNVs in cancer and found numerous studies on the consequences of sSNVs on gene function with supporting in vitro evidence. We also found reports of sSNVs that have statistically significant associations with specific cancer types but for which in vitro studies are lacking to support the reported associations. Additionally, we found reports of germline and somatic sSNVs that were observed in numerous clinical studies and for which in silico analysis predicts possible effects on gene function. We provide a review of these investigations and discuss necessary future studies to elucidate the mechanisms by which sSNVs disrupt protein function and are play a role in tumorigeneses, cancer progression, and treatment efficacy. As splicing dysregulation is one of the most well recognized mechanisms by which sSNVs impact protein function, we also include our own in silico analysis for predicting which sSNVs may disrupt pre-mRNA splicing.
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Affiliation(s)
- Nayiri M Kaissarian
- Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Douglas Meyer
- Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Chava Kimchi-Sarfaty
- Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US Food and Drug Administration, Silver Spring, MD, USA
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13
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Universal Immunohistochemistry for Lynch Syndrome: A Systematic Review and Meta-analysis of 58,580 Colorectal Carcinomas. Clin Gastroenterol Hepatol 2022; 20:e496-e507. [PMID: 33887476 DOI: 10.1016/j.cgh.2021.04.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 04/09/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Lynch syndrome is a form of hereditary colorectal cancer (CRC) caused by pathogenic germline variants (PV) in DNA mismatch repair (MMR) genes. Currently, many Western countries perform universal immunohistochemistry testing on CRC to increase the identification of Lynch syndrome patients and their relatives. For a clear understanding of health benefits and costs, data on its outcomes are required: proportions of Lynch syndrome, sporadic MMR-deficient (MMRd) cases, and unexplained MMRd cases. METHODS Ovid Medline, Embase, and Cochrane CENTRAL were searched for studies reporting on universal MMR immunohistochemistry, followed by MMR germline analysis, until March 20, 2020. Proportions were calculated, subgroup analyses were performed based on age and diagnostics used, and random effects meta-analyses were conducted. Quality was assessed using the Joanna Briggs Critical Appraisal Tool for Prevalence Studies. RESULTS Of 2723 identified articles, 56 studies covering 58,580 CRCs were included. In 6.22% (95% CI, 5.08%-7.61%; I2 = 96%) MMRd was identified. MMR germline PV was present in 2.00% (95% CI, 1.59%-2.50%; I2 = 92%), ranging from 1.80% to 7.27% based on completeness of diagnostics and age restriction. Immunohistochemistry outcomes were missing in 11.81%, and germline testing was performed in 76.30% of eligible patients. In 7 studies, including 6848 CRCs completing all diagnostic stages, germline PV and biallelic somatic MMR inactivation were found in 3.01% and 1.75%, respectively; 0.61% remained unexplained MMRd. CONCLUSIONS Age, completeness, and type of diagnostics affect the percentage of MMR PV and unexplained MMRd percentages. Complete diagnostics explain almost all MMRd CRCs, reducing the amount of subsequent multigene panel testing. This contributes to optimizing testing and surveillance in MMRd CRC patients and relatives.
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14
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Abrahamsson S, Eiengård F, Rohlin A, Dávila López M. PΨFinder: a practical tool for the identification and visualization of novel pseudogenes in DNA sequencing data. BMC Bioinformatics 2022; 23:59. [PMID: 35114952 PMCID: PMC8812246 DOI: 10.1186/s12859-022-04583-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 01/24/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Processed pseudogenes (PΨgs) are disabled gene copies that are transcribed and may affect expression of paralogous genes. Moreover, their insertion in the genome can disrupt the structure or the regulatory region of a gene, affecting its expression level. These events have been identified as occurring mutations during cancer development, thus being able to identify PΨgs and their location will improve their impact on diagnostic testing, not only in cancer but also in inherited disorders. RESULTS We have implemented PΨFinder (P-psy-finder), a tool that identifies PΨgs, annotates known ones and predicts their insertion site(s) in the genome. The tool screens alignment files and provides user-friendly summary reports and visualizations. To demonstrate its applicability, we scanned 218 DNA samples from patients screened for hereditary colorectal cancer. We detected 423 PΨgs distributed in 96% of the samples, comprising 7 different parent genes. Among these, we confirmed the well-known insertion site of the SMAD4-PΨg within the last intron of the SCAI gene in one sample. While for the ubiquitous CBX3-PΨg, present in 82.6% of the samples, we found it reversed inserted in the second intron of the C15ORF57 gene. CONCLUSIONS PΨFinder is a tool that can automatically identify novel PΨgs from DNA sequencing data and determine their location in the genome with high sensitivity (95.92%). It generates high quality figures and tables that facilitate the interpretation of the results and can guide the experimental validation. PΨFinder is a complementary analysis to any mutational screening in the identification of disease-causing mutations within cancer and other diseases.
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Affiliation(s)
- Sanna Abrahamsson
- Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Box 115, 405 30, Gothenburg, Sweden
| | - Frida Eiengård
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anna Rohlin
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Unit of Genetic Analysis and Bioinformatics, Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Marcela Dávila López
- Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Box 115, 405 30, Gothenburg, Sweden.
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15
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Lee JK, Kwon WK, Hong SN, Chang DK, Kim HC, Jang JH, Kim JW. Necessity of Multiplex Ligation Probe Amplification in Genetic Tests: Germline variant analysis of the APC gene in familial adenomatous polyposis patients. Cancer Genet 2022; 262-263:95-101. [DOI: 10.1016/j.cancergen.2022.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 01/10/2022] [Accepted: 02/09/2022] [Indexed: 11/02/2022]
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16
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Gupta N, Drogan C, Kupfer SS. How many is too many? Polyposis syndromes and what to do next. Curr Opin Gastroenterol 2022; 38:39-47. [PMID: 34839308 PMCID: PMC8648991 DOI: 10.1097/mog.0000000000000796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE OF REVIEW The goal of this review is to help providers recognize, diagnose and manage gastrointestinal (GI) polyposis syndromes. RECENT FINDINGS Intestinal polyps include a number of histological sub-types such as adenomas, serrated, hamartomas among others. Over a quarter of individuals undergoing screening colonoscopy are expected to have colonic adenomas. Although it is not uncommon for adults to have a few GI polyps in their lifetime, some individuals are found to have multiple polyps of varying histology throughout the GI tract. In these individuals, depending on polyp histology, number, location and size as well as extra-intestinal features and/or family history, a polyposis syndrome should be considered with appropriate testing and management. SUMMARY Diagnosis and management of polyposis syndromes has evolved with advent of multigene panel testing and new data on optimal surveillance strategies. Evidence-based recommendations and current practice guidelines for polyposis syndromes are reviewed here. Areas of uncertainty and future research are also highlighted.
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Affiliation(s)
- Nina Gupta
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois, USA
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17
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Bridger JM, Pereira RT, Pina C, Tosi S, Lewis A. Alterations to Genome Organisation in Stem Cells, Their Differentiation and Associated Diseases. Results Probl Cell Differ 2022; 70:71-102. [PMID: 36348105 DOI: 10.1007/978-3-031-06573-6_3] [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] [Indexed: 06/16/2023]
Abstract
The organisation of the genome in its home, the cell nucleus, is reliant on a number of different aspects to establish, maintain and alter its functional non-random positioning. The genome is dispersed throughout a cell nucleus in specific chromosome territories which are further divided into topologically associated domains (TADs), where regions of the genome from different and the same chromosomes come together. This organisation is both controlled by DNA and chromatin epigenetic modification and the association of the genome with nuclear structures such as the nuclear lamina, the nucleolus and nuclear bodies and speckles. Indeed, sequences that are associated with the first two structures mentioned are termed lamina-associated domains (LADs) and nucleolar-associated domains (NADs), respectively. The modifications and nuclear structures that regulate genome function are altered through a cell's life from stem cell to differentiated cell through to reversible quiescence and irreversible senescence, and hence impacting on genome organisation, altering it to silence specific genes and permit others to be expressed in a controlled way in different cell types and cell cycle statuses. The structures and enzymes and thus the organisation of the genome can also be deleteriously affected, leading to disease and/or premature ageing.
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Affiliation(s)
- Joanna M Bridger
- Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance (cenGEM), College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK.
| | - Rita Torres Pereira
- Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance (cenGEM), College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK
| | - Cristina Pina
- Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance (cenGEM), College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK
| | - Sabrina Tosi
- Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance (cenGEM), College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK
| | - Annabelle Lewis
- Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance (cenGEM), College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK
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18
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Jelsig AM, Byrjalsen A, Busk Madsen M, Kuhlmann TP, van Overeem Hansen T, Wadt KAW, Karstensen JG. Novel Genetic Causes of Gastrointestinal Polyposis Syndromes. Appl Clin Genet 2021; 14:455-466. [PMID: 34866929 PMCID: PMC8637176 DOI: 10.2147/tacg.s295157] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Hereditary polyposis syndromes are characterized by a large number and/or histopathologically specific polyps in the gastrointestinal tract and a high risk of both colorectal cancer and extracolonic cancer at an early age. While the genes responsible for some of the syndromes, eg, APC in familial adenomatous polyposis and STK11 in Peutz-Jeghers syndrome, have been known for decades, novel genetic causes have recently been detected that have shed light on the broader clinical spectrum of syndromes. Genetic diagnoses are important because they can facilitate a personalized surveillance program. Furthermore, at-risk members of the patient's family can be tested and enrolled in surveillance as needed. In some cases, prenatal diagnostics should be offered. In this paper, we describe the development in germline genetics of the hereditary polyposis syndromes over the last 10-12 years, their clinical characteristics, as well as how to implement genetic analyses in the diagnostic pipeline.
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Affiliation(s)
- Anne Marie Jelsig
- Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Anna Byrjalsen
- Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Majbritt Busk Madsen
- Center for Genomic Medicine, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Tine Plato Kuhlmann
- Department of Pathology, University Hospital of Copenhagen, Herlev Hospital, Herlev, Denmark
| | | | - Karin A W Wadt
- Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - John Gásdal Karstensen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.,Danish Polyposis Registry, Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark
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19
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Jelsig AM, Karstensen JG, Jespersen N, Ketabi Z, Lautrup C, Rønlund K, Sunde L, Wadt K, Thorlacius-Ussing O, Qvist N. Danish guidelines for management of non-APC-associated hereditary polyposis syndromes. Hered Cancer Clin Pract 2021; 19:41. [PMID: 34620187 PMCID: PMC8499431 DOI: 10.1186/s13053-021-00197-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
Hereditary Polyposis Syndromes are a group of rare, inherited syndromes characterized by the presence of histopathologically specific or numerous intestinal polyps and an increased risk of cancer. Some polyposis syndromes have been known for decades, but the development in genetic technologies has allowed the identification of new syndromes.. The diagnosis entails surveillance from an early age, but universal guideline on how to manage and surveille these new syndromes are lacking. This paper represents a condensed version of the recent guideline (2020) from a working group appointed by the Danish Society of Medical Genetics and the Danish Society of Surgery on recommendations for the surveillance of patients with hereditary polyposis syndromes, including rare polyposis syndromes.
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Affiliation(s)
- Anne Marie Jelsig
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
| | - John Gásdal Karstensen
- Danish Polyposis Registry, Gastrounit, Hvidovre Hospital, Hvidovre, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Niels Jespersen
- Danish Polyposis Registry, Gastrounit, Hvidovre Hospital, Hvidovre, Denmark
| | - Zohreh Ketabi
- Department of Gynecology and Obstetrics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Charlotte Lautrup
- Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark
| | - Karina Rønlund
- Department of Clinical Genetics, University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark
| | - Lone Sunde
- Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark
| | - Karin Wadt
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Ole Thorlacius-Ussing
- Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Niels Qvist
- Research Unit for Surgery, Odense University Hospital, Odense, Denmark
- University of Southern Denmark, Odense, Denmark
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20
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Olkinuora AP, Peltomäki PT, Aaltonen LA, Rajamäki K. From APC to the genetics of hereditary and familial colon cancer syndromes. Hum Mol Genet 2021; 30:R206-R224. [PMID: 34329396 PMCID: PMC8490010 DOI: 10.1093/hmg/ddab208] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 11/12/2022] Open
Abstract
Hereditary colorectal cancer (CRC) syndromes attributable to high penetrance mutations represent 9-26% of young-onset CRC cases. The clinical significance of many of these mutations is understood well enough to be used in diagnostics and as an aid in patient care. However, despite the advances made in the field, a significant proportion of familial and early-onset cases remains molecularly uncharacterized and extensive work is still needed to fully understand the genetic nature of CRC susceptibility. With the emergence of next-generation sequencing and associated methods, several predisposition loci have been unraveled, but validation is incomplete. Individuals with cancer-predisposing mutations are currently enrolled in life-long surveillance, but with the development of new treatments, such as cancer vaccinations, this might change in the not so distant future for at least some individuals. For individuals without a known cause for their disease susceptibility, prevention and therapy options are less precise. Herein, we review the progress achieved in the last three decades with a focus on how CRC predisposition genes were discovered. Furthermore, we discuss the clinical implications of these discoveries and anticipate what to expect in the next decade.
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Affiliation(s)
- Alisa P Olkinuora
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
| | - Päivi T Peltomäki
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
| | - Lauri A Aaltonen
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland
| | - Kristiina Rajamäki
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland
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21
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Mio C, Verrienti A, Pecce V, Sponziello M, Damante G. Rare germline variants in DNA repair-related genes are accountable for papillary thyroid cancer susceptibility. Endocrine 2021; 73:648-657. [PMID: 33821390 PMCID: PMC8325654 DOI: 10.1007/s12020-021-02705-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 03/19/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Understanding the molecular mechanisms underlying papillary thyroid cancer (PTC) proved to be vital not only for diagnostic purposes but also for tailored treatments. Despite the strong evidence of heritability, only a small subset of alterations has been implicated in PTC pathogenesis. To this reason, we used targeted next-generation sequencing (NGS) to identify candidate variants implicated in PTC pathogenesis, progression, and invasiveness. METHODS A total of 42 primary PTC tissues were investigated using a targeted next-generation sequencing (NGS) panel enlisting 47 genes involved in DNA repair and tumor progression. RESULTS We identified 57 point mutations in 78.5% of samples (n = 32). Thirty-two somatic mutations were identified exclusively in known thyroid cancer genes (BRAF, KRAS, NRAS, and TERT). Unpredictably, 45% of the all identified mutations (n = 25) resulted to be germline, most affecting DNA repair genes. Interestingly, none of the latter variants was in the main population databases. Following ACMG classification, 20% of pathogenic/likely pathogenic and 68% of variant of unknown significance were identified. CONCLUSIONS Overall, our results support the hypothesis that rare germline variants in DNA repair genes are accountable for PTC susceptibility. More data, including the segregation analysis in affected families, should be collected before definitely annotate these alterations and to establish their potential prognostic and treatment implications.
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Affiliation(s)
- Catia Mio
- Department of Medicine, University of Udine, 33100, Udine, Italy.
| | - Antonella Verrienti
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, 00161, Rome, Italy
| | - Valeria Pecce
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, 00161, Rome, Italy
| | - Marialuisa Sponziello
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, 00161, Rome, Italy
| | - Giuseppe Damante
- Department of Medicine, University of Udine, 33100, Udine, Italy
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22
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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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Shen N, Wang X, Lu Y, Xiao F, Xiao J. Importance of early detection of juvenile polyposis syndrome: A case report and literature review. Medicine (Baltimore) 2020; 99:e23494. [PMID: 33327285 PMCID: PMC7738017 DOI: 10.1097/md.0000000000023494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
RATIONALE Juvenile polyposis syndrome (JPS) is a rare genetic gastrointestinal disorder with hidden and variable clinical features. Early detection is crucial for good prognosis. PATIENT CONCERNS A 20-year-old female went to hospital for fever, and was unexpectedly diagnosed as JPS during treatment. She reported no clinical signs or family history of JPS. DIAGNOSIS Blood routine examination on hospital admission suggested a moderate anemia. Bone marrow cytology and leukemia fusion gene test were performed to rule out leukemia. Other examinations including ultrasound and computed tomography were also conducted for differential diagnosis. Further electronic colonoscopy identified more than 20 pedicle polyps located at her ileocecum and rectum. Mutation analysis detected a novel de novo pathogenic variant, c.910C>T (p.Gln304Ter) within bone morphogenetic protein receptor type 1A gene, establishing the diagnosis of JPS. INTERVENTIONS The patient was treated with endoscopic interventions. We also provided a genetic counseling for this family. OUTCOMES The patient's polyps were removed, some of which already had adenomatous changes. The patient received surveillance of hereditary colorectal cancer according to guidelines. LESSONS Variable features and lack of family history probably lead to a great underestimation of potential JPS population. It is recommended to perform genetic testing by a multigene panel in individuals who have suspected symptoms of polyposis.
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Affiliation(s)
- Na Shen
- Department of Laboratory Medicine
| | | | | | | | - Juan Xiao
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Djursby M, Madsen MB, Frederiksen JH, Berchtold LA, Therkildsen C, Willemoe GL, Hasselby JP, Wikman F, Okkels H, Skytte AB, Nilbert M, Wadt K, Gerdes AM, van Overeem Hansen T. New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients. Front Genet 2020; 11:566266. [PMID: 33193653 PMCID: PMC7541943 DOI: 10.3389/fgene.2020.566266] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 08/24/2020] [Indexed: 12/30/2022] Open
Abstract
A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.
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Affiliation(s)
- Malene Djursby
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Majbritt B Madsen
- Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jane H Frederiksen
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Lukas A Berchtold
- Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christina Therkildsen
- The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
| | - Gro L Willemoe
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jane P Hasselby
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Friedrik Wikman
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Henrik Okkels
- Section of Molecular Diagnostics, Department of Clinical Chemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Anne-Bine Skytte
- Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
| | - Mef Nilbert
- The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
| | - Karin Wadt
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Anne-Marie Gerdes
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Thomas van Overeem Hansen
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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Lou H, Zhai C, Gong L, Pan H, Pan H, Zhang Y, Yang M, Hu Z. NF1 germline mutation in a Chinese family with colon cancer. J Int Med Res 2020; 48:300060519896435. [PMID: 32814491 PMCID: PMC7444156 DOI: 10.1177/0300060519896435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Recent advances in genomic medicine have identified novel gene mutations that contribute to an increased risk of CRC. Here, we describe a diagnosis of colon cancer in a 63-year-old woman and also in her brother. Next-generation sequencing showed that both patients harbored a germline mutation in NF1. The female patient also carried co-mutations in KRAS and NRAS. Furthermore, the NF1 germline mutation was identified in a healthy offspring of the brother. The female patient received three cycles of bevacizumab plus capecitabine/oxaliplatin therapy and achieved stable disease of the primary lesion in the colon and partial response of metastasis in the right abdominal cavity. This study highlights the association of NF1 germline mutations with colon cancer.
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Affiliation(s)
- Haizhou Lou
- Department of Medical Oncology 1, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chongya Zhai
- Department of Medical Oncology 1, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liu Gong
- Department of Medical Oncology 1, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Hong Pan
- Department of Medical Oncology 1, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Hongming Pan
- Department of Medical Oncology 1, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | | | | | - Zimin Hu
- Department of Respiratory Disease, Cixi Sixth Hospital, Ningbo, China
- Zimin Hu, Department of Respiratory Disease, Cixi Sixth Hospital, 100 Youth Palace South Road, Ningbo 315300, China.
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Peltomäki P, Olkinuora A, Nieminen TT. Updates in the field of hereditary nonpolyposis colorectal cancer. Expert Rev Gastroenterol Hepatol 2020; 14:707-720. [PMID: 32755332 DOI: 10.1080/17474124.2020.1782187] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Up to one third of colorectal cancers show familial clustering and 5% are hereditary single-gene disorders. Hereditary non-polyposis colorectal cancer comprises DNA mismatch repair-deficient and -proficient subsets, represented by Lynch syndrome (LS) and familial colorectal cancer type X (FCCTX), respectively. Accurate knowledge of molecular etiology and genotype-phenotype correlations are critical for tailored cancer prevention and treatment. AREAS COVERED The authors highlight advances in the molecular dissection of hereditary non-polyposis colorectal cancer, based on recent literature retrieved from PubMed. Future possibilities for novel gene discoveries are discussed. EXPERT COMMENTARY LS is molecularly well established, but new information is accumulating of the associated clinical and tumor phenotypes. FCCTX remains poorly defined, but several promising candidate genes have been discovered and share some preferential biological pathways. Multi-level characterization of specimens from large patient cohorts representing multiple populations, combined with proper bioinformatic and functional analyses, will be necessary to resolve the outstanding questions.
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Affiliation(s)
- Paivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland
| | - Alisa Olkinuora
- Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland
| | - Taina T Nieminen
- Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland
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Gao XH, Li J, Zhao ZY, Xu XD, Du YQ, Yan HL, Liu LJ, Bai CG, Zhang W. Juvenile polyposis syndrome might be misdiagnosed as familial adenomatous polyposis: a case report and literature review. BMC Gastroenterol 2020; 20:167. [PMID: 32487124 PMCID: PMC7268223 DOI: 10.1186/s12876-020-01238-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 03/26/2020] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Juvenile polyposis syndrome (JPS) is a rare disorder characterized by the presence of multiple juvenile polyps in the gastrointestinal tract, and germline mutations in SMAD4 or BMPR1A. Due to its rarity and complex clinical manifestation, misdiagnosis often occurs in clinical practice. CASE PRESENTATION A 42-year-old man with multiple pedunculated colorectal polyps and concomitant rectal adenocarcinoma was admitted to our hospital. His mother had died of colon cancer. He was diagnosed with familial adenomatous polyposis (FAP) and underwent total proctocolectomy and ileal pouch anal anastomosis. Two polyps were selected for pathological examination. One polyp had cystically dilated glands with slight dysplasia. The other polyp displayed severe dysplasia and was diagnosed as adenoma. Three years later, his 21-year-old son underwent a colonoscopy that revealed more than 50 pedunculated colorectal juvenile polyps. Both patients harbored a germline pathogenic mutation in BMPR1A. Endoscopic resection of all polyps was attempted but failed. Finally, the son received endoscopic resection of polyps in the rectum and sigmoid colon, and laparoscopic subtotal colectomy. Ten polyps were selected for pathological examination. All were revealed to be typical juvenile polyps, with cystically dilated glands filled with mucus. Thus, the diagnosis of JPS was confirmed in the son. A review of the literatures revealed that patients with JPS can sometimes have adenomatous change. Most polyps in patients with JPS are benign hamartomatous polyps with no dysplasia. A review of 767 colorectal JPS polyps demonstrated that 8.5% of the polyps contained mild to moderate dysplasia, and only 0.3% had severe dysplasia or cancer. It is difficult to differentiate juvenile polyps with dysplasia from adenoma, which could explain why juvenile polyps have been reported to have adenomatous changes in patients with JPS. Therefore, patients with JPS, especially those with concomitant dysplasia and adenocarcinoma, might be easily diagnosed as FAP in clinical practice. CONCLUSIONS Juvenile polyp with dysplasia is often diagnosed as adenoma, which might lead to the misdiagnosis of JPS as FAP. The differential diagnosis of JPS versus FAP, should be based on comprehensive evaluation of clinical presentation, endoscopic appearance and genetic investigations; not on the presence or absence of adenoma.
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Affiliation(s)
- Xian Hua Gao
- Department of Colorectal Surgery, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China
- Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, Shanghai, China
| | - Juan Li
- Department of Nephrology, Changhai Hospital, Shanghai, China
| | - Zi Ye Zhao
- Department of Colorectal Surgery, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China
- Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, Shanghai, China
| | - Xiao Dong Xu
- Department of Colorectal Surgery, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China
- Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, Shanghai, China
| | - Yi Qi Du
- Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, Shanghai, China
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Hong Li Yan
- Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, Shanghai, China
- Reproductive Medicine Center, Changhai Hospital, Shanghai, China
| | - Lian Jie Liu
- Department of Colorectal Surgery, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China.
| | - Chen Guang Bai
- Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, Shanghai, China.
- Department of Pathology, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China.
| | - Wei Zhang
- Department of Colorectal Surgery, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China.
- Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, Shanghai, China.
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Abstract
BACKGROUND It is known that colorectal cancers (CRC) are frequently seen and constitute an important part of cancer-related deaths. Lynch syndrome (LS) is responsible for 3-5% of CRCs and develops due to mutations in DNA mismatch repair (MMR) genes. The most important MMR genes are MutL homolog1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and postmeiotic segregation increased 2 (PMS2). PMS2 and MSH6 mutations are very rarely seen in LS. CASE PRESENTATION We present a case that developed metastatic CRC, which we diagnosed as LS in association with a very rarely seen PMS2 and MSH6 germline mutation. Genetic counseling was recommended for the family, and screening programs were initiated for the family of the patient whose chemotherapy was continued after the diagnosis. CONCLUSION With the increase in daily use of next-generation sequencing (NGS) technology, it is thought that detection rate of both combined mutations and rare mutations will be increased.
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29
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González-Acosta M, Hinrichsen I, Fernández A, Lázaro C, Pineda M, Plotz G, Capellá G. Validation of an in Vitro Mismatch Repair Assay Used in the Functional Characterization of Mismatch Repair Variants. J Mol Diagn 2019; 22:376-385. [PMID: 31881334 DOI: 10.1016/j.jmoldx.2019.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 09/27/2019] [Accepted: 12/05/2019] [Indexed: 10/25/2022] Open
Abstract
A significant proportion of DNA-mismatch repair (MMR) variants are classified as of unknown significance, precluding diagnosis. The in vitro MMR assay is used to assess their MMR capability, likely the most important function of an MMR protein. However, the robustness of the assay, crucial for its use in the clinical setting, has been rarely evaluated. The aim of the present work was to validate an in vitro MMR assay approach to the functional characterization of MMR variants, as a first step to meeting quality standards of diagnostic laboratories. The MMR assay was optimized by testing a variety of reagents and experimental conditions. Reference materials and standard operating procedures were established. To determine the intra- and interexperimental variability of the assay and its reproducibility among centers, independent transfections of six previously characterized MLH1 variants were performed in two independent laboratories. Reagents and conditions optimal for performing the in vitro MMR assay were determined. The validated assay demonstrated no significant intra- or interexperimental variability and good reproducibility between centers. We set up a robust in vitro MMR assay that can provide relevant in vitro functional evidence for MMR variant pathogenicity assessment, eventually improving the molecular diagnosis of hereditary cancer syndromes associated with MMR deficiency.
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Affiliation(s)
- Maribel González-Acosta
- Hereditary Cancer Program, the Catalan Institute of Oncology (ICO), Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Ciber Oncología (CIBERONC) Instituto Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Inga Hinrichsen
- Biomedical Research Laboratory, Department of Internal Medicine 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Anna Fernández
- Hereditary Cancer Program, the Catalan Institute of Oncology (ICO), Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Ciber Oncología (CIBERONC) Instituto Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Conxi Lázaro
- Hereditary Cancer Program, the Catalan Institute of Oncology (ICO), Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Ciber Oncología (CIBERONC) Instituto Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Marta Pineda
- Hereditary Cancer Program, the Catalan Institute of Oncology (ICO), Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Ciber Oncología (CIBERONC) Instituto Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Guido Plotz
- Biomedical Research Laboratory, Department of Internal Medicine 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Gabriel Capellá
- Hereditary Cancer Program, the Catalan Institute of Oncology (ICO), Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Ciber Oncología (CIBERONC) Instituto Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain.
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30
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Lorca V, Garre P. Current status of the genetic susceptibility in attenuated adenomatous polyposis. World J Gastrointest Oncol 2019; 11:1101-1114. [PMID: 31908716 PMCID: PMC6937445 DOI: 10.4251/wjgo.v11.i12.1101] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 08/18/2019] [Accepted: 10/14/2019] [Indexed: 02/05/2023] Open
Abstract
Adenomatous polyposis (AP) is classified according to cumulative adenoma number in classical AP (CAP) and attenuated AP (AAP). Genetic susceptibility is the major risk factor in CAP due to mutations in the known high predisposition genes APC and MUTYH. However, the contribution of genetic susceptibility to AAP is lower and less understood. New predisposition genes have been recently proposed, and some of them have been validated, but their scarcity hinders accurate risk estimations and prevalence calculations. AAP is a heterogeneous condition in terms of severity, clinical features and heritability. Therefore, clinicians do not have strong discriminating criteria for the recommendation of the genetic study of known predisposition genes, and the detection rate is low. Elucidation and knowledge of new AAP high predisposition genes are of great importance to offer accurate genetic counseling to the patient and family members. This review aims to update the genetic knowledge of AAP, and to expound the difficulties involved in the genetic analysis of a highly heterogeneous condition such as AAP.
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Affiliation(s)
- Víctor Lorca
- Laboratorio de Oncología Molecular, Grupo de Investigación Clínica y Traslacional en Oncología, Hospital Clínico San Carlos, Madrid 28040, Spain
| | - Pilar Garre
- Laboratorio de Oncología Molecular, Servicio de Oncología, Hospital Clínico San Carlos, Madrid 28040, Spain
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31
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Terradas M, Munoz-Torres PM, Belhadj S, Aiza G, Navarro M, Brunet J, Capellá G, Valle L. Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1- and MSH3-associated polyposes. Hum Mutat 2019; 40:1910-1923. [PMID: 31243857 DOI: 10.1002/humu.23853] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 06/12/2019] [Accepted: 06/24/2019] [Indexed: 12/14/2022]
Abstract
Technological advances have allowed the identification of new adenomatous and serrated polyposis genes, and of several candidate genes that require additional supporting evidence of causality. Through an exhaustive literature review and mutational screening of 177 unrelated polyposis patients, we assessed the involvement of MCM9, FOCAD, POLQ, and RNF43 in the predisposition to (nonserrated) colonic polyposis, as well as the prevalence of NTHL1 and MSH3 mutations among genetically unexplained polyposis patients. Our results, together with previously reported data and mutation frequency in controls, indicate that: MCM9 and POLQ mutations are not associated with polyposis; germline RNF43 mutations, with a prevalence of 1.5-2.5% among serrated polyposis patients, do not cause nonserrated polyposis; MSH3 biallelic mutations are highly infrequent among European polyposis patients, and the prevalence of NTHL1 biallelic mutations among unexplained polyposes is ~2%. Although nonsignificant, FOCAD predicted deleterious variants are overrepresented in polyposis patients compared to controls, warranting larger studies to provide definite evidence in favor or against their causal association with polyposis predisposition.
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Affiliation(s)
- Mariona Terradas
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Pau M Munoz-Torres
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Sami Belhadj
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Gemma Aiza
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Matilde Navarro
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain
| | - Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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32
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You YN, Borras E, Chang K, Price BA, Mork M, Chang GJ, Rodriguez-Bigas MA, Bednarski BK, Meric-Bernstam F, Vilar E. Detection of Pathogenic Germline Variants Among Patients With Advanced Colorectal Cancer Undergoing Tumor Genomic Profiling for Precision Medicine. Dis Colon Rectum 2019; 62:429-437. [PMID: 30730459 PMCID: PMC6415928 DOI: 10.1097/dcr.0000000000001322] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Genomic profiling of colorectal cancer aims to identify actionable somatic mutations but can also discover incidental germline findings. OBJECTIVE The purpose of this study was to report the detection of pathogenic germline variants that confer heritable cancer predisposition. DESIGN This was a retrospective study. SETTINGS The study was conducted at a tertiary-referral institution. PATIENTS Between 2012 and 2015, 1000 patients with advanced cancer underwent targeted exome sequencing of a 202-gene panel. The subgroup of 151 patients with advanced colorectal cancer who underwent matched tumor-normal (blood) sequencing formed our study cohort. INTERVENTIONS Germline variants in 46 genes associated with hereditary cancer predisposition were classified according to a defined algorithm based on in silico predictions of pathogenicity. Patients with presumed pathogenic variants were examined for type of mutation, as well as clinical, pedigree, and clinical genetic testing data. MAIN OUTCOME MEASURES We measured detection of pathogenic germline variants. RESULTS A total of 1910 distinct germline variants were observed in 151 patients. After filtering, 15 pathogenic germline variants (9.9%) were found in 15 patients, arising from 9 genes of varying penetrance for colorectal cancer (APC (n = 2; 13%), ATM (n = 1; 6%), BRCA1 (n = 2; 13%), CDH1 (n = 2; 13%), CHEK2 (n = 4; 27%), MSH2 (n = 1; 7%), MSH6 (n = 1; 7%), NF2 (n = 1; 7%), and TP53 (n = 1; 7%)). Patients with pathogenic variants were diagnosed at a younger age than those without (median, 45 vs 52 y; p = 0.03). Of the 15 patients, 7 patients (46.7%) with variants in low/moderate- penetrant genes for colorectal cancer would likely have not been tested based on clinical and pedigree criteria, where 2 harbored clinically actionable variants (CDH1 and NF2, 28.5% of 7). LIMITATIONS This study was limited by its small sample size and advanced-stage patients. CONCLUSIONS Tumor-normal sequencing can incidentally discover clinically unsuspected germline variants that confer cancer predisposition in 9.9% of patients with advanced colorectal cancer. Precision medicine should integrate clinical cancer genetics to inform and interpret the actionability of germline variants and to provide follow-up care to mutation carriers. See Video Abstract at http://links.lww.com/DCR/A906.
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Affiliation(s)
- Y. Nancy You
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ester Borras
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kyle Chang
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Brandee A. Price
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Maureen Mork
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - George J. Chang
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Brian K. Bednarski
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Funda Meric-Bernstam
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
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Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition. Genet Med 2018; 21:1868-1873. [PMID: 30573798 PMCID: PMC6752675 DOI: 10.1038/s41436-018-0405-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 12/03/2018] [Indexed: 12/31/2022] Open
Abstract
PURPOSE Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes. METHODS Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of ~1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. RESULTS Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability. CONCLUSION Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.
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Martin-Morales L, Rofes P, Diaz-Rubio E, Llovet P, Lorca V, Bando I, Perez-Segura P, de la Hoya M, Garre P, Garcia-Barberan V, Caldes T. Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition. PLoS One 2018; 13:e0203885. [PMID: 30256826 PMCID: PMC6157886 DOI: 10.1371/journal.pone.0203885] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/29/2018] [Indexed: 12/12/2022] Open
Abstract
Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening methods. The aim of this study is the use of a Next Generation Sequencing panel in order to find the genes involved in the cancer predisposition of these families. For this study, 98 patients from these unexplained families were tested with a multigene panel targeting 94 genes involved in cancer predisposition. The mutations found were validated by Sanger sequencing and the segregation was studied when possible. We identified 19 likely pathogenic variants in 18 patients. Out of these, 8 were found in MMR genes (5 in MLH1, 1 in MSH6 and 2 in PMS2). In addition, 11 mutations were detected in other genes, including high penetrance genes (APC, SMAD4 and TP53) and moderate penetrance genes (BRIP1, CHEK2, MUTYH, HNF1A and XPC). Mutations c.1194G>A in SMAD4, c.714_720dup in PMS2, c.2050T>G in MLH1 and c.1635_1636del in MSH6 were novel. In conclusion, the detection of new pathogenic mutations in high and moderate penetrance genes could contribute to the explanation of the heritability of colorectal cancer, changing the individual clinical management. Multigene panel testing is a more effective method to identify germline variants in cancer patients compared to single-gene approaches and should be therefore included in clinical laboratories.
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Affiliation(s)
- Lorena Martin-Morales
- Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
- CIBERONC (Centro de Investigacion Biomedica en Red de Cancer), Carlos III Health Institute, Madrid, Spain
| | - Paula Rofes
- Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
| | - Eduardo Diaz-Rubio
- CIBERONC (Centro de Investigacion Biomedica en Red de Cancer), Carlos III Health Institute, Madrid, Spain
- Medical Oncology, Hospital Clinico San Carlos, Madrid, Spain
| | - Patricia Llovet
- Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
- CIBERONC (Centro de Investigacion Biomedica en Red de Cancer), Carlos III Health Institute, Madrid, Spain
| | - Victor Lorca
- Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
| | - Inmaculada Bando
- Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
- CIBERONC (Centro de Investigacion Biomedica en Red de Cancer), Carlos III Health Institute, Madrid, Spain
| | | | - Miguel de la Hoya
- Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
- CIBERONC (Centro de Investigacion Biomedica en Red de Cancer), Carlos III Health Institute, Madrid, Spain
| | - Pilar Garre
- Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
- CIBERONC (Centro de Investigacion Biomedica en Red de Cancer), Carlos III Health Institute, Madrid, Spain
| | - Vanesa Garcia-Barberan
- Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
- CIBERONC (Centro de Investigacion Biomedica en Red de Cancer), Carlos III Health Institute, Madrid, Spain
| | - Trinidad Caldes
- Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
- CIBERONC (Centro de Investigacion Biomedica en Red de Cancer), Carlos III Health Institute, Madrid, Spain
- * E-mail:
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Henriksson I, Henriksson K, Ehrencrona H, Gebre-Medhin S. Hereditary colorectal cancer diagnostics in southern Sweden: retrospective evaluation and future considerations with emphasis on Lynch syndrome. J Community Genet 2018; 10:259-266. [PMID: 30251116 PMCID: PMC6435770 DOI: 10.1007/s12687-018-0385-1] [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: 12/19/2017] [Accepted: 08/31/2018] [Indexed: 01/16/2023] Open
Abstract
Overlapping phenotypes between different hereditary colorectal cancer (CRC) syndromes together with a growing demand for cancer genetic testing and improved sequencing technology call for adjusted patient selection and adapted diagnostic routines. Here we present a retrospective evaluation of family history of cancer, laboratory diagnostic procedure, and outcome for 372 patients tested for Lynch syndrome (LS), i.e., the single most common hereditary cause of CRC. Based on number of affected family members and age at cancer diagnosis in families with genetically confirmed LS, we developed local patient selection criteria for a simplified one-step gene panel mutation screening strategy targeting also less common Mendelian CRC syndromes. Pros and cons of this strategy are discussed.
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Affiliation(s)
- Isabelle Henriksson
- Department of Clinical Genetics and Pathology, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden
| | - Karin Henriksson
- Department of Clinical Genetics and Pathology, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden
| | - Hans Ehrencrona
- Department of Clinical Genetics and Pathology, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.,Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Samuel Gebre-Medhin
- Department of Clinical Genetics and Pathology, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden. .,Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. .,Department of Clinical Genetics and Pathology, University Hospital, SE-221 85, Lund, Sweden.
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Abstract
Relatively little is known on the genotype-phenotype correlations between SMAD4 gene mutations, juvenile polyposis of the intestine and Hereditary Hemorrhagic Teleangectasia. We describe a family in which the proband (a 46-year old woman) had massive polyposis of the stomach-leading to surgery-with high-grade dysplasia at histology. Molecular analysis was carried out using Next Generation sequencing techniques with Miseq Illumina Platforms and a minimal coverage of 40 reads. In the proband, the analysis showed the presence of a truncating mutation in the SMAD4 gene (c.1213dupC, a variant previously associated with juvenile polyposis and Hereditary Hemorrhagic Teleangectasia). The same mutation was detected in two other members of the family (father and brother of the proband), who showed massive polypoid involvement of the stomach at gastroscopy. By taking the family history, subtle evidence of Hereditary Teleangectasia was found (nasal bleeding and arterovenous malformations) in the three gene carriers. Colonoscopy showed polyp occurrence in all three affected members with SMAD4 mutation, with prevalence of adenomatous lesions in one (father), of hamartomas in the brother, and of a mix of histological types in the proband. The main features of the family can be summarized as follows: (A) In hereditary juvenile polyposis, lesions of different histology can be detected at colonoscopy; (B) In the gene carriers of SMAD4 mutations, lesions of the stomach require careful surveillance and, when necessary, surgical interventions; (C) Signs and symptoms of Hereditary Hemorrhagic Teleangectasia should be suspected (and searched) in individuals with SMAD4 constitutional mutations.
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Cragun DL, Kechik J, Pal T. Complexities of genetic screening and testing in hereditary colorectal cancer. SEMINARS IN COLON AND RECTAL SURGERY 2018. [DOI: 10.1053/j.scrs.2018.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Abstract
Lynch Syndrome (LS) is the most common dominantly inherited colorectal cancer (CRC) predisposition and is caused by a heterozygous germline defect in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. High microsatellite instability (MSI-H) and loss of MMR protein expression in tumours reflecting a defective MMR are indicators for LS, as well as a positive family history of early onset CRC. MSH2 and MSH6 form a major functional heterodimer, and MSH3 is an alternative binding partner for MSH2. So far, the role of germline MSH3 variants remains unclear, as to our knowledge heterozygous truncating variants are not regarded causative for LS, but were detected in patients with CRC, and recently biallelic MSH3 defects have been identified in two patients with adenomatous polyposis. By gene screening we investigated the role of MSH3 in 11 LS patients with truncating MSH6 germline variants and an unexplained MSH2 protein loss in their corresponding MSI-H tumours. We report the first two LS patients harbouring heterozygous germline variants c.1035del and c.2732T>G in MSH3 coincidentally with truncating variants in MSH6. In the patient with truncating germline variants in MSH3 and MSH6, two additional somatic second hits in both genes abrogate all binding partners for the MSH2 protein which might subsequently be degraded. The clinical relevance of MSH3 germline variants is currently under re-evaluation, and heterozygous MSH3 defects alone do not seem to induce a LS phenotype, but might aggravate the MSH6 phenotype in affected family members.
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Blount J, Prakash A. The changing landscape of Lynch syndrome due to PMS2 mutations. Clin Genet 2018; 94:61-69. [PMID: 29286535 PMCID: PMC5995637 DOI: 10.1111/cge.13205] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 12/12/2017] [Accepted: 12/24/2017] [Indexed: 12/11/2022]
Abstract
DNA repair pathways are essential for cellular survival as our DNA is constantly under assault from both exogenous and endogenous DNA damaging agents. Five major mammalian DNA repair pathways exist within a cell to maintain genomic integrity. Of these, the DNA mismatch repair (MMR) pathway is highly conserved among species and is well documented in bacteria. In humans, the importance of MMR is underscored by the discovery that a single mutation in any 1 of 4 genes within the MMR pathway (MLH1, MSH2, MSH6 and PMS2) results in Lynch syndrome (LS). LS is a autosomal dominant condition that predisposes individuals to a higher incidence of many malignancies including colorectal, endometrial, ovarian, and gastric cancers. In this review, we discuss the role of PMS2 in the MMR pathway, the evolving testing criteria used to identify variants in the PMS2 gene, the LS phenotype as well as the autosomal recessive condition called constitutional mismatch repair deficiency syndrome, and current methods used to elucidate the clinical impact of PMS2 mutations.
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Affiliation(s)
- Jessa Blount
- Mitchell Cancer Institute, The University of South Alabama, 1660 Springhill Avenue, Mobile, AL - 36604
| | - Aishwarya Prakash
- Mitchell Cancer Institute, The University of South Alabama, 1660 Springhill Avenue, Mobile, AL - 36604
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40
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Jia S, Zhang M, Sun Y, Yan H, Zhao F, Li Z, Ji J. A Chinese family affected by lynch syndrome caused by MLH1 mutation. BMC MEDICAL GENETICS 2018; 19:106. [PMID: 29929473 PMCID: PMC6014015 DOI: 10.1186/s12881-018-0605-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 05/15/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Lynch syndrome (LS) is caused by mutations in DNA mismatch repair (MMR) genes, which accounts for 3-5% of colorectal cancer. The risks of several types of cancer are greatly increased among individuals with LS. In this study, 4 members of a Chinese family with a MLH1 pathogenic variant, resulting in colonic carcinoma, was reported. CASE PRESENTATION A 52-year-old colon cancer female was brought to us with a family history of colon cancer. Genetic counseling traced 4 members in her family with colon cancer (mother and 3 siblings including the proband) as well as other cancer types. Next generation sequencing (NGS) with a multiple gene panel including MMR genes showed a germline mutation in MLH1 (c.1852_1854delAAG, p.K618del) in all 3 affected family members and confirmed the diagnosis of Lynch syndrome. In addition, this mutation was also identified in a asymptomatic offspring, who was then recommended to a prophylactic measure against cancer. A personalized health care plan was implemented for monitoring the condition and progression of the affected individuals. CONCLUSION Based on public database searching followed by pedigree verification, p.K618del variant in MLH1 is a pathogenic mutation, which supported the diagnosis of LS. This case highlights the importance of diagnosis and management in patients with hereditary cancer syndromes, particularly for asymptomatic family members.
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Affiliation(s)
- Shuqin Jia
- Center for Molecular Diagnostics, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing, 100142 China
| | - Meng Zhang
- Center for Molecular Diagnostics, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing, 100142 China
| | - Yu Sun
- Department of Pathology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Hai Yan
- Center for Molecular Diagnostics, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing, 100142 China
- Department of Pathology, Duke University Medical Center, Durham, NC USA
| | | | - Ziyu Li
- Department of Gastrointestinal Surgery, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing, 100142 China
| | - Jiafu Ji
- Center for Molecular Diagnostics, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing, 100142 China
- Department of Gastrointestinal Surgery, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing, 100142 China
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Taylor A, Brady AF, Frayling IM, Hanson H, Tischkowitz M, Turnbull C, Side L. Consensus for genes to be included on cancer panel tests offered by UK genetics services: guidelines of the UK Cancer Genetics Group. J Med Genet 2018; 55:372-377. [PMID: 29661970 PMCID: PMC5992364 DOI: 10.1136/jmedgenet-2017-105188] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 03/02/2018] [Accepted: 03/05/2018] [Indexed: 01/26/2023]
Abstract
Genetic testing for hereditary cancer predisposition has evolved rapidly in recent years with the discovery of new genes, but there is much debate over the clinical utility of testing genes for which there are currently limited data regarding the degree of associated cancer risk. To address the discrepancies that have arisen in the provision of these tests across the UK, the UK Cancer Genetics Group facilitated a 1-day workshop with representation from the majority of National Health Service (NHS) clinical genetics services. Using a preworkshop survey followed by focused discussion of genes without prior majority agreement for inclusion, we achieved consensus for panels of cancer genes with sufficient evidence for clinical utility, to be adopted by all NHS genetics services. To support consistency in the delivery of these tests and advice given to families across the country, we also developed management proposals for individuals who are found to have pathogenic mutations in these genes. However, we fully acknowledge that the decision regarding what test is most appropriate for an individual family rests with the clinician, and will depend on factors including specific phenotypic features and the family structure.
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Affiliation(s)
- Amy Taylor
- East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Angela F Brady
- North West Thames Regional Genetics Service, Northwick Park and St Mark's Hospitals, Harrow, UK
| | - Ian M Frayling
- All Wales Medical Genetics Service, Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.,Institute of Cancer & Genetics, Cardiff University, Cardiff, UK
| | - Helen Hanson
- South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Marc Tischkowitz
- East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.,Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Clare Turnbull
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.,South East Thames Regional Genetics Service, Guys and St Thomas NHS Foundation Trust, London, UK.,William Harvey Research Institute, Queen Mary University, London, UK
| | - Lucy Side
- Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
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Xue L, Williamson A, Gaines S, Andolfi C, Paul-Olson T, Neerukonda A, Steinhagen E, Smith R, Cannon LM, Polite B, Umanskiy K, Hyman N. An Update on Colorectal Cancer. Curr Probl Surg 2018; 55:76-116. [PMID: 29631699 DOI: 10.1067/j.cpsurg.2018.02.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Lai Xue
- Department of Surgery, University of Chicago Medicine, Chicago, IL
| | | | - Sara Gaines
- Department of Surgery, University of Chicago Medicine, Chicago, IL
| | - Ciro Andolfi
- Department of Surgery, University of Chicago Medicine, Chicago, IL
| | - Terrah Paul-Olson
- Department of Surgery, Emory University School of Medicine, Atlanta, GA
| | - Anu Neerukonda
- Department of Medicine, University of Chicago Medicine, Chicago, IL
| | - Emily Steinhagen
- Department of Surgery, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Radhika Smith
- Department of Surgery, University of Chicago Medicine, Chicago, IL
| | - Lisa M Cannon
- Department of Surgery, University of Chicago Medicine, Chicago, IL
| | - Blasé Polite
- Department of Medicine, University of Chicago Medicine, Chicago, IL
| | | | - Neil Hyman
- Department of Surgery, University of Chicago Medicine, Chicago, IL.
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Lorans M, Dow E, Macrae FA, Winship IM, Buchanan DD. Update on Hereditary Colorectal Cancer: Improving the Clinical Utility of Multigene Panel Testing. Clin Colorectal Cancer 2018; 17:e293-e305. [PMID: 29454559 DOI: 10.1016/j.clcc.2018.01.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 12/17/2017] [Accepted: 01/09/2018] [Indexed: 12/30/2022]
Abstract
Colorectal cancer (CRC), one of the most common cancers, is a major public health issue globally, especially in Westernized countries. Up to 35% of CRCs are thought to be due to heritable factors, but currently only 5% to 10% of CRCs are attributable to high-risk mutations in known CRC susceptibility genes, predominantly the mismatch repair genes (Lynch syndrome) and adenomatous polyposis coli gene (APC; familial adenomatous polyposis). In this era of precision medicine, high-risk mutation carriers, when identified, can be offered various risk management options that prevent cancers and improve survival, including risk-reducing medication, screening for early detection, and surgery. The practice of clinical genetics is currently transitioning from phenotype-directed single gene testing to multigene panels, now offered by numerous providers. For CRC, the genes included across these panels vary, ranging from well established, clinically actionable susceptibility genes with quantified magnitude of risk, to genes that lack extensive validation or have less evidence of association with CRC and, therefore, have minimal clinical utility. The current lack of consensus regarding inclusion of genes in CRC panels presents challenges in patient counseling and management, particularly when a variant in a less validated gene is identified. Furthermore, there remain considerable challenges regarding variant interpretation even for the well established CRC susceptibility genes. Ironically though, only through more widespread testing and the accumulation of large international data sets will sufficient information be generated to (i) enable well powered studies to determine if a gene is associated with CRC susceptibility, (ii) to develop better models for variant interpretation and (iii) to facilitate clinical translation.
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Affiliation(s)
- Marie Lorans
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Eryn Dow
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Finlay A Macrae
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia; Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Ingrid M Winship
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia; Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Victoria, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
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Nyqvist J, Persson F, Parris TZ, Helou K, Kenne Sarenmalm E, Einbeigi Z, Borg Å, Karlsson P, Kovács A. Metachronous and Synchronous Occurrence of 5 Primary Malignancies in a Female Patient between 1997 and 2013: A Case Report with Germline and Somatic Genetic Analysis. Case Rep Oncol 2017; 10:1006-1012. [PMID: 29279706 PMCID: PMC5731098 DOI: 10.1159/000484403] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 10/18/2017] [Indexed: 12/15/2022] Open
Abstract
The number of patients with multiple primary malignancies has been increasing steadily in recent years. In the present study, we describe a unique case of an 81-year-old woman with 5 metachronous and synchronous primary malignant neoplasms. The patient was first diagnosed with an endometrium adenocarcinoma in 1997 and a colon adenocarcinoma in 2002. Eleven years after her colon surgery, in 2013, the patient presented with 3 other primary malignancies within a 4-month time span: an invasive malignant melanoma on the lower leg, an invasive mucinous breast carcinoma in the right breast, and a pleomorphic spindle cell sarcoma on the left upper arm. Subsequent routine medical checkups in 2013–2017 revealed no metastases of the primary malignancies. The patient mentioned a familial aggregation of malignant tumors, including 2 sisters with breast cancer and a brother with lung cancer. Interestingly, next-generation sequencing analysis of the patient's blood sample detected no mutations in the BRCA1, BRCA2, TP53, PTEN, CDH1, PALB2, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, STK11, BMPR1A, SMAD4, PTEN, POLE, POLD1, GREM1, and GALNT12 genes. Therefore, whole genome sequencing is warranted to identify cancer-related genetic alterations in this patient with quintuple primary malignancies.
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Affiliation(s)
- Jenny Nyqvist
- Department of Surgery, Skaraborgs Hospital, Lidköping and Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Fredrik Persson
- Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Toshima Z Parris
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Khalil Helou
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | | | - Zakaria Einbeigi
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Åke Borg
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Per Karlsson
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Anikó Kovács
- Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
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Basso G, Bianchi P, Malesci A, Laghi L. Hereditary or sporadic polyposis syndromes. Best Pract Res Clin Gastroenterol 2017; 31:409-417. [PMID: 28842050 DOI: 10.1016/j.bpg.2017.05.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 05/31/2017] [Indexed: 01/31/2023]
Abstract
Polyposis syndromes are encountered in endoscopy practice, and are considered rare entities, accounting for ≤1% of colorectal cancer. Polyposis can occur within inherited syndromes or as "sporadic" cases of unknown etiology. Their proper characterization is relevant for patient management, and should nowadays drive appropriate genetic tests which have a key role in clinical practice for driving surveillance and colorectal cancer prevention, enlarged to relatives. Polyposis classification is based upon polyp number and histology, familial and personal history. This review will explore the polyposis nosology and their genetic determinants in the emerging scenario of Next Generation Sequencing which allow testing multiples genes in parallel. This capability will likely continue to increase the range of polyposis predisposing genes, contributing to define new clinical entities.
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Affiliation(s)
- Gianluca Basso
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (Milan), Italy
| | - Paolo Bianchi
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (Milan), Italy
| | - Alberto Malesci
- Department of Biotechnologies and Translational Medicine, University of Milan, Via Vanvitelli 32, 20133 Milan, Italy; Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (Milan), Italy
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (Milan), Italy; Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (Milan), Italy; Hereditary Cancer Genetics Clinic, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (Milan), Italy.
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