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López Riquelme I, Martínez García S, Serrano Ordónez A, Martínez Pilar L. Germline mutations predisposing to melanoma and associated malignancies and syndromes: a narrative review. Int J Dermatol 2025; 64:1027-1041. [PMID: 39651613 DOI: 10.1111/ijd.17602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/17/2024] [Accepted: 11/25/2024] [Indexed: 12/11/2024]
Abstract
The pathogenesis of melanoma is influenced by a complex combination of environmental factors and individual genetic susceptibility. Familial melanoma refers to cases where there are two first-degree relatives with a melanoma diagnosis. Less strict definitions include second-degree relatives or even three or more of any degree from the same family, although this is not clearly defined in the literature. The term hereditary melanoma is reserved for sporadic or familial melanomas linked to high-risk genes with high penetrance. The first genes related to melanoma were CDKN2A and CDK4, but recently, other genes, mostly tumor suppressor genes, have been described. Internal malignancies, particularly pancreatic cancer, have also been associated with melanoma. Recent studies suggest that there could be a link between melanoma and other neoplasms and tumor predisposition syndromes. This review presents an updated overview of familial melanoma criteria and genes involved in melanoma pathogenesis, emphasizing their clinicopathological aspects and other associated malignancies.
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Affiliation(s)
- Irene López Riquelme
- Dermatology Department, Hospital Regional Universitario de Málaga, Malaga, Spain
| | | | - Ana Serrano Ordónez
- Dermatology Department, Hospital Regional Universitario de Málaga, Malaga, Spain
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Mohamed G, Munir M, Rai A, Gaddam S. Pancreatic Cancer: Screening and Early Detection. Gastroenterol Clin North Am 2025; 54:205-221. [PMID: 39880528 DOI: 10.1016/j.gtc.2024.09.006] [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: 01/31/2025]
Abstract
Pancreatic cancer, often diagnosed at advanced stages, has poor survival rates. Effective screening aims to detect the disease early, improving outcomes. Current guidelines recommend screening high-risk groups, including those with a family history or genetic predispositions, using methods like endoscopic ultrasound and MRI. The American Gastroenterological Association and other organizations advise annual surveillance for high-risk individuals, typically starting at the age of 50 or 10 years younger than the youngest affected relative. For certain genetic syndromes, such as Peutz-Jeghers syndrome or hereditary pancreatitis, screening may begin as early as the age of 35 to 40 years.
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Affiliation(s)
- Ghada Mohamed
- Department of Internal Medicine, Lahey Hospital & Medical Center, 41 Mall Road, Burlington, MA 01805, USA
| | - Malak Munir
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, ST, Suite 7705, Los Angeles, CA 90048, USA
| | - Amar Rai
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, ST, Suite 7705, Los Angeles, CA 90048, USA
| | - Srinivas Gaddam
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, ST, Suite 7705, Los Angeles, CA 90048, USA.
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Matsubara Y, Nakamura Y, Nakayama Y, Yano T, Ishikawa H, Kumagai H, Umeno J, Uchida K, Jimbo K, Yamamoto T, Ishida H, Suzuki O, Okamoto K, Kakuta F, Koike Y, Kawasaki Y, Sakamoto H. Prevalence and Incidence of Peutz-Jeghers Syndrome and Juvenile Polyposis Syndrome in Japan: A Nationwide Epidemiological Survey in 2022. J Gastroenterol Hepatol 2025; 40:473-481. [PMID: 39623880 DOI: 10.1111/jgh.16839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/17/2024] [Accepted: 11/17/2024] [Indexed: 02/11/2025]
Abstract
BACKGROUND AND AIM Peutz-Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS) are autosomal dominant diseases associated with high cancer risk. In Japan, knowledge about the prevalence and incidence of PJS and JPS is lacking despite being crucial for providing appropriate medical support. We aimed to determine the prevalence and incidence of these diseases. METHODS In 2022, a nationwide questionnaire survey was conducted to determine the number of patients with PJS or JPS by sex and the number of newly confirmed cases from 2019 to 2021. The target facilities included gastroenterology, pediatrics, and pediatric surgery departments, which were stratified into seven classes on the basis of the total number of beds. We randomly selected target facilities using different extraction rates in each class, resulting in 1748/2912 facilities (extraction rate: 60%) as the final sample. We calculated the estimated number of patients using the response and extraction rates. RESULTS A total of 1077 facilities responded to the survey. The estimated numbers of patients with PJS and JPS were 701 (95% confidence interval [CI]: 581-820) and 188 (95% CI: 147-230), respectively. The 3-year period prevalences of PJS and JPS were 0.6/100000 and 0.15/100000, whereas the incidences in 2021 were 0.07/100000 and 0.02/100000, respectively. Male patients constituted 53.5% and 59.6% in the PJS and JPS groups, respectively. CONCLUSIONS We determined the prevalence and incidence of PJS and JPS in Japan for the first time. Further research is needed to obtain more detailed information, including the clinical differences and outcomes in Japan.
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Affiliation(s)
- Yuri Matsubara
- Department of Public Health, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | | | - Yoshiko Nakayama
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomonori Yano
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Hideki Ishikawa
- Department of Molecular-Targeting Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hideki Kumagai
- Department of Pediatrics, Jichi Medical University, Tochigi, Japan
| | - Junji Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keiichi Uchida
- Department of Pediatric Surgery, Mie Prefectural General Medical Center, Yokkaichi, Japan
| | - Keisuke Jimbo
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Toshiki Yamamoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Okihide Suzuki
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Fumihiko Kakuta
- Department of General Pediatrics, Miyagi Children's Hospital, Sendai, Japan
| | - Yuhki Koike
- Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yuko Kawasaki
- College of Nursing Art and Science, University of Hyogo, Akashi, Japan
| | - Hirotsugu Sakamoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
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Rutherford CR, Rives TA, Piecoro DW, Dietrich CS. Malignant STK11 adnexal tumor harboring a somatic mutation in a woman previously diagnosed with mesothelioma, a case report. Gynecol Oncol Rep 2024; 56:101521. [PMID: 39411561 PMCID: PMC11474483 DOI: 10.1016/j.gore.2024.101521] [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: 08/14/2024] [Revised: 09/18/2024] [Accepted: 09/30/2024] [Indexed: 10/19/2024] Open
Abstract
STK11 germline pathogenic variants are typically associated with Peutz-Jeghers syndrome, an autosomal dominant disease characterized by hamartomatous polyps in the gastrointestinal tract, hyperpigmented patches, and increased risk of stomach, colorectal, small bowel, and breast cancers (Beggs et al., 2010). Mutations in this gene have also been identified in skin, pancreatic, testicular, and stromal ovarian cancer (Fagerberg et al., 2014). To date, there have been less than 30 cases of ovarian cancer reported associated with mutated STK11 (Bennett et al., 2021). In this report, we discuss a rare case of a STK11 adnexal tumor in a 39-year-old woman previously diagnosed with malignant mesothelioma. After 33 months with no evidence of disease following cytoreductive surgery with HIPEC and adjuvant chemotherapy, a new retroperitoneal lesion was noted on imaging. After resection, molecular testing indicated an STK11 mutation, and histology was consistent with an STK11 adnexal tumor. A high index of suspicion is required to make the diagnosis of STK11 adnexal tumor due to its non-distinct pathology and IHC staining. Due to the rarity of this neoplasm, analysis of current and future cases of the STK11 adnexal tumor is necessary to understand its pathogenesis, genetic mutational analysis, clinical course, and best treatment options.
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Affiliation(s)
- Christina R. Rutherford
- University of Kentucky College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Taylor A. Rives
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY 40536, USA
| | - Dava W. Piecoro
- Department of Pathology, University of Kentucky, Lexington, KY 40536, USA
| | - Charles S. Dietrich
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY 40536, USA
- Markey Comprehensive Cancer Center, University of Kentucky, Lexington, KY 40536, USA
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Yilmaz M, Bebek O, Colak Y, Türkyılmaz A. Somatic STK11 mosaicism in a Turkish patient with Peutz-Jeghers syndrome. Fam Cancer 2024; 23:641-645. [PMID: 38822937 DOI: 10.1007/s10689-024-00405-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 05/26/2024] [Indexed: 06/03/2024]
Abstract
Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder, caused by germline variants in the serine/threonine kinase 11 (STK11) gene. However, mosaic variants in STK11 gene have been rarely described. A 25-year-old woman diagnosed with PJS due to multiple hamartomatous polyps in the gastrointestinal tract was referred to our clinic. In the molecular diagnosis, the patient was evaluated using the STK11 gene sequence analysis and multiplex ligation-dependent probe amplification (MLPA) method, which suggested no pathogenic variant to account for the clinical picture. Given that the clinical findings of the patient were consistent with those of PJS, the raw data from next-generation sequencing (NGS) were re-examined for mosaicism which led to the detection of a novel mosaic c.920 + 1G > T variant in STK11 gene with a rate of 23% (1860x). Deep read-level NGS was performed on buccal mucosa and polyp samples to determine mosaicism levels in other tissues. Variant frequencies were 29% (710x) and 31% (1301x), respectively. Mosaicism should be considered in cases with clear clinical diagnostic criteria, such as PJS, where the pathogenic variant cannot be detected by sequence analysis and MLPA methods. Identification of mosaicism in these patients is very important as it can have an impact on patient follow-up and genetic counseling for relatives.
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Affiliation(s)
- Mustafa Yilmaz
- Department of Medical Genetics, Faculty of Medicine, Karadeniz Technical University, Ortahisar Trabzon, Trabzon, 61100, Turkey
| | - Ogun Bebek
- Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey
| | - Yavuzhan Colak
- Department of Medical Genetics, Faculty of Medicine, Karadeniz Technical University, Ortahisar Trabzon, Trabzon, 61100, Turkey
| | - Ayberk Türkyılmaz
- Department of Medical Genetics, Faculty of Medicine, Karadeniz Technical University, Ortahisar Trabzon, Trabzon, 61100, Turkey.
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Kocic M, Rasic P, Marusic V, Prokic D, Savic D, Milickovic M, Kitic I, Mijovic T, Sarajlija A. Age-specific causes of upper gastrointestinal bleeding in children. World J Gastroenterol 2023; 29:6095-6110. [PMID: 38186684 PMCID: PMC10768410 DOI: 10.3748/wjg.v29.i47.6095] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 11/05/2023] [Accepted: 12/01/2023] [Indexed: 12/19/2023] Open
Abstract
The etiology of upper gastrointestinal bleeding (UGIB) varies by age, from newborns to adolescents, with some of the causes overlapping between age groups. While particular causes such as vitamin K deficiency and cow's milk protein allergy are limited to specific age groups, occurring only in neonates and infants, others such as erosive esophagitis and gastritis may be identified at all ages. Furthermore, the incidence of UGIB is variable throughout the world and in different hospital settings. In North America and Europe, most UGIBs are non-variceal, associated with erosive esophagitis, gastritis, and gastric and duodenal ulcers. In recent years, the most common causes in some Middle Eastern and Far Eastern countries are becoming similar to those in Western countries. However, variceal bleeding still predominates in certain parts of the world, especially in South Asia. The most severe hemorrhage arises from variceal bleeding, peptic ulceration, and disseminated intravascular coagulation. Hematemesis is a credible indicator of a UGI source of bleeding in the majority of patients. Being familiar with the most likely UGIB causes in specific ages and geographic areas is especially important for adequate orientation in clinical settings, the use of proper diagnostic tests, and rapid initiation of the therapy. The fundamental approach to the management of UGIB includes an immediate assessment of severity, detecting possible causes, and providing hemodynamic stability, followed by early endoscopy. Unusual UGIB causes must always be considered when establishing a diagnosis in the pediatric population because some of them are unique to children. Endoscopic techniques are of significant diagnostic value, and combined with medicaments, may be used for the management of acute bleeding. Finally, surgical treatment is reserved for the most severe bleeding.
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Affiliation(s)
- Marija Kocic
- Department of Gastroenterology, Hepatology and Nutrition, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
| | - Petar Rasic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
| | - Vuk Marusic
- Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Dragan Prokic
- Department of Gastroenterology, Hepatology and Nutrition, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Djordje Savic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Maja Milickovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Ivana Kitic
- Department of Gastroenterology, Hepatology and Nutrition, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Tanja Mijovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
| | - Adrijan Sarajlija
- Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
- Pediatric Day Care Hospital Department, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
- Faculty of Medicine, University of Eastern Sarajevo, Foča 73300, Bosnia and Herzegovina
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Li C, Song W, Xu Y, Guo T, Zhou X, Liu F, Xu Y. A one-stop approach to diagnosing hereditary colorectal cancer in the Chinese population. J Gastroenterol Hepatol 2023; 38:1980-1987. [PMID: 37749864 DOI: 10.1111/jgh.16319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 07/05/2023] [Accepted: 07/22/2023] [Indexed: 09/27/2023]
Abstract
BACKGROUND AND AIM The current procedure for identifying hereditary colorectal cancer (HCRC) is time consuming in clinical practice. This study aimed to develop a time-saving approach to diagnosing HCRC. METHODS A total of 100 suspected HCRC patients were prospectively enrolled (cohort 1) and 116 colorectal cancer patients with DNA mismatch repair-deficient were retrospectively included (cohort 2). Next-generation sequencing (NGS) tests were performed on tumors and matched white blood cells (WBCs) or normal tissues. Using the conventional method upon WBC/normal tissue-based NGS data as a reference, the performance of the ColonCore method using tumor-only-based NGS data in predicting germline variants was explored in cohort 1 and validated in cohort 2. RESULTS In cohort 1, the ColonCore method diagnosed 17 Lynch syndrome (LS) and 14 familial adenomatous polyposis (FAP); and by the conventional method, the cases were 16 and 10, respectively. The ColonCore method showed sensitivities of 100% in diagnosing LS (positive predictive value [PPV] 94.1%) and FAP (PPV 71.4%). Moreover, two of seven patients with multiple adenomas/polyps who did not meet existing clinical criteria for HCRC were predicted to harbor germline variants in APC and MUTYH. Additionally, the sensitivity of the ColonCore method in identifying LS patients from cohort 2 reached 85.7% with a PPV of 85.7%. CONCLUSION The ColonCore method might be an acceptable tool for predicting germline variants associated with HCRC. Our work indicates the essentiality of NGS tests in CRC patients for precision diagnosis and treatment.
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Affiliation(s)
- Cong Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wang Song
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yun Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Tianan Guo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoyan Zhou
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fangqi Liu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ye Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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Stewart J, Fleishman NR, Staggs VS, Thomson M, Stoecklein N, Lawson CE, Washburn MP, Umar S, Attard TM. Small Intestinal Polyp Burden in Pediatric Peutz-Jeghers Syndrome Assessed through Capsule Endoscopy: A Longitudinal Study. CHILDREN (BASEL, SWITZERLAND) 2023; 10:1680. [PMID: 37892343 PMCID: PMC10605554 DOI: 10.3390/children10101680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/22/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023]
Abstract
The management of pediatric Peutz-Jeghers Syndrome (PJS) focuses on the prevention of intussusception complicating small intestinal (SI) polyposis. This hinges on the accurate appraisal of the polyp burden to tailor therapeutic interventions. Video Capsule Endoscopy (VCE) is an established tool to study SI polyps in children, but an in-depth characterization of polyp burden in this population is lacking. Methods: We performed a retrospective longitudinal cross-sectional analysis of VCE studies in pediatric PJS patients at our institution (CMKC) from 2010 to 2020. Demographic, clinical, and VCE findings reported by three reviewers in tandem were accrued. Polyp burden variables were modeled as functions of patient and study characteristics using linear mixed models adjusted for clustering. Results: The cohort included 15 patients. The total small bowel polyp count and largest polyp size clustered under 30 polyps and <20 mm in size. Luminal occlusion correlated closely with the estimated polyp size. Polyp distribution favored proximal (77%) over distal (66%) small bowel involvement. The adjusted largest polyp size was greater in males. Double Balloon Enteroscopy was associated with a decreased polyp burden. Conclusions: The polyp burden in pediatric PJS patients favors the proximal third of the small intestine, with relatively small numbers and a polyp size amenable to resection through enteroscopy. Male gender and older age were related to an increased polyp burden.
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Affiliation(s)
- Jeremy Stewart
- Division of Pediatric Gastroenterology, University of Texas Southwestern Medical Center, Children’s Medical Center, Dallas, TX 75235, USA
| | - Nathan R. Fleishman
- Division of Gastroenterology, Levine Children’s Hospital, Charlotte, NC 28203, USA
| | - Vincent S. Staggs
- Biostatistics and Epidemiology Core, Division of Health Services and Outcomes Research, Children’s Mercy Hospital, Kansas City, MO 64108, USA
| | - Mike Thomson
- Department of Paediatric Gastroenterology, Sheffield Children’s Hospital NHS Foundation Trust, Sheffield University, Sheffield S10 2TH, UK
| | - Nicole Stoecklein
- Division of Gastroenterology, Children’s Mercy Hospital, Kansas City, MO 64108, USA
| | - Caitlin E. Lawson
- Division of Genetics, Children’s Mercy Hospital, Kansas City, MO 64108, USA
| | - Michael P. Washburn
- Department of Cancer Biology, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Shahid Umar
- Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Thomas M. Attard
- Division of Gastroenterology, Children’s Mercy Hospital, Kansas City, MO 64108, USA
- University of Missouri–Kansas City School of Medicine, 2464 Charlotte St, Kansas City, MO 64108, USA
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Balinisteanu I, Panzaru MC, Caba L, Ungureanu MC, Florea A, Grigore AM, Gorduza EV. Cancer Predisposition Syndromes and Thyroid Cancer: Keys for a Short Two-Way Street. Biomedicines 2023; 11:2143. [PMID: 37626640 PMCID: PMC10452453 DOI: 10.3390/biomedicines11082143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/20/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Cancer predisposition syndromes are entities determined especially by germinal pathogenic variants, with most of them autosomal dominantly inherited. The risk of a form of cancer is variable throughout life and affects various organs, including the thyroid. Knowing the heterogeneous clinical picture and the existing genotype-phenotype correlations in some forms of thyroid cancer associated with these syndromes is important for adequate and early management of patients and families. This review synthesizes the current knowledge on genes and proteins involved in cancer predisposition syndromes with thyroid cancer and the phenomena of heterogeneity (locus, allelic, mutational, and clinical).
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Affiliation(s)
- Ioana Balinisteanu
- Endocrinology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.B.); (M.-C.U.)
- Endocrinology Department, “Sf. Spiridon” Hospital, 700106 Iasi, Romania
| | - Monica-Cristina Panzaru
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.F.); (E.V.G.)
| | - Lavinia Caba
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.F.); (E.V.G.)
| | - Maria-Christina Ungureanu
- Endocrinology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.B.); (M.-C.U.)
- Endocrinology Department, “Sf. Spiridon” Hospital, 700106 Iasi, Romania
| | - Andreea Florea
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.F.); (E.V.G.)
| | - Ana Maria Grigore
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.F.); (E.V.G.)
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.F.); (E.V.G.)
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Jiang LX, Chen YR, Xu ZX, Zhang YH, Zhang Z, Yu PF, Dong ZW, Yang HR, Gu GL. Peutz-Jeghers syndrome without STK11 mutation may correlate with less severe clinical manifestations in Chinese patients. World J Gastroenterol 2023; 29:3302-3317. [PMID: 37377590 PMCID: PMC10292148 DOI: 10.3748/wjg.v29.i21.3302] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/06/2023] [Accepted: 05/04/2023] [Indexed: 06/01/2023] Open
Abstract
BACKGROUND Peutz-Jeghers syndrome (PJS) is an autosomal dominant genetic disease with skin mucosal pigment spots and gastrointestinal (GI) multiple hamartoma polyps as clinical characteristics. At present, it is considered that the germline mutation of STK11 gene is the genetic cause of PJS. However, not all PJS patients can be detected STK11 germline mutations. The specific clinical characteristics of these PJS patients without STK11 mutation is an interesting clinical question. Or, like wild type GI stromal tumor, whether these PJS without STK11 mutation are also called PJS is worth discussing. Therefore, we designed the study to understand the clinical characteristics of these PJS patients without STK11 mutation. AIM To investigates whether PJS patients with known STK11 mutations have a more severe spectrum of clinical phenotypes compared to those without. METHODS A total of 92 patients with PJS admitted to the Air Force Medical Center from 2010 to 2022 were randomly selected for study. Genomic DNA samples were extracted from peripheral blood samples, and pathogenic germline mutations of STK11 were detected by high-throughput next-generation gene sequencing. Clinical-pathologic manifestations of patients with and without STK11/LKB1 mutations were compared. RESULTS STK11 germline mutations were observed in 73 patients with PJS. Among 19 patients with no detectable STK11 mutations, six had no pathogenic germline mutations of other genes, while 13 had other genetic mutations. Compared with PJS patients with STK11 mutations, those without tended to be older at the age of initial treatment, age of first intussusception and age of initial surgery. They also had a lower number of total hospitalizations relating to intussusception or intestinal obstruction, and a lower load of small intestine polyps. CONCLUSION PJS patients without STK11 mutations might have less severe clinical-pathologic manifestations than those with.
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Affiliation(s)
- Li-Xin Jiang
- Air Force Clinical College of China Medical University, Beijing 100142, China
| | - Yu-Rui Chen
- Air Force Clinical College of China Medical University, Beijing 100142, China
| | - Zu-Xin Xu
- Fifth Clinical College (Air Force Clinical College) of Anhui Medical University, Beijing 100142, China
| | - Yu-Hui Zhang
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Fifth Clinical (Air Force Clinical College) of China Medical University, Beijing 100142, China
| | - Zhi Zhang
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Fifth Clinical (Air Force Clinical College) of China Medical University, Beijing 100142, China
| | - Peng-Fei Yu
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Fifth Clinical (Air Force Clinical College) of China Medical University, Beijing 100142, China
| | - Zhi-Wei Dong
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Fifth Clinical (Air Force Clinical College) of China Medical University, Beijing 100142, China
| | - Hai-Rui Yang
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Fifth Clinical (Air Force Clinical College) of China Medical University, Beijing 100142, China
| | - Guo-Li Gu
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Fifth Clinical (Air Force Clinical College) of China Medical University, Beijing 100142, China
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11
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Ovechkin D, Awuah WA, Wellington J, Adebusoye FT, Moskalenko R, Dmytruk S, Abdul-Rahman T, Ovechkina Y. Intestinal intussusception in a child with Peutz-Jeghers syndrome: case report. Ann Med Surg (Lond) 2023; 85:2216-2220. [PMID: 37228960 PMCID: PMC10205367 DOI: 10.1097/ms9.0000000000000675] [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: 01/13/2023] [Accepted: 04/02/2023] [Indexed: 05/27/2023] Open
Abstract
Peutz-Jeghers syndrome (PJS), an uncommon inherited autosomal dominant disorder, is distinguished by mucocutaneous pigmentations, many gastrointestinal hamartomatous polyps, and a higher incidence of gastrointestinal tract, genitourinary, and extracolonic malignancies. Recurrent acute intestinal obstruction, in particular intussusception in the young, is a serious sequalae of PJS. Case presentation A clinical observation of a 5-year-old patient with a complicated course of PJS is presented. Emphasis on recurring episodes of acute abdomen, clinical diagnosis including polyp histopathology, and surgical management is emphasised. Clinical findings and investigations While an inpatient, bloodwork demonstrated severe iron deficiency anaemia (haemoglobin 72 g/l, red blood cell 3.1×1012/l) and multiple melanin pigmentations measuring 2-4 mm in size on the lip mucosa during a physical examination. Erosive duodenopathy and polyposis of the stomach were discovered via fibroesophagogastroduodenoscopy (multiple gastric polyps 5-10 mm in size). Acute intussusception of the intestine was discovered by ultrasonography. Interventions and outcome A mid-median laparotomy was performed alongside manual disinvagination with gut viability intact. Histopathology of excised polyps revealed smooth muscle hyperplasia and Ki67 protein (MIB-1) positivity with small intestinal hamartomatous polyps seen macroscopically. Conservative management was initiated for standard postoperative care and intestinal motility. Patient was discharged 9 days postoperatively. Relevance and impact Based on literature data, modern ideas concerning aetiology, diagnosis, and management of patients with PJS are considered. Attention is focused on the high risk of developing cancer of various localisation in PJS, recommendations are given for cancer screening and clinical observation of patients with hereditary gastrointestinal syndromes in childhood.
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Affiliation(s)
| | | | - Jack Wellington
- Cardiff University School of Medicine, Cardiff University, Wales, UK
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12
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Imyanitov EN, Kuligina ES, Sokolenko AP, Suspitsin EN, Yanus GA, Iyevleva AG, Ivantsov AO, Aleksakhina SN. Hereditary cancer syndromes. World J Clin Oncol 2023; 14:40-68. [PMID: 36908677 PMCID: PMC9993141 DOI: 10.5306/wjco.v14.i2.40] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/09/2022] [Accepted: 02/14/2023] [Indexed: 02/21/2023] Open
Abstract
Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity; in addition, there are several dozen less frequent types of familial tumors. The development of the majority albeit not all hereditary malignancies involves two-hit mechanism, i.e. the somatic inactivation of the remaining copy of the affected gene. Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes; however, population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status. Hereditary cancer research initially focused mainly on cancer detection and prevention. Recent studies identified multiple HCS-specific drug vulnerabilities, which translated into the development of highly efficient therapeutic options.
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Affiliation(s)
- Evgeny N Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Ekaterina S Kuligina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Anna P Sokolenko
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Evgeny N Suspitsin
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Grigoriy A Yanus
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Aglaya G Iyevleva
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Alexandr O Ivantsov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Svetlana N Aleksakhina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
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13
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Yu Z, Liu L, Jiang F, Ji Y, Wang X, Liu L. A novel missense mutation of the STK11 gene in a Chinese family with Peutz-Jeghers syndrome. BMC Gastroenterol 2022; 22:536. [PMID: 36550395 PMCID: PMC9784088 DOI: 10.1186/s12876-022-02617-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disease caused by mutations in the Serine-Threonine Kinase 11 (STK11) gene. This study aimed to diagnose a Chinese pedigree with PJS and to expand the spectrum of STK11 variants. METHODS We performed an inductive analysis of clinical features, gastrointestinal endoscopy, radiologic imaging, and pathological findings in a Chinese family with PJS. Whole-exome sequencing (WES), Sanger sequencing, and STK11 protein 3D structure prediction were performed for establishing a molecular diagnosis. RESULTS The proband, her mother, and grandfather presented with pigmentation spots on lips, oral mucosa, and fingers. Her mother and grandfather also had pigmentation spots on face and feet, while her brother had pigmentation spots only on the lower lip. On endoscopy, polyps were discovered in the proband, her mother, and grandfather. A novel heterozygous mutation (c.521A > C) in exon 4 of STK11 was identified in all four patients, leading to a change from histidine to proline in amino acid 174. The variable site p.H174 was highly conserved in different species on multiple sequence alignment analysis. CONCLUSIONS We diagnosed a Chinese pedigree with PJS based on clinical features, gastrointestinal endoscopy, and genetic testing results. Our results expanded the spectrum of STK11 variants, which will be helpful for genetic counseling.
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Affiliation(s)
- Zhen Yu
- grid.27255.370000 0004 1761 1174Department of Pediatrics, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, 250012 Shandong People’s Republic of China
| | - Lin Liu
- grid.27255.370000 0004 1761 1174Shandong Provincial Maternal and Child Health Care Hospital, Shandong University, 238 Jing Shi Dong Road, Jinan, 250012 Shandong People’s Republic of China
| | - Fang Jiang
- grid.27255.370000 0004 1761 1174Department of Pediatrics, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, 250012 Shandong People’s Republic of China
| | - Yimin Ji
- grid.27255.370000 0004 1761 1174Department of Pediatrics, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, 250012 Shandong People’s Republic of China
| | - Xiao Wang
- grid.27255.370000 0004 1761 1174Department of Pediatrics, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, 250012 Shandong People’s Republic of China
| | - Lili Liu
- grid.27255.370000 0004 1761 1174Department of Pediatrics, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, 250012 Shandong People’s Republic of China
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14
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Repaci A, Salituro N, Vicennati V, Monari F, Cavicchi O, de Biase D, Ciarrocchi A, Acquaviva G, De Leo A, Gruppioni E, Pagotto U, Tallini G. Unexpected Widespread Bone Metastases from a BRAF K601N Mutated Follicular Thyroid Carcinoma within a Previously Resected Multinodular Goiter. Endocr Pathol 2022; 33:519-524. [PMID: 34843063 DOI: 10.1007/s12022-021-09698-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/26/2021] [Indexed: 02/05/2023]
Abstract
Follicular thyroid carcinoma (FTC) represents the second most common malignant thyroid neoplasm after papillary carcinoma (PTC). FTC is characterized by the tendency to metastasize to distant sites such as bone and lung. In the last 20 years, the understanding of the molecular pathology of thyroid tumors has greatly improved. Uncommon BRAF non-V600E mutations have been identified and are generally believed to associate with follicular patterned tumors of low malignant potential, particularly non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) (i.e., non-invasive encapsulated follicular variant PTC). We here report for the first time widespread bone metastases from a BRAF K601N mutated follicular tumor.
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Affiliation(s)
- Andrea Repaci
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy.
| | - Nicola Salituro
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Valentina Vicennati
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Fabio Monari
- Radiotherapy Unit, Policlinico Di Sant'Orsola, University of Bologna, Bologna, Italy
| | - Ottavio Cavicchi
- Department of Otolaryngology, Policlinico Di Sant'Orsola, University of Bologna, Bologna, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology (FaBit), Molecular Diagnostic Unit, University of Bologna, Azienda USL Di Bologna, Bologna, Italy
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS Di Reggio Emilia, Reggio Emilia, Italy
| | - Giorgia Acquaviva
- Department of Experimental, Diagnostic and Specialty Medicine, Anatomic Pathology - Molecular Diagnostic Unit, University of Bologna, Azienda USL Di Bologna, Bologna, Italy
| | - Antonio De Leo
- Department of Experimental, Diagnostic and Specialty Medicine, Anatomic Pathology - Molecular Diagnostic Unit, University of Bologna, Azienda USL Di Bologna, Bologna, Italy
| | - Elisa Gruppioni
- Department of Pathology, Azienda Ospedaliero-Universitaria Di Bologna IRCCS Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Uberto Pagotto
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Giovanni Tallini
- Department of Experimental, Diagnostic and Specialty Medicine, Anatomic Pathology - Molecular Diagnostic Unit, University of Bologna, Azienda USL Di Bologna, Bologna, Italy
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15
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Germline Testing for Individuals with Pancreatic Adenocarcinoma and Novel Genetic Risk Factors. Hematol Oncol Clin North Am 2022; 36:943-960. [DOI: 10.1016/j.hoc.2022.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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16
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Wang S, Huang G, Wang JX, Tian L, Zuo XL, Li YQ, Yu YB. Altered Gut Microbiota in Patients With Peutz-Jeghers Syndrome. Front Microbiol 2022; 13:881508. [PMID: 35910641 PMCID: PMC9326469 DOI: 10.3389/fmicb.2022.881508] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/06/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Peutz-Jeghers syndrome (PJS) is a rare genetic disorder characterized by the development of pigmented spots and gastrointestinal polyps and increased susceptibility to cancers. It remains unknown whether gut microbiota dysbiosis is linked to PJS. AIM This study aimed to assess the structure and composition of the gut microbiota, including both bacteria and fungi, in patients with PJS and investigate the relationship between gut microbiota dysbiosis and PJS pathogenesis. METHODS The bacterial and fungal composition of the fecal microbiota was analyzed in 23 patients with PJS (cases), 17 first-degree asymptomatic relatives (ARs), and 24 healthy controls (HCs) using 16S (MiSeq) and ITS2 (pyrosequencing) sequencing for bacteria and fungi, respectively. Differential analyses of the intestinal flora were performed from the phylum to species level. RESULTS Alpha-diversity distributions of bacteria and fungi indicated that the abundance of both taxa differed between PJS cases and controls. However, while the diversity and composition of fecal bacteria in PJS cases were significantly different from those in ARs and HCs, fungal flora was more stable. High-throughput sequencing confirmed the special characteristics and biodiversity of the fecal bacterial and fungal microflora in patients with PJS. They had lower bacterial biodiversity than controls, with a higher frequency of the Proteobacteria phylum, Enterobacteriaceae family, and Escherichia-Shigella genus, and a lower frequency of the Firmicutes phylum and the Lachnospiraceae and Ruminococcaceae families. Of fungi, Candida was significantly higher in PJS cases than in controls. CONCLUSION The findings reported here confirm gut microbiota dysbiosis in patients with PJS. This is the first report on the bacterial and fungal microbiota profile of subjects with PJS, which may be meaningful to provide a structural basis for further research on intestinal microecology in PJS.
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Affiliation(s)
- Sui Wang
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
| | - Gang Huang
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
| | - Jue-Xin Wang
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
| | - Lin Tian
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiu-Li Zuo
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
| | - Yan-Qing Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
| | - Yan-Bo Yu
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China
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17
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Dzung A, Saltari A, Tiso N, Lyck R, Dummer R, Levesque MP. STK11 Prevents Invasion through Signal Transducer and Activator of Transcription 3/5 and FAK Repression in Cutaneous Melanoma. J Invest Dermatol 2022; 142:1171-1182.e10. [PMID: 34757069 DOI: 10.1016/j.jid.2021.09.035] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 08/23/2021] [Accepted: 09/01/2021] [Indexed: 11/18/2022]
Abstract
The STK11/LKB1 is a tumor suppressor involved in metabolism and cell motility. In BRAFV600E melanoma, STK11 is inactivated by extracellular signal‒regulated kinase and RSK, preventing it from binding and activating adenosine monophosphate-activated protein kinase and promoting melanoma cell proliferation. Although STK11 mutations occur in 5‒10% of cutaneous melanoma, few functional studies have been performed. By knocking out STK11 with CRISPR/Cas9 in two human BRAF-mutant melanoma cell lines, we found that STK11 loss reduced the sensitivity to a BRAF inhibitor. More strikingly, STK11 loss led to an increased invasive phenotype in both three-dimensional spheroids and in vivo zebrafish xenograft models. STK11 overexpression consistently reversed the invasive phenotype. Interestingly, STK11 knockout increased invasion also in an NRAS-mutant melanoma cell line. Furthermore, although STK11 was expressed in primary human melanoma tumors, its expression significantly decreased in melanoma metastases, especially in brain metastases. In the STK11-knockout cells, we observed increased activating phosphorylation of signal transducer and activator of transcription 3/5 and FAK. Using inhibitors of signal transducer and activator of transcription 3/5 and FAK, we reversed the invasive phenotype in both BRAF- and NRAS-mutated cells. Our findings confirm an increased invasive phenotype on STK11 inactivation in BRAF- and NRAS-mutant cutaneous melanoma that can be targeted by signal transducer and activator of transcription 3/5 and FAK inhibition.
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Affiliation(s)
- Andreas Dzung
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Annalisa Saltari
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Natascia Tiso
- Laboratory of Developmental Genetics, Department of Biology, University of Padova, Padova, Italy
| | - Ruth Lyck
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Reinhard Dummer
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Mitchell P Levesque
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
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18
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Golmard L, Vasta LM, Duflos V, Corsini C, d’Enghien CD, McMaster ML, Harney LA, Carr AG, Ling A, Dijoud F, Gauthier A, Miettinen M, Cost NG, Gauthier-Villars M, Orbach D, Irtan S, Haouy S, Schultz KAP, Stoppa-Lyonnet D, Coupier I, Stewart DR, Sirvent N. Testicular Sertoli cell tumour and potentially testicular Leydig cell tumour are features of DICER1 syndrome. J Med Genet 2022; 59:346-350. [PMID: 33782093 PMCID: PMC9743800 DOI: 10.1136/jmedgenet-2020-107434] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 12/19/2020] [Accepted: 01/10/2021] [Indexed: 12/14/2022]
Abstract
DICER1 syndrome is a rare paediatric autosomal dominant inherited disorder predisposing to various benign and malignant tumours. It is caused by a germline pathogenic variant in DICER1, and the second hit for tumour development is usually a missense hotspot pathogenic variant in the DICER1 ribonuclease IIIb domain. While DICER1 predisposing variants account for about 60% of ovarian Sertoli-Leydig cell tumours, no DICER1-related testicular stromal tumours have been described. Here we report the first two cases of testicular stromal tumours in children carrying a DICER1 germline pathogenic variant: a case of Sertoli cell tumour and a case of Leydig cell tumour diagnosed at 2 and 12 years of age, respectively. A somatic DICER1 hotspot pathogenic variant was detected in the Sertoli cell tumour. This report extends the spectrum of DICER1-related tumours to include testicular Sertoli cell tumour and potentially testicular Leydig cell tumour. Diagnosis of a testicular Sertoli cell tumour should prompt DICER1 genetic testing so that patients with a DICER1 germline pathogenic variant can benefit from established surveillance guidelines. DICER1 genetic evaluation may be considered for testicular Leydig cell tumour. Our findings suggest that miRNA dysregulation underlies the aetiology of some testicular stromal tumours.
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Affiliation(s)
- Lisa Golmard
- Department of Genetics, Institut Curie, PSL Research University, Paris, France
| | - Lauren M. Vasta
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA,National Capital Consortium, Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Valérie Duflos
- Department of Pediatric oncology, Montpellier University Hospital, Montpellier, France
| | - Carole Corsini
- Department of Oncogenetics, Montpellier University Hospital, Montpellier, France
| | | | - Mary L. McMaster
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | | | | | | | | | - Arnaud Gauthier
- Department of Pathology, Institut Curie, PSL Research University, Paris, France
| | - Markku Miettinen
- National Cancer Institute Laboratory of Pathology, Bethesda, MD, USA
| | - Nicholas G. Cost
- Department of Surgery, Division of Urology, Pediatric Urology and Urologic Oncology, Department of Pediatrics, Section of Hematology and Oncology, Pediatric Oncology, University of Colorado School of Medicine
| | | | - Daniel Orbach
- SIREDO Oncology Center (Care, Innovation and Research for Children and AYA with Cancer), PSL Research University, Institut Curie, Paris, France
| | - Sabine Irtan
- Department of Pediatric surgery, Trousseau hospital, AP-HP, Paris, France
| | - Stéphanie Haouy
- Department of Pediatric oncology, Montpellier University Hospital, Montpellier, France
| | - Kris Ann P. Schultz
- International Pleuropulmonary Blastoma/DICER1 Registry, Children’s Minnesota, Minneapolis, MN, USA,Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, MN, USA,International Ovarian and Testicular Stromal Tumor Registry, Children’s Minnesota, Minneapolis, MN, USA
| | - Dominique Stoppa-Lyonnet
- Department of Genetics, Institut Curie, PSL Research University, Paris, France,Paris University, Paris, France
| | - Isabelle Coupier
- Department of Oncogenetics, Montpellier University Hospital, Montpellier, France
| | - Douglas R. Stewart
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Nicolas Sirvent
- Department of Pediatric oncology, Montpellier University Hospital, Montpellier, France
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19
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Ogawa C, Hirasawa A, Ida N, Nakamura K, Masuyama H. Hereditary gynecologic tumors and precision cancer medicine. J Obstet Gynaecol Res 2022; 48:1076-1090. [PMID: 35229413 DOI: 10.1111/jog.15197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/09/2022] [Indexed: 11/29/2022]
Abstract
Gynecologic cancers are more often caused by genetic factors than other cancers. Genetic testing has become a promising avenue for the prevention, prognosis, and treatment of cancers. This review describes molecular features of gynecologic tumors linked to hereditary syndromes, gives an overview of the current state of clinical management, and clarifies the role of gynecology in the treatment of hereditary tumors. Typical hereditary gynecologic tumors include hereditary breast and ovarian cancer, Lynch syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. Multigene panel testing, which analyzes a preselected subset of genes for genetic variants, has recently become the first-choice test because it can provide more accurate risk assessment than a single test. Furthermore, comprehensive genomic cancer profiling enables personalized cancer treatment and aids in germline findings.
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Affiliation(s)
- Chikako Ogawa
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Akira Hirasawa
- Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Naoyuki Ida
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Keiichiro Nakamura
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hisashi Masuyama
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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20
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Tong T, Fan Q, Shi S, Li Y, Wang Y. Gastric-type mucinous adenocarcinoma of the cervix in a woman with Peutz-Jeghers syndrome: a case report. Acta Chir Belg 2022:1-6. [PMID: 35135434 DOI: 10.1080/00015458.2022.2040110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
BACKGROUND Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by a predisposition to the development of multiple neoplasms. Gastric-type mucinous adenocarcinoma (GAS), a new variant of carcinoma of the cervix according to 2014 WHO classification, is less common compared with squamous cell carcinoma, is more aggressive and has a lower 5-year survival rate compared with the usual-type endocervical adenocarcinoma, and is also unrelated to human papillomavirus (HPV) infection. CASE SUMMARY We herein present the case of a 32-year-old patient with PJS who was diagnosed with GAS of the cervix. The patient was not sexually active and had been diagnosed with PJS at 2 years of age. A tumor ∼6 cm was found on the cervix and was diagnosed as GAS of the cervix of clinical-stage IB3. The patient was treated with intra-arterial chemotherapy for one course, followed by radical surgery and then systematic chemotherapy. CONCLUSION The present case highlights the need for more thorough cancer screening for patients with PJS, as this disorder is rare and is associated with a high risk of malignancies. Young patients with PJS, including those who are not sexually active, who present with watery vaginal discharge or bleeding should be screened for cervical carcinoma, even if the cytological results or HPV tests are negative.
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Affiliation(s)
- Tong Tong
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China; Shanghai Municipal Key Clinical Speciality, Shanghai, China
| | - Qiong Fan
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China; Shanghai Municipal Key Clinical Speciality, Shanghai, China
| | - Shu Shi
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China; Shanghai Municipal Key Clinical Speciality, Shanghai, China
| | - Yuhong Li
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China; Shanghai Municipal Key Clinical Speciality, Shanghai, China
| | - Yudong Wang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China; Shanghai Municipal Key Clinical Speciality, Shanghai, China
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Marmo C, Tortora A, Costamagna G, Nicolò R, Riccioni ME. Risk for Surgery in Patients with Polyposis Syndrome after Therapy by Device-Assisted Enteroscopy (DAE): Long-Term Follow Up. J Clin Med 2022; 11:899. [PMID: 35207172 PMCID: PMC8876636 DOI: 10.3390/jcm11040899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/29/2022] [Accepted: 02/05/2022] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND AND AIM OF THE STUDY Polyposis syndromes such as Peutz-Jeghers (PJ) and familial adenomatous polyposis (FAP) are associated with the growth of small bowel polyps; the risk is approximately 60-90% for PJ and 40-70% for FAP. The primary aim of this study was to evaluate the efficacy of device-assisted enteroscopy (DAE) in the detection and treatment of small bowel polyps to reduce the risk of surgery. The secondary objective was to study complications and mortality. METHODS We conducted a retrospective cohort study by analyzing a structured database. Between September 2006 and October 2019, we observed and followed 42 consecutive patients with polyposis syndromes; they underwent device-assisted enteroscopy and three were excluded from elective surgery after the exam. The endoscopic exams were performed for diagnostic and therapeutic purposes. RESULTS Thirty-nine patients were evaluated with a mean follow up of 6.7 years (±SD 2.7), 79.5% were female with a mean age of 43.8 years (±SD 15.02), and 68 enteroscopies were performed with the removal of 64 polypoid lesions. One bleeding episode occurred after operative enteroscopy, and the need for subsequent surgery occurred in six patients with PJ and in five patients with FAP. The surgical indications in PJ patients were the presence of large polyps (three patients) and three cases of intussusception, one of which was a patient with a polyp in the proximal ileum, not reachable with the scope. One patient with PJ died from pancreatic cancer during follow up. The surgical indications in patients with FAP were the presence of four large polyps with high-grade dysplasia and one ampullary neoplasia recurrence. CONCLUSIONS In PJ patients, the endoscopic treatment of small bowel polyps was safe. During the follow-up period, the patients with successful endoscopic treatment did not need surgery. In FAP patients treated with DAE, none developed cancer.
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Affiliation(s)
- Clelia Marmo
- UOC Endoscopia Digestiva Chirurgica, Fondazione Policlinico Universitario A Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (G.C.); (M.E.R.)
| | - Annalisa Tortora
- UOC Gastroenterologia e Medicina Interna, Fondazione Policlinico Universitario A Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Guido Costamagna
- UOC Endoscopia Digestiva Chirurgica, Fondazione Policlinico Universitario A Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (G.C.); (M.E.R.)
| | - Rebecca Nicolò
- UOC Medicina d’Urgenza e Pronto Soccorso, Fondazione Policlinico Universitario A Gemelli IRCCS, 00168 Rome, Italy;
| | - Maria Elena Riccioni
- UOC Endoscopia Digestiva Chirurgica, Fondazione Policlinico Universitario A Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (G.C.); (M.E.R.)
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22
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Kim JC, Bodmer WF. Genotypic and Phenotypic Characteristics of Hereditary Colorectal Cancer. Ann Coloproctol 2021; 37:368-381. [PMID: 34961301 PMCID: PMC8717071 DOI: 10.3393/ac.2021.00878.0125] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 10/21/2021] [Indexed: 12/20/2022] Open
Abstract
The genomic causes and clinical manifestations of hereditary colorectal cancer (HCRC) might be stratified into 2 groups, namely, familial (FCRC) and a limited sense of HCRC, respectively. Otherwise, FCRC is canonically classified into 2 major categories; Lynch syndrome (LS) or associated spectra and inherited polyposis syndrome. By contrast, despite an increasing body of genotypic and phenotypic traits, some FCRC cannot be clearly differentiated as definitively single type, and the situation has become more complex as additional causative genes have been discovered. This review provides an overview of HCRC, including 6 LS or associated spectra and 8 inherited polyposis syndromes, according to molecular pathogenesis. Variants and newly-identified FCRC are particularly emphasized, including MUTYH (or MYH)-associated polyposis, Muir-Torre syndrome, constitutional mismatch repair deficiency, EPCAM-associated LS, polymerase proofreading-associated polyposis, RNF43- or NTHL1-associated serrated polyposis syndrome, PTEN hamartoma tumor syndrome, and hereditary mixed polyposis syndrome. We also comment on the clinical utility of multigene panel tests, focusing on comprehensive cancer panels that include HCRC. Finally, HCRC surveillance strategies are recommended, based on revised or notable concepts underpinned by competent validation and clinical implications, and favoring major guidelines. As hereditary syndromes are mainly attributable to genomic constitutions of distinctive ancestral groups, an integrative national HCRC registry and guideline is an urgent priority.
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Affiliation(s)
- Jin Cheon Kim
- Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.,Laboratory of Cancer Biology and Genetics, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
| | - Walter F Bodmer
- Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
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Liu BL, Zhou H, Risech M, Ky A, Houldsworth J, Ward SC. Solitary Peutz-Jeghers Type Polyp of Jejunum with Gastric Fundic and Antral Gland Lining Mucosa: A Case Report and Review of Literature. Int J Surg Pathol 2021; 30:539-542. [DOI: 10.1177/10668969211067760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Solitary Peutz-Jeghers type polyps are characterized by a hamartomatous polyp of the gastrointestinal (GI) tract in a patient without mucocutaneous pigmentation, family history of Peutz-Jeghers syndrome, or STK11/LKB1 mutations. Histologically identical to the polyps in Peutz-Jeghers syndrome, these sporadic polyps can arise anywhere along the GI tract, with typical arborizing smooth muscles extending from the muscularis mucosa. While the lining mucosa is generally the same as the organ in which it arises, gastric pyloric and osseous metaplasia have been reported in intestinal polyps in Peutz-Jeghers syndrome. Herein, the authors report the first case of a small intestinal solitary Peutz-Jeghers type polyp with gastric antral and fundic gland lining mucosa. A 43-year-old male was admitted for small bowel obstruction. Diagnostic laparoscopy revealed jejuno-jejunal intussusception with an associated polyp measuring 7.2 cm. Histological examination showed a hamartomatous polyp with arborizing smooth muscle bundles extending from the muscularis mucosae. The polyp was lined by non-dysplastic gastric antral and fundic gland mucosa, and was sharply demarcated from the adjacent non-polypoid intestinal mucosa. Colonoscopy, esophagogastroduodenoscopy and small bowel enteroscopy revealed no additional polyps or masses. Thorough investigation of the patient's family history was negative for Peutz-Jeghers syndrome or mucocutaneous pigmentation. Molecular analysis of the lesion was negative for STK11/LKB1 mutations. A diagnosis of solitary Peutz-Jeghers type polyp of the small bowel with gastric antral and fundic gland mucosal lining was rendered.
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Affiliation(s)
- Bella Lingjia Liu
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Huifang Zhou
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Martina Risech
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Alex Ky
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Jane Houldsworth
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Stephen C. Ward
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
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24
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A Review of Breast Cancer Risk Factors in Adolescents and Young Adults. Cancers (Basel) 2021; 13:cancers13215552. [PMID: 34771713 PMCID: PMC8583289 DOI: 10.3390/cancers13215552] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/29/2021] [Accepted: 11/03/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Cancer diagnosed in patients between the ages of 15 and 39 deserves special consideration. Diagnoses within this cohort of adolescents and young adults include childhood cancers which present at an older age than expected, or an early presentation of cancers that are typically observed in older adults, such as breast cancer. Cancers within this age group are associated with worse disease-free and overall survival rates, and the incidence of these cases are rising. Knowing an individual’s susceptibility to disease can change their clinical management and allow for the risk-testing of relatives. This review discusses the risk factors that contribute to breast cancer in this unique cohort of patients, including inherited genetic risk factors, as well as environmental and lifestyle factors. We also describe risk models that allow clinicians to quantify a patient’s lifetime risk of developing disease. Abstract Cancer in adolescents and young adults (AYAs) deserves special consideration for several reasons. AYA cancers encompass paediatric malignancies that present at an older age than expected, or early-onset of cancers that are typically observed in adults. However, disease diagnosed in the AYA population is distinct to those same cancers which are diagnosed in a paediatric or older adult setting. Worse disease-free and overall survival outcomes are observed in the AYA setting, and the incidence of AYA cancers is increasing. Knowledge of an individual’s underlying cancer predisposition can influence their clinical care and may facilitate early tumour surveillance strategies and cascade testing of at-risk relatives. This information can further influence reproductive decision making. In this review we discuss the risk factors contributing to AYA breast cancer, such as heritable predisposition, environmental, and lifestyle factors. We also describe a number of risk models which incorporate genetic factors that aid clinicians in quantifying an individual’s lifetime risk of disease.
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Ercoskun P, Yuce Kahraman C, Ozkan G, Tatar A. Genetic Characterization of Hereditary Cancer Syndromes Based on Targeted Next-Generation Sequencing. Mol Syndromol 2021; 13:123-131. [DOI: 10.1159/000518927] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 08/06/2021] [Indexed: 11/19/2022] Open
Abstract
A hereditary cancer syndrome is a genetic predisposition to cancer caused by a germline mutation in cancer-related genes. Identifying the disease-causing variant is important for both the patient and relatives at risk in cancer families because this could be a guide in treatment and secondary cancer prevention. In this study, hereditary cancer panel harboring cancer-related genes was performed on MiSeq Illumina NGS system from peripheral blood samples. Sequencing files were fed into a cloud-based data analysis pipeline. Reportable variants were classified according to the American College of Medical Genetics and Genomics guidelines. Three hundred five individuals were included in the study. Different pathogenic/likely pathogenic variants were detected in 75 individuals. The majority of these variants were in the <i>MUTYH</i>, <i>BRCA2</i>, and <i>CHEK2</i> genes. Nine novel pathogenic/likely pathogenic variants were identified in <i>BRCA1</i>, <i>BRCA2</i>, <i>GALNT12</i>, <i>ATM</i>, <i>MLH1</i>, <i>MSH2</i>, <i>APC</i>, and <i>KIT</i> genes. We obtained interesting and novel variants which could be related to hereditary cancer, and this study confirmed that NGS is an indispensable method for the risk assessment in cancer families.
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Buhagiar A, Seria E, Borg M, Borg J, Ayers D. Overview of microRNAs as liquid biopsy biomarkers for colorectal cancer sub-type profiling and chemoresistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:934-945. [PMID: 35582382 PMCID: PMC8992439 DOI: 10.20517/cdr.2021.62] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/01/2021] [Accepted: 09/24/2021] [Indexed: 11/27/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. It has also been demonstrated that over the last ten years the incidence of CRC among younger people below the age of 50 is also increasing. Screening for colorectal cancer is of utmost importance; the rationale behind screening is to target the malignancy and reduce the incidence and mortality of the disease. Diagnostic methods to screen for incidence or relapse are therefore a requisite to detect cancer as early as possible. Scientific findings demonstrate that many deaths are due to lack of screening and therefore early identification will lead to greater survivability. In colorectal cancer, diagnostic tests include liquid biopsy biomarkers. Since the discovery of microRNAs (miRNAs), many studies have demonstrated the relationship between miRNAs and the various sub-types of CRC. Several miRNAs have been identified after analysing serum or plasma samples in patients, and such miRNAs were found to be significantly dysregulated. Such findings place the possibility of miRNAs to be at the epicentre of novel diagnostic techniques for CRC identification and sub-type stratification, including other characteristics associated with CRC development such as patient prognosis. The following review serves to underline the latest findings for miRNAs with such potential for routine diagnostic employment in CRC diagnostics and treatments.
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Affiliation(s)
- Alfred Buhagiar
- Faculty of Medicine and Surgery, University of Malta, Msida 2080, Malta
| | - Elisa Seria
- Centre for Molecular Medicine and Biobanking, University of Malta, Msida 2080, Malta
| | - Miriana Borg
- Faculty of medical sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Joseph Borg
- Faculty of Health Sciences, University of Malta, Msida 2080, Malta
| | - Duncan Ayers
- Centre for Molecular Medicine and Biobanking, University of Malta, Msida 2080, Malta
- Faculty of Biology, Medicine and Health Sciences, The University of Manchester, Manchester M13 9PL, UK
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García Picazo A, López de la Torre B, Vivas A, García FJ, Ferrero E. Minimally Invasive Elective Surgery as a Treatment of Bowel Invagination in a Peutz-Jeghers Syndrome Case. Case Rep Gastroenterol 2021; 15:495-500. [PMID: 34616246 PMCID: PMC8454248 DOI: 10.1159/000512423] [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: 10/06/2020] [Accepted: 10/16/2020] [Indexed: 11/19/2022] Open
Abstract
We present a case of a 24-year-old woman with Peutz-Jeghers syndrome, recurrent colic abdominal pain, and lower gastrointestinal bleed for the last 5 years. Colonoscopy showed hamartomas without any dysplasia. In the enteral magnetic resonance imaging, a distal jejunum and ileum invagination, secondary to hamartomas was detected. The patient was referred to the Surgery Department and despite few symptoms, elective surgery was proposed. By laparoscopic surgery approach, the entire bowel was carefully revised, 3 intussusceptions and bowel volvulus were found, 2 in jejunum and 1 in ileum, causing incomplete obstruction and intestinal dilatation, with a diameter of 6 cm. These intussusception areas were marked with a silk filament, after achieving devolvulation and disinvagination. A 5-cm laparotomy was done, to externalize the entire bowel, to explore it manually, to verify the absence of other lesions, and locate silk points. By longitudinal enterotomies on the antimesenteric intestinal border where silk filaments were located, the polyps were removed through their stalk, and the enterotomies were transversely closed. Postoperative evolution was favorable, starting oral tolerance on the fourth day and being discharged from the hospital on the seventh day. Eight months later, the patient was asymptomatic with a better quality of life.
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Affiliation(s)
- Alberto García Picazo
- General Surgery and Abdominal Organs Transplantation Department, 12th October University Hospital, Complutense University of Madrid, Madrid, Spain
| | - Beatriz López de la Torre
- General Surgery and Abdominal Organs Transplantation Department, 12th October University Hospital, Complutense University of Madrid, Madrid, Spain
| | - Alfredo Vivas
- General Surgery and Abdominal Organs Transplantation Department, 12th October University Hospital, Complutense University of Madrid, Madrid, Spain
| | - Francisco J García
- General Surgery and Abdominal Organs Transplantation Department, 12th October University Hospital, Complutense University of Madrid, Madrid, Spain
| | - Eduardo Ferrero
- General Surgery and Abdominal Organs Transplantation Department, 12th October University Hospital, Complutense University of Madrid, Madrid, Spain
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Zvizdic Z, Milisic E, Ibisevic N, Pasic IS, Vranic S. Appendiceal carcinoid in a pediatric patient with Peutz-Jeghers syndrome: A case report and comprehensive literature review. Medicine (Baltimore) 2021; 100:e27389. [PMID: 34596162 PMCID: PMC8483869 DOI: 10.1097/md.0000000000027389] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/15/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Peutz-Jeghers syndrome (PJS), a rare autosomal dominant disorder, is characterized by mucocutaneous pigmentations, hamartomatous polyps in the gastrointestinal tract, and a high risk of developing various malignancies. To the best of our knowledge, only 1 case of appendiceal carcinoid associated with PJS has been previously reported in the pediatric population. PATIENT CONCERNS We report a 7-year-old girl who was admitted for severe, intermittent abdominal pain and cramps, nausea, and vomiting. Multiple brown melanotic macules on the lips, buccal mucosa, and the tongue were noted. DIAGNOSIS A plain abdominal X-ray in a standing position revealed dilated intestinal loops with multiple air-fluid levels. A computed tomography scan of the abdomen showing a "coffee bean" appearance of the jejunal loop with a transition point to the duodenal loop. Axial-contrast-enhanced computed tomography scan of the abdomen showing dilated jejunum loops, filled with fluid with the swirled appearance of mesentery typical for volvulus. The diagnosis of PJS was based on clinical findings along with the histopathologic confirmation of the hamartomatous polyps. INTERVENTIONS An emergency laparotomy was performed, revealing a jejunojejunal intussusception starting 40 cm from the duodenojejunal flexure. Jejunotomy revealed that a lead-point intussusception was a necrotic hamartomatous polyp. After resecting the involved jejunal necrotic segment, including the polyp, end-to-end jejuno-jejunal anastomosis was performed. Further exploration revealed the presence of a jejunal mass 80 cm from the duodenojejunal flexure identified as another hamartomatous pedunculated polyp. The polyp was resected, and the enterotomy was then closed transversely. The grossly normal appendix was also removed. OUTCOMES Clinical findings along with the histopathologically confirmed hamartomatous polyps were consistent with PJS. An appendiceal carcinoid (well-differentiated neuroendocrine tumor, European Neuroendocrine Tumor Society stage pT2) was incidentally detected during histological examination of the appendix. The patient and parents were counseled accordingly, focusing on active surveillance and control of symptoms. Two additional hamartomatous polyps (gastric and jejunal) were detected endoscopically and resected in the fourth postoperative week. A regular, 1-year follow-up and surveillance revealed no complications or recurrences. LESSONS Unusual neoplasms can occasionally be encountered in well-defined syndromes such as PJS. Therefore, active follow-up and surveillance are mandatory for all patients with PJS.
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Affiliation(s)
- Zlatan Zvizdic
- Clinic of Pediatric Surgery, University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Emir Milisic
- Clinic of Pediatric Surgery, University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Nermina Ibisevic
- Department of Pathology, University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Irmina Sefic Pasic
- Department of Radiology, University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Semir Vranic
- College of Medicine, QU Health, Qatar University, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
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Abstract
STK11 encodes for the protein liver kinase B1, a serine/threonine kinase which is involved in a number of physiological processes including regulation of cellular metabolism, cell polarity and the DNA damage response. It acts as a tumour suppressor via multiple mechanisms, most classically through AMP-activated protein kinase-mediated inhibition of the mammalian target of rapamycin signalling pathway. Germline loss-of-function mutations in STK11 give rise to Peutz-Jeghers syndrome, which is associated with hamartomatous polyps of the gastrointestinal tract, mucocutaneous pigmentation and a substantially increased lifetime risk of many cancers. In the sporadic setting, STK11 mutations are commonly seen in a subset of adenocarcinomas of the lung in addition to a number of other tumours occurring at various sites. Mutations in STK11 have been associated with worse prognoses across a range of malignancies and may be a predictor of poor response to immunotherapy in a subset of lung cancers, though further studies are needed before the presence of STK11 mutations can be implemented as a routine clinical biomarker.
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Affiliation(s)
- Roman E Zyla
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Elan Hahn
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Anatomic Pathology, University Health Network, Toronto, Ontario, Canada
| | - Anjelica Hodgson
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada .,Anatomic Pathology, University Health Network, Toronto, Ontario, Canada
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Lam V, Sachan A, Kumar A. Peutz-Jeghers Syndrome Presented as Jejunojejunal Intussusception. Indian J Surg 2021. [DOI: 10.1007/s12262-021-02947-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Abstract
PURPOSE OF REVIEW Peutz-Jeghers syndrome is a rare, autosomal dominant, hereditary polyposis syndrome defined by gastrointestinal hamartomas and mucocutaneous pigmentations, caused by a germline mutation in the serine/ threonine kinase 11 or liver kinase B1 (STK11/LKB1) genes. Hamartomatous polyps located throughout the gastrointestinal tract can be complicated by bleeding and small bowel intussusception, potentially leading to the need for emergency surgery. Individuals suffering from Peutz-Jeghers syndrome have an increased lifetime risk of various forms of cancer (gastrointestinal, pancreatic, lung, breast, uterine, ovarian and testicular). Surveillance should lead to the prevention of complications and thus a reduction in mortality and morbidity of patients. RECENT FINDINGS A combined approach based on wireless capsule endoscopy, magnetic resonance enterography and device-assisted enteroscopy is effective in reduction of the polyp burden and thus decreasing the risk of bleeding and intussusception. Current guidelines for screening and surveillance are mostly based on expert opinion rather than evidence. SUMMARY Peutz-Jeghers syndrome is an emerging disease that significantly affects the quality of life enjoyed by patients. Despite of all the progress in improved early diagnostics, options for advanced endoscopic therapy and elaborate surveillance, acute and chronic complications decrease the life expectancy of patients suffering from Peutz-Jeghers syndrome.
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Affiliation(s)
- Ilja Tacheci
- 2nd Department of Internal Medicine - Gastroenterology, Charles University, Faculty of Medicine in Hradec Kralove and University Hospital, Hradec Kralove, Czech Republic
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Han SA, Kim SW. BRCA and Breast Cancer-Related High-Penetrance Genes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1187:473-490. [PMID: 33983595 DOI: 10.1007/978-981-32-9620-6_25] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Genetic susceptibility explains 5-10% of all breast cancer cases. High-penetrance breast cancer susceptibility genes deliberate a greater than tenfold relative risk of breast cancer. BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer, and TP53, PTEN, and SKT11 (LKB1) are rarely present. The prevalence of BRCA1 and BRCA2 genetic alterations differ in various ethnic groups. The Korean Hereditary Breast Cancer (KOHBRA) Study, nationwide-scale study, was established to acquire evidence for the accurate risk assessment and management of hereditary breast and ovarian cancer (HBOC) in Korea prospectively since 2007. In this chapter, we review previous research related to hereditary breast cancer and summarize the present concepts and research results centered on the Korean Hereditary Breast Cancer Research at this time.
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Affiliation(s)
- Sang-Ah Han
- Kyung Hee University, School of Medicine, Seoul, South Korea.
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Implications of Splicing Alterations in the Onset and Phenotypic Variability of a Family with Subclinical Manifestation of Peutz-Jeghers Syndrome: Bioinformatic and Molecular Evidence. Int J Mol Sci 2020; 21:ijms21218201. [PMID: 33147782 PMCID: PMC7662643 DOI: 10.3390/ijms21218201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/21/2020] [Accepted: 10/27/2020] [Indexed: 12/11/2022] Open
Abstract
Peutz–Jeghers Syndrome (PJS) is an autosomal dominant pre-cancerous disorder caused in 80–90% of cases by germline mutations in the tumor suppressor gene STK11. We performed a genetic test of the STK11 gene in two Italian young sisters suspected of PJS, since they showed pathognomonic café au lait spots in absence of other symptoms and familiarity. Sequencing of all exons of STK11 gene and other 8 genes, suggested to be involved in hamartomatous syndromes, (PTEN, BMPR1A, SDHB, SDHD, SMAD4, AKT1, ENG, PIK3CA) led to the identification in both the probands of a novel germline silent mutation named c.597 G>A, hitting the last nucleotide of exon 4. Interestingly, genetic testing of the two probands’ parents showed that their unaffected father was carrier of this mutation. Moreover, he carried a second intronic substitution named c.465-51 T>C (rs2075606) which was not inherited by his daughters. We also observed that all the family members carrying the c.597 G>A mutation presented an aberrant splice variant of STK11 mRNA lacking exon 4. Furthermore, in silico analysis of c.465-51 T>C substitution showed that it may activate an Enhancer Splicing Element. Finally, qRT-PCR analysis of STK11 expression levels showed a slight downregulation of the wild type allele in the father and a 2-fold downregulation in the probands compared to the unaffected mother. Our results have led the hypothesis that the c.465-51 T>C intronic variant, which segregates with the wild type allele, could increase the splicing effectiveness of STK11 wild-type allele and compensate the side effect of the c.597 G>A splicing mutation, being responsible for the phenotypic variability observed within this family. This finding highlight the importance of RNA analysis in genetic testing, remarking that silent DNA variant can often be splicing variant involved in disease onset and progression. The identification of these variants has a crucial role to ensure an appropriate follow-up and cancer prevention in at-risk individuals.
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Zhang Z, Duan FX, Gu GL, Yu PF. Mutation analysis of related genes in hamartoma polyp tissue of Peutz-Jeghers syndrome. World J Gastroenterol 2020; 26:1926-1937. [PMID: 32390703 PMCID: PMC7201153 DOI: 10.3748/wjg.v26.i16.1926] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/29/2020] [Accepted: 04/04/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Peutz-Jeghers syndrome (PJS) is a rare disease with clinical manifestations of pigmented spots on the lips, mucous membranes and extremities, scattered gastrointestinal polyps, and susceptibility to tumors. The clinical heterogeneity of PJS is obvious, and the relationship between clinical phenotype and genotype is still unclear. AIM To investigate the mutation status of hereditary colorectal tumor-associated genes in hamartoma polyp tissue of PJS patients and discuss its relationship with the clinicopathological data of PJS. METHODS Twenty patients with PJS were randomly selected for this study and were treated in the Air Force Medical Center (former Air Force General Hospital) PLA between 2008 and 2017. Their hamartoma polyp tissues were used for APC, AXIN2, BMPR1A, EPCAM, MLH1, MLH3, MSH2, MSH6, MUTYH, PMS1, PMS2, PTEN, SMAD4, and LKB1/STK11 gene sequencing using next-generation sequencing technology. The correlations between the sequencing results and clinical pathological data of PJS were analyzed. RESULTS Fourteen types of LKB1/STK11 mutations were detected in 16 cases (80.0%), of which 8 new mutations were found (3 types of frameshift deletion mutations: c.243delG, c.363_364delGA, and c.722delC; 2 types of frameshift insertions: c. 144_145insGCAAG, and c.454_455insC; 3 types of splice site mutations: c.464+1G>T, c.464+1G>A, and c.598-1G>A); 9 cases (45.0%) were found to have 18 types of heterozygous mutations in the remaining 13 genes except LKB1/STK11. Of these, MSH2: c.792+1G>A, MSH6: c.3689C>G, c.4001+13C>CTTAC, PMS1: c.46C>t, and c.922G>A were new mutations. CONCLUSION The genetic mutations in hamartoma polyp tissue of PJS are complex and diverse. Moreover, other gene mutations in PJS hamartoma polyp tissue were observed, with the exception of LKB1/STK11 gene, especially the DNA mismatch repair gene (MMR). Colorectal hamartoma polyps with LKB1/STK11 mutations were larger in diameter than those with other gene mutations.
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Affiliation(s)
- Zhi Zhang
- Air Force Clinical College (Air Force Medical Center) of Anhui Medical University, Beijing 100142, China
| | - Fu-Xiao Duan
- Department of General Surgery, the General Hospital of Northern Theater Command PLA, Shenyang 110016, Liaoning Province, China
| | - Guo-Li Gu
- Department of General Surgery, Air Force Medical Center, PLA, Beijing 100142, China
| | - Peng-Fei Yu
- Department of General Surgery, Air Force Medical Center, PLA, Beijing 100142, China
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Li BR, Sun T, Li J, Zhang YS, Ning SB, Jin XW, Zhu M, Mao GP. Primary experience of small bowel polypectomy with balloon-assisted enteroscopy in young pediatric Peutz-Jeghers syndrome patients. Eur J Pediatr 2020; 179:611-617. [PMID: 31863304 DOI: 10.1007/s00431-019-03534-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 01/13/2023]
Abstract
For Peutz-Jeghers syndrome (PJS) patients, small bowel polyps develop and result in symptoms at an early age. Balloon-assisted enteroscopy (BAE) is verified as a safe and efficient choice to evaluate and remove small intestinal polyps in adult PJS. But the safety of BAE, especially BAE-facilitated polypectomy for young pediatrics, is little known. This prospective study focused on the effectiveness and safety of BAE-facilitated polypectomy in small bowel for young pediatric PJS. PJS patients (aged 0-14 years old) with BAE (including both single-balloon and double-balloon enteroscopies) were included from 1 September 2012 to 30 April 2018. The demographic data, medical history, and details of BAE were recorded. BAE-related complications and symptom relief after BAE were evaluated and compared between the PJS patients aged 5-10 years old (the younger pediatric group) and those aged 11-14 years old (the older pediatric group). A total of 41 pediatric PJS patients (5-14 years old) subjected to 82 BAEs were included. BAE-facilitated polypectomy was performed for 33 children (80.5%), and 242 polyps in small bowel were removed. For 10 (24.4%) patients, one or more giant polyps (maximum diameter larger than 5 cm) were removed. For eight patients, no polypectomy was done as no polyps were observed (six subjects) or not suitable for BAE-facilitated polypectomy (two subjects) because of high risk of perforation. The complication rates of BAE and BAE-facilitated polypectomy were 1.2% (1/82) and 1.8% (1/55), and the symptom relief rate was 70.8% (17/24). Compared with the older pediatric group, the younger pediatric group showed no increased BAE complication rate (0.0% vs. 5.0%, p = 0.488) and a comparable rate of symptom relief after BAE therapy (80.8% vs. 55.6%, p = 0.356).Conclusion: BAE-facilitated polypectomy in young pediatric PJS is safe and effective.What is known:• Small bowel evaluation and prophetic polypectomy are important for pediatric PJS patients to avoid polyp-related intussusception, obstruction, and bleeding.• BAE polypectomy was a recommended intervention for removing small bowel polyps in adult PJS patients.What is new:• BAE-facilitated small bowel polypectomy is safe and effective for young pediatric PJS, even for those aged less than 10 years old.
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Affiliation(s)
- Bai-Rong Li
- Department of Gastroenterology, Air Force Medical Center, The Fourth Military Medical University, PLA, NO.30 Fucheng Road, Beijing, 100023, China
| | - Tao Sun
- Department of Gastroenterology, Air Force Medical Center, The Fourth Military Medical University, PLA, NO.30 Fucheng Road, Beijing, 100023, China
| | - Jing Li
- Department of Gastroenterology, Air Force Medical Center, The Fourth Military Medical University, PLA, NO.30 Fucheng Road, Beijing, 100023, China
| | - Yan-Shuang Zhang
- Department of Gastroenterology, Air Force Medical Center, The Fourth Military Medical University, PLA, NO.30 Fucheng Road, Beijing, 100023, China
| | - Shou-Bin Ning
- Department of Gastroenterology, Air Force Medical Center, The Fourth Military Medical University, PLA, NO.30 Fucheng Road, Beijing, 100023, China.
| | - Xiao-Wei Jin
- Department of Gastroenterology, Air Force Medical Center, The Fourth Military Medical University, PLA, NO.30 Fucheng Road, Beijing, 100023, China
| | - Ming Zhu
- Department of Gastroenterology, Air Force Medical Center, The Fourth Military Medical University, PLA, NO.30 Fucheng Road, Beijing, 100023, China
| | - Gao-Ping Mao
- Department of Gastroenterology, Air Force Medical Center, The Fourth Military Medical University, PLA, NO.30 Fucheng Road, Beijing, 100023, China
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Balsamo F, Cardoso PAS, do Amaral Junior SA, Theodoro TR, de Sousa Gehrke F, da Silva Pinhal MA, Bianco B, Waisberg J. Birt-Hogg-Dubé syndrome with simultaneous hyperplastic polyposis of the gastrointestinal tract: case report and review of the literature. BMC MEDICAL GENETICS 2020; 21:52. [PMID: 32171268 PMCID: PMC7071710 DOI: 10.1186/s12881-020-0991-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 03/04/2020] [Indexed: 12/12/2022]
Abstract
Background Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant genodermatosis characterized by benign growth of the hair follicles, the presence of pulmonary cysts, spontaneous pneumothorax, and bilateral renal tumors that are usually hybrid oncocytic or multifocal chromophobe renal cell carcinoma. The diagnosis is confirmed by the presence of a pathogenic variant in the tumor suppressor folliculin (FLCN) gene mapped at 17p11.2. Although the dermatological lesions typical of BHDS are benign and only cause aesthetic concerns, and the pulmonary manifestations are controllable, the greater tendency of patients with this syndrome to present benign or malignant renal tumors, often bilateral and multifocal, makes the diagnosis of this syndrome important for the prognosis of the patients. The objective was to report the case of a patient with BHDS, without pulmonary manifestations and with hyperplastic polyposis of the gastrointestinal tract, and to perform a literature review. Case presentation A 60-year-old man complained of abdominal pain and diarrhoea for 2 months. Physical examination was normal except for the presence of normochromic papules in the frontal region of the face associated with hyperkeratotic and hyperchromic papules in the dorsal region. The excisional biopsies of the skin lesions indicated trichodiscomas. Esophagogastroduodenoscopy, enteroscopy, and colonoscopy showed the presence of hyperplastic polyps in the stomach, duodenum, jejunum, colon, and rectum. Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen revealed multiple expansive solid lesions in both kidneys, with necrotic and calcified areas. Renal magnetic resonance angiography also showed a solid lesion in the right kidney measuring 5 cm in diameter and another solid lesion in the left kidney measuring 8 cm in diameter, both suggestive of renal angiomyolipoma. CT scans of the skull, chest, and temporal bones were normal. The genetic study revealed the presence of a variant of FLCN in the intron 13. Conclusions To the best of our knowledge, this is the first reported case of BHDS with the simultaneous finding of gastrointestinal hyperplastic polyposis, which may represent a possible phenotypic expression of this syndrome that has not yet been described.
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Affiliation(s)
- Flávia Balsamo
- Section of General Surgery and Gastrointestinal Surgery, Department of Surgery I, Faculdade de Medicina do ABC, Avenida Lauro Gomes, 2000, Santo André/São Paulo, CEP 09060-870, Brazil
| | - Pedro Augusto Soffner Cardoso
- Section of General Surgery and Gastrointestinal Surgery, Department of Surgery I, Faculdade de Medicina do ABC, Avenida Lauro Gomes, 2000, Santo André/São Paulo, CEP 09060-870, Brazil
| | - Sergio Aparecido do Amaral Junior
- Section of General Surgery and Gastrointestinal Surgery, Department of Surgery I, Faculdade de Medicina do ABC, Avenida Lauro Gomes, 2000, Santo André/São Paulo, CEP 09060-870, Brazil
| | - Therésè Rachell Theodoro
- Section of Biochemistry, Department of Morfology and Physiology, Faculdade de Medicina do ABC, Avenida Lauro Gomes, 2000, Santo André/São Paulo, CEP 09060-870, Brazil
| | - Flavia de Sousa Gehrke
- Section of General Surgery and Gastrointestinal Surgery, Department of Surgery I, Faculdade de Medicina do ABC, Avenida Lauro Gomes, 2000, Santo André/São Paulo, CEP 09060-870, Brazil
| | - Maria Aparecida da Silva Pinhal
- Section of Biochemistry, Department of Morfology and Physiology, Faculdade de Medicina do ABC, Avenida Lauro Gomes, 2000, Santo André/São Paulo, CEP 09060-870, Brazil
| | - Bianca Bianco
- Section of Sexual and Reproductive Health and Populational Genetics, Department of Collective Health, Faculdade de Medicina do ABC, Avenida Lauro Gomes, 2000, Santo André/São Paulo, CEP 09060-870, Brazil.
| | - Jaques Waisberg
- Section of General Surgery and Gastrointestinal Surgery, Department of Surgery I, Faculdade de Medicina do ABC, Avenida Lauro Gomes, 2000, Santo André/São Paulo, CEP 09060-870, Brazil
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Lipsa A, Kowtal P, Sarin R. Novel germline STK11 variants and breast cancer phenotype identified in an Indian cohort of Peutz-Jeghers syndrome. Hum Mol Genet 2020; 28:1885-1893. [PMID: 30689838 DOI: 10.1093/hmg/ddz027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 12/17/2018] [Accepted: 01/22/2019] [Indexed: 12/26/2022] Open
Abstract
Peutz-Jeghers syndrome (PJS) caused by germline STK11 variants is a rare autosomal dominant cancer predisposition syndrome characterized by multiple gastrointestinal (GI) hamartomatous polyps, mucocutaneous pigmentation and a high inherited risk of developing GI, breast and other cancers. Despite GI and breast being the two most common PJS-associated cancer sites, the immunohistochemical (IHC) and molecular features of these tumors in carriers of STK11 variant is not known. Detailed phenotyping including tumor IHC and its correlation with comprehensive STK11 genotyping by full gene sequencing followed by large genomic rearrangement analysis was performed in an Indian PJS cohort. A total of 4 distinct STK11 pathogenic or likely pathogenic variants were identified in 10 PJS cases from 7 of the 19 families tested-in 4/5 classical PJS families and 3/14 suspected PJS families. The pathogenic STK11 variant identified was novel in 3/7 families. In addition, four distinct, likely benign variants identified in seven families were also novel. All of the four breast cancer cases in families with STK11 pathogenic variant were estrogen receptor (ER)-positive and Her2-negative. Several novel STK11 variants identified in this Indian PJS cohort highlight the need to study PJS in different populations across the world. This is the first report showing ER positivity in breast cancer in carriers of STK11 variants and needs confirmation in a larger pooled cohort of PJS associated breast cancers. This could help establish the role of chemoprevention or prophylactic oophorectomy in female carriers of STK11 pathogenic variants.
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Affiliation(s)
- Anuja Lipsa
- Sarin Lab, Advanced Centre for Treatment Research and Education in Cancer-Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, India
| | - Pradnya Kowtal
- Sarin Lab, Advanced Centre for Treatment Research and Education in Cancer-Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, India
| | - Rajiv Sarin
- Sarin Lab, Advanced Centre for Treatment Research and Education in Cancer-Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Cancer Genetics Clinic, Tata Memorial Hospital, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, India
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Cai HJ, Wang H, Cao N, Wang W, Sun XX, Huang B. Peutz-Jeghers syndrome with mesenteric fibromatosis: A case report and review of literature. World J Clin Cases 2020; 8:577-586. [PMID: 32110669 PMCID: PMC7031834 DOI: 10.12998/wjcc.v8.i3.577] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 01/07/2020] [Accepted: 01/11/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Peutz-Jeghers syndrome (PJS) and mesenteric fibromatosis (MF) are rare diseases, and PJS accompanying MF has not been previously reported. Here, we report a case of a 36-year-old man with both PJS and MF, who underwent total colectomy and MF surgical excision without regular follow-up. Two years later, he sought treatment for recurrent acute abdominal pain. Emergency computed tomography showed multiple soft tissue masses in the abdominal and pelvic cavity, and adhesions in the small bowel and peritoneum. Partial intestinal resection and excision of the recurrent MF were performed to relieve the symptoms.
CASE SUMMARY A 36-year-old male patient underwent total colectomy for PJS with MF. No regular reexamination was performed after the operation. Two years later, due to intestinal obstruction caused by MF enveloping part of the small intestine and peritoneum, the patient came to our hospital for treatment. Extensive recurrence was observed in the abdomen and pelvic cavity. The MF had invaded the small intestine and could not be relieved intraoperatively. Finally, partial bowel resection, proximal stoma, and intravenous nutrition were performed to maintain life.
CONCLUSION Regular detection is the primary way to prevent deterioration from PJS. Although MF is a benign tumor, it has characteristics of invasive growth and ready recurrence. Therefore, close follow-up of both the history of MF and gastrointestinal surgery are advisable. Early detection and early treatment are the main means of improving patient prognosis.
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Affiliation(s)
- Huai-Jie Cai
- The Fourth Clinical Medicine College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Han Wang
- The Fourth Clinical Medicine College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Nan Cao
- The Fourth Clinical Medicine College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Wei Wang
- The Fourth Clinical Medicine College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Xi-Xi Sun
- The Fourth Clinical Medicine College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Bin Huang
- Department of Ultrasound, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China
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Kastrinos F, Samadder NJ, Burt RW. Use of Family History and Genetic Testing to Determine Risk of Colorectal Cancer. Gastroenterology 2020; 158:389-403. [PMID: 31759928 DOI: 10.1053/j.gastro.2019.11.029] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 11/11/2019] [Accepted: 11/18/2019] [Indexed: 12/20/2022]
Abstract
Approximately 35% of patients with colorectal cancer (CRC) have a family history of the disease attributed to genetic factors, common exposures, or both. Some families with a history of CRC carry genetic variants that cause CRC with high or moderate penetrance, but these account for only 5% to 10% of CRC cases. Most families with a history of CRC and/or adenomas do not carry genetic variants associated with cancer syndromes; this is called common familial CRC. Our understanding of familial predisposition to CRC and cancer syndromes has increased rapidly due to advances in next-generation sequencing technologies. As a result, there has been a shift from genetic testing for specific inherited cancer syndromes based on clinical criteria alone, to simultaneous testing of multiple genes for cancer-associated variants. We summarize current knowledge of common familial CRC, provide an update on syndromes associated with CRC (including the nonpolyposis and polyposis types), and review current recommendations for CRC screening and surveillance. We also provide an approach to genetic evaluation and testing in clinical practice. Determination of CRC risk based on family cancer history and results of genetic testing can provide a personalized approach to cancer screening and prevention, with optimal use of colonoscopy to effectively decrease CRC incidence and mortality.
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Affiliation(s)
- Fay Kastrinos
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York; Division of Digestive and Liver Diseases, Columbia University Irving Medical Center and the Vagelos College of Physicians and Surgeons, New York, New York.
| | - N Jewel Samadder
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona
| | - Randall W Burt
- Department of Gastroenterology, University of Utah, Salt Lake City, Utah; Emeritus Professor of Medicine, University of Utah, Salt Lake City, Utah
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Iwamuro M, Aoyama Y, Suzuki S, Kobayashi S, Toyokawa T, Moritou Y, Hori S, Matsueda K, Yoshioka M, Tanaka T, Okada H. Long-Term Outcome in Patients with a Solitary Peutz-Jeghers Polyp. Gastroenterol Res Pract 2019; 2019:8159072. [PMID: 31582972 PMCID: PMC6754916 DOI: 10.1155/2019/8159072] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 08/07/2019] [Accepted: 08/29/2019] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Clinical characteristics and prognosis of patients with a solitary Peutz-Jeghers polyp (PJP) have not been fully investigated. METHODS Solitary PJP was diagnosed when a single hamartomatous lesion was identified in the gastrointestinal tract of patients without mucocutaneous pigmentation or a family history of Peutz-Jeghers syndrome. We retrospectively reviewed 51 patients (32 men and 19 women) with a solitary PJP and analyzed the sex, age at diagnosis, endoscopic features, and outcomes in this patient group. The STK11/LKB1 germline mutation was not investigated in any of the patients. RESULTS The mean age of the 51 patients was 66.1 years. The polyp was found in the duodenum (N = 10), jejunum (N = 2), cecum (N = 2), transverse colon (N = 5), sigmoid colon (N = 21), or rectum (N = 11). Most of the polyps presented as a pedunculated lesion (N = 40), followed by semipedunculated (N = 9) and sessile (N = 2) morphologies. The mean size of a solitary PJP was 15.6 mm (range: 5 to 33 mm). During a mean endoscopic follow-up period of 4.5 years (range: 0.1 to 16.1 years), no recurrence was identified. Eighteen of the enrolled patients had a history of cancer or concomitant cancer. Five patients died due to non-gastrointestinal-related causes. No additional cancer or death directly related to solitary PJP was observed. CONCLUSIONS Solitary PJPs did not recur in this study. Although examination of the entire gastrointestinal tract using esophagogastroduodenoscopy, enteroscopy, and colonoscopy is desirable to exclude Peutz-Jeghers syndrome, follow-up endoscopy after endoscopic polyp resection may be unnecessary, once the diagnosis of a solitary PJP is made.
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Affiliation(s)
- Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Yuki Aoyama
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Takamatsu 760-8557, Japan
| | - Seiyuu Suzuki
- Department of Gastroenterology, Sumitomo Besshi Hospital, Niihama 792-8543, Japan
| | - Sayo Kobayashi
- Department of Internal Medicine, Fukuyama City Hospital, Fukuyama 721-8511, Japan
| | - Tatsuya Toyokawa
- Department of Gastroenterology, Fukuyama Medical Center, Fukuyama 720-8520, Japan
| | - Yuki Moritou
- Department of Internal Medicine, Hiroshima City Hiroshima Citizens Hospital, Hiroshima 730-8518, Japan
| | - Shinichiro Hori
- Department of Endoscopy, Shikoku Cancer Center, Matsuyama 791-0280, Japan
| | - Kazuhiro Matsueda
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki 710-8602, Japan
| | - Masao Yoshioka
- Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama 700-8511, Japan
| | - Takehiro Tanaka
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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Abstract
Solitary congenital or early apparent pigmented macules are usually without relevance; however, when multiple, extensive or in a patterned arrangement, they are not uncommonly the first sign of an underlying genetic syndrome. The present article gives an overview on the clinical significance of multiple café-au-lait macules, multiple lentigines and pigmentary mosaicism and discusses the differential diagnosis of associated syndromes. Early diagnosis with the essential contribution of the dermatologist is not only important for genetic counseling but can also contribute to avoidance of sometimes life-threatening complications.
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Affiliation(s)
- H Hamm
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Deutschland.
| | - K Emmerich
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Deutschland
| | - J Olk
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Deutschland
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Tatsi C, Faucz FR, Blavakis E, Carneiro BA, Lyssikatos C, Belyavskaya E, Quezado M, Stratakis CA. Somatic PRKAR1A Gene Mutation in a Nonsyndromic Metastatic Large Cell Calcifying Sertoli Cell Tumor. J Endocr Soc 2019; 3:1375-1382. [PMID: 31286102 PMCID: PMC6608558 DOI: 10.1210/js.2019-00022] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 05/06/2019] [Indexed: 12/22/2022] Open
Abstract
Large cell calcifying Sertoli cell tumors (LCCSCTs) are rare testicular tumors, representing <1% of all testicular neoplasms. Almost 40% of patients with LCCSCTs will present in the context of an inherited tumor predisposition condition, such as Carney complex (CNC) or Peutz-Jeghers syndrome. We report the case of a 42-year-old man who had presented with a right testicular mass, and was diagnosed with metastatic LCCSCT. The patient underwent radical orchiectomy, achieving initial remission of his disease. However, lymph node and hepatic metastases were identified. He received chemotherapy without response, and he died of complications of his disease 4 years after the initial diagnosis. Genetic analysis of the tumor and a lymph node metastasis identified a somatic frameshift mutation in the PRKAR1A gene (c.319delG, p.E107fs*22). The mutation was predicted to result in premature termination of the PRKAR1A protein and, thus, not be expressed at the protein level, consistent with other PRKAR1A nonsense mutations. The patient was extensively screened for signs of CNC, but he had no stigmata of the complex. To the best of our knowledge, the present report is the first of a somatic mutation in the PRKAR1A gene shown to be associated with a seemingly sporadic case of LCCSCT. Somatic PRKAR1A mutations are rare in sporadic tumors, and it is unknown whether this mutation was causative of LCCSCT in our patient who did not have CNC, or contributed to the malignancy of the tumor, which might have been caused by additional mutations.
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Affiliation(s)
- Christina Tatsi
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Fabio R Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Emmanouil Blavakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Benedito A Carneiro
- Lifespan Cancer Institute, Division of Hematology/Oncology, Alpert Medical School, Brown University, Providence, Rhode Island
| | - Charalampos Lyssikatos
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Elena Belyavskaya
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Martha Quezado
- Laboratory of Pathology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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Benzel J, Fendrich V. Familial Pancreatic Cancer. Oncol Res Treat 2018; 41:611-618. [PMID: 30269130 DOI: 10.1159/000493473] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 09/04/2018] [Indexed: 12/13/2022]
Abstract
Familial pancreatic cancer accounts for 10% of all patients with pancreatic cancer. Because the 5-year survival rate of pancreatic cancer is only 7%, screening programs for high-risk individuals are essential and might be advantageous. Pancreatic ductal adenocarcinoma mostly shows symptoms at an advanced state and treatment is not efficient enough to cure most patients. People with hereditary tumor syndromes or their affected relatives can also be included in such screening programs. Besides the collection of data to investigate the background of the disease, these screening programs aim to diagnose and treat precursor lesions so that more dangerous, invasive lesions are prevented. These precursor lesions can be pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm. This review summarizes the latest knowledge of pancreatic screening programs, shows the procedure of pancreatic cancer screening, and gives an overview of current guidelines.
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Mahon S. Hereditary Polyposis Syndromes: Opportunities for Early Detection in Individuals and Families. Clin J Oncol Nurs 2018; 22:151-156. [DOI: 10.1188/18.cjon.151-156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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