Germline testing of patients with personal history of colorectal polyposis by cancer genetics counseling services.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 47-47
Author(s):  
Gideon T Dosunmu ◽  
Cassandra Gurganus ◽  
Veena Krishnan ◽  
Delmer Alfredo Montoya Motino ◽  
Sana Ozair ◽  
...  
Keyword(s):  
Cancer Genetics ◽  
Germline Mutations ◽  
Colorectal Polyps ◽  
Personal History ◽  
Counseling Services ◽  
Polyposis Syndrome ◽  
Hamartomatous Polyps ◽  
Colorectal Polyposis ◽  
History Of ◽  
Germline Testing

47 Background: National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals with >10 adenomatous polyps, ≥2 hamartomatous polyps, or ≥5 serrated polyps proximal to the sigmoid colon have detailed risk assessment and potential genetic testing to rule out polyposis syndrome. Here, we describe germline testing of patients with a personal history of colorectal polyposis by Cancer Genetics Counseling Services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of colorectal polyposis were identified (N=20) and their germline testing results were summarized. Results: The reasons for referral to the Cancer Genetics Counseling Services were personal history of >10 adenomatous polyps (N=13), personal and family history of colorectal polyposis (N=3), personal history of juvenile colorectal polyps (N=3) or personal history of ≥2 hamartomatous polyps (N=1). The median age is 58 years-old (1-84). Ten (50%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 80%, 10% and 10% respectively. In our cohort, 6 out of 20 (30%) patients had a pathogenic germline mutation, 5 (25%) patients had variant of unknown significance (VUS) and 9 (45%) patients had negative testing. Among patients with pathogenic germline mutations, 3 patients had a pathogenic APC mutation (APC c.1659G>A, APC c.2802C>A and APC c.1643dupT) and were diagnosed with Familial Adenomatous Polyposis (FAP). One patient had 2 pathogenic MUTYH mutations (MUTYH c.536A>G and MUTYH c.1187G>A) and was diagnosed with One patient had a pathogenic PTEN c.634+5G>A mutation and was diagnosed with PTEN Hamartoma Tumor Syndrome. Among the 3 patients with a personal history of juvenile colorectal polyps, one patient had a CHEK2 c.190G>A mutation while the other two had negative genetic test results. The VUS mutations in our cohort were MRE11A c.826C>T, BLM c.3478T>C, BRCA2 c.2519T>C, CHEK2 p.V395L and CTNNA1 c.392dupT. Conclusions: In our cohort of patients with personal history of colorectal polyposis, the majority of patients (45%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 30% and 25% of the patients, respectively. FAP Syndrome was the most commonly diagnosed hereditary polyposis syndrome with 3 patients found to have APC germline mutations. Other pathogenic mutations were identified in the MUTYH, PTEN and CHEK2 genes. Patients with MUTYH and PTEN mutations were diagnosed with MAP and PTEN Hamartoma Tumor Syndromes respectively.

The clinical and molecular characteristics of patients with personal history of colorectal cancer evaluated by cancer genetics counseling services.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 46-46
Author(s):  
Veena Krishnan ◽  
Cassandra Gurganus ◽  
Delmer Alfredo Montoya Motino ◽  
Gideon T Dosunmu ◽  
Sana Ozair ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Cancer Genetics ◽  
Germline Mutations ◽  
Personal History ◽  
Molecular Characteristics ◽  
Counseling Services ◽  
Polyposis Syndrome ◽  
History Of ◽  
Germline Testing

46 Background: Genetic susceptibility to colorectal cancer (CRC) include well-defined hereditary syndromes such as Lynch Syndrome, Familial Adenomatous Polyposis syndrome (FAP), MUTYH-Associated Polyposis syndrome (MAP) and other less common syndromes. National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals meeting certain criteria have detailed risk assessment and potential genetic testing. Here, we describe the clinical and molecular characteristics of patients with personal history of CRC evaluated by cancer genetics counseling services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of CRC were identified (N = 52) and their clinical and molecular characteristics were summarized. Results: The median age is 50 years-old (29-82). Thirty-five (67%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 75%, 19% and 6% respectively. The primary tumor location was in the right colon, left colon and rectum in 29%, 37% and 27% of our cohort respectively. In 7%, the primary location of the tumor was not available. In our cohort, 11 out of 52 (21%) patients had a pathogenic germline mutation and 9 patients (17%) had a germline variant of unknown significance (VUS). Among patients with pathogenic germline mutations (N = 11), 4 patients had MSH2 mutations (MSH2 c.1759+1G > A, MSH2 c. 1687dupT, MSH2 c.1861C > T and MSH2 c.811_814delTCTG), 1 patient had a MSH6 mutation (MSH6 c.1012A > T), 1 patient had a PMS2 mutation (PMS2 c.2182_2184delACTinsG), 3 patients had CHEK2 mutations (CHEK2 c.1100delC and CHEK2 c.470T > C (p.I157T)), 2 patients had MUTYH mutations (MUTYH c.1187G > A and MUTYH c.536A > G) and 1 patient had a BRCA2 mutation (BRCA2 c.2808_2811delACAA). One patient had a CHEK2 and a MUTYH mutation. The VUS mutations in our cohort were POLE c.1645T > C, POLE c.5480C > T, c.2999G > A, MLH1 c.1628A > G, CTNNA1 c.503G > A, MSH2 c.128A > G, NBN c.16C > T, ATM c.6537T > G and AXIN2, BRCA1, NTHL1 mutations. Conclusions: In our cohort of patients with personal history of CRC, the majority of patients (62%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 21% and 17% of the patients respectively. Lynch Syndrome was the most commonly diagnosed hereditary CRC syndrome with 6 out of 11 patients found to have MMR germline mutations. Other pathogenic mutations were identified in the CHEK2, MUTYH and BRCA2 genes.

scholarly journals Peutz-Jeghers Type Polyp of the Appendix with Review of Literature

2019 ◽  
Vol 2019 ◽  
pp. 1-4
Author(s):  
Jolanta Jedrzkiewicz ◽  
Keith Quencer ◽  
Anna P. Matynia ◽  
Ellen Morrow ◽  
Maria Pletneva ◽  
...  
Keyword(s):  
Unusual Case ◽  
Review Of Literature ◽  
Hepatitis C Infection ◽  
Muscularis Mucosae ◽  
Polyposis Syndrome ◽  
Hamartomatous Polyps ◽  
Histopathologic Evaluation ◽  
History Of ◽  
Sporadic Cases ◽  
Generation Sequencing

Hamartomatous polyps of Peutz-Jeghers type are strongly associated with Peutz-Jeghers polyposis syndrome and are predominantly encountered in the small intestine. Sporadic cases are uncommonly reported. We report a case of a polyp identified incidentally in the appendix of a patient undergoing diagnostic imaging due to a history of hepatitis C infection. Histopathologic evaluation after appendectomy showed a polyp with bands of muscularis mucosae bundles with arborizing architecture and variable amounts of inspissated mucin, morphologically indistinguishable from Peutz-Jeghers type hamartomatous polyp. A family or personal history of abdominal cancers was not reported by the patient, suggesting a sporadic occurrence. Next generation sequencing revealed only two pathogenic low-level STK11 mutations, presumed to be somatic. In conclusion, this is an unusual case of a sporadic Peutz-Jeghers type polyp occurring in the appendix.

scholarly journals Homozygous Germline APC p.I1307K Variants: A Case Series

2021 ◽  
pp. 1295-1303
Author(s):  
Alexa Rosenblum ◽  
Michelle Springer ◽  
Amanda Eppolito ◽  
Lisen Axell ◽  
Lisa Mohler
Keyword(s):  
Breast Cancer ◽  
Colon Cancer ◽  
Family History ◽  
Cancer Genetics ◽  
Phenotypic Variability ◽  
Case Series ◽  
Personal History ◽  
Ashkenazi Jewish ◽  
Screening And Surveillance ◽  
History Of

Approximately 10% of all colorectal cancer is estimated to be due to an inherited predisposition. Identification of a germline pathogenic variant can aid in treatment, screening, and surveillance and help stratify familial cancer risks based on gene-specific cancer associations. The <i>APC</i> gene contributes to a small percentage of hereditary colon cancer, with most pathogenic <i>APC</i> variants causing familial adenomatous polyposis syndrome. However, one specific variant in <i>APC</i> called p.I1307K, found in approximately 10% of Ashkenazi Jewish individuals, is associated with a moderate risk for colon cancer, but not polyposis. Heterozygous carriers of one p.I1307K variant are well documented in the literature, and guidelines recommend earlier and more frequent colonoscopies. Conversely, reports of homozygous carriers of 2 p.I1307K variants are limited, and guidelines for medical management are lacking. This case series describes 4 homozygous p.I1307K patients of Ashkenazi Jewish ancestry identified in cancer genetics clinics. Case 1 is a 73-year-old pancreatic cancer patient with a family history of melanoma and colon cancer. Case 2 is a 62-year-old patient with a personal history of 4 adenomatous colorectal polyps and a family history of breast, pancreatic, colon, and prostate cancers. Case 3 is a 52-year-old patient with a personal history of early-onset breast cancer and uveal melanoma and a family history of breast, prostate, and stomach cancers. Case 4 is a 70-year-old patient with a personal history of gallbladder adenocarcinoma and a family history of breast cancer. These cases exhibit wide phenotypic variability and contribute to the limited reports of homozygous p.I1307K variant carriers.

Emerging value of multigene panels for germline testing in patients with neuroendocrine tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 226-226
Author(s):  
Julia Whitman ◽  
Brandon Shih ◽  
Amie Blanco ◽  
Salina Chan ◽  
Alan Paciorek ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Cancer Genetics ◽  
Statistical Significance ◽  
Single Gene ◽  
Logistic Models ◽  
Germline Mutations ◽  
Significant Difference ◽  
Multigene Panels ◽  
Over Time ◽  
Germline Testing

226 Background: Neuroendocrine tumors (NETs) are known to be associated with hereditary syndromes stemming from MEN1, VHL, SDH or TSC mutations. Recent data suggest that additional germline mutations may be relevant, implying a role of germline testing with multigene panels. We examined genetic counseling (GC) referral and testing patterns, test results, and their changes over time in NET patients (pts). Methods: Retrospective chart review was conducted in 236 NET pts referred to UCSF Cancer Genetics and Prevention Program 2004-2017. Univariate logistic models were used to assess relationship between binary outcome and covariate. STATA was used for analysis and statistical significance was based on p < 0.05. Results: 139 referred pts (59%) followed up with GC. Pts with >1 family members diagnosed with cancer were more likely to attend GC [OR=2.75, p=0.010]. Among 107 pts tested, small bowel NETs were less associated with testing than pancreatic NETs [OR=0.15, p=0.001]. Single-gene tests were routine until 2015, when panels up to 130 genes became standard. Overall, 31 pts (29% of 107 tested) had a pathogenic/likely pathogenic (P/LP) result. There was no significant difference between single and multi-gene tests in identifying P/LP mutations (likely due to changes in threshold for testing over time), but greater diversity in P/LP mutations was noted with larger panels. Functional tumors showed lower rate of P/LP mutations than non-functional [OR=0.17, p=0.037]. Conclusions: Only 59% of referred pts followed up with GC, suggesting significant barriers to testing exist. Of those tested, 29% harbored a P/LP mutation. Germline mutations not traditionally associated with NETs were identified, highlighting the potential importance of larger panels to detect rare mutations. [Table: see text]

Low likelihood that potential germline findings identified during somatic tumor testing are evaluated: Room for improvement.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13037-e13037
Author(s):  
Heather Wright ◽  
Cuke Melissa ◽  
Edmund Folefac ◽  
Claire F. Verschraegen ◽  
Marie Wood
Keyword(s):  
Genetic Counseling ◽  
Hereditary Cancer ◽  
Retrospective Chart Review ◽  
Germline Mutations ◽  
Cancer Center ◽  
Genomic Testing ◽  
Opportunity Identification ◽  
History Of ◽  
Record Review ◽  
Germline Testing

e13037 Background: Genomic testing, useful for treatment planning, may indicate the presence of a germline mutation. We evaluate the incidence of potentially actionable germline mutations detected via genomic testing and determined rates of follow-up referrals for genetic counseling and germline testing among patients with potential germline mutations. Methods: This was a retrospective chart review of patients who underwent genomic testing at The University of Vermont Cancer Center (UVMCC). Test reports were reviewed for mutations in 24 genes associated with hereditary cancer and recognized as clinically actionable by the American College of Medical Genetics. Medical record review was performed to identify patients referred for genetic counseling and results of germline testing. Results: Between 8/2009 and 9/2016 157 patients underwent genomic testing at UVMCC. Eighty-one percent (127/157) had a mutation in ≥ 1 gene associated with hereditary cancer (range 0-4 mutations per patient), and 46% (73/157) had mutations in more than one gene. Potential germline mutations were most commonly identified in TP53, CDKN2A, RB1, PTEN, STK11 and APC (each with mutations in > 10% of patients). To date only 12% (15/127) of patients with potential germline mutations have been referred for genetic counseling. Two were referred for evaluation of findings seen on genomic testing others being referred for personal or family history of cancer. The majority (11/15) of referred patients have undergone genetic testing with 27% (3/11) having germline mutations identified; 2/3 of which were also identified on genomic testing. Conclusions: Genomic testing can be an important tool for identifying hereditary cancer syndromes. While the majority (81%) of patient’s undergoing genomic testing had mutations genes associated with hereditary cancer, the low rate of referral (12%) for genetic counseling to determine if these are truly germline represents a significant missed opportunity. Identification of germline mutations has implications for both the patient (for treatment and risk of second cancers) and their family. Patients and their providers should be aware of the potential for germline findings when genomic testing is performed.

scholarly journals GREM1 germline mutation screening in Ashkenazi Jewish patients with familial colorectal cancer

2015 ◽  
Vol 97 ◽  
Author(s):  
YAEL LAITMAN ◽  
EMMA JAEGER ◽  
LIOR KATZ ◽  
IAN TOMLINSON ◽  
EITAN FRIEDMAN
Keyword(s):  
Colorectal Cancer ◽  
Founder Mutation ◽  
Mutation Screening ◽  
Colorectal Polyps ◽  
Ashkenazi Jewish ◽  
Polyposis Syndrome ◽  
Familial Colorectal Cancer ◽  
Amsterdam Criteria ◽  
History Of ◽  
Cancer Types

SummaryBackground: A 40 kb ancestral germline duplication upstream of the GREM1 gene was reported in Ashkenazi families with hereditary mixed polyposis syndrome (HMPS). Objective: Assess the contribution of the GREM1 mutation to familial colorectal cancer (CRC) in Ashkenazim. Methods: Jewish Ashkenazi individuals (n = 472 155 males, 317 females) were genotyped for the GREM1 duplication, 194 with CRC, 131 had other cancer types (endometrial, pancreatic and ovarian) that show a syndromic association with CRC, and 147 were cancer-free with a suggestive family history of CRC. Results: One mutation carrier was found who fulfills the Amsterdam criteria for Lynch Syndrome (LS). The prevalence of this mutation amongst LS Ashkenazim is 0·7%. Conclusion: If validated in additional studies it seems rational to recommend to look for the GREM1 founder mutation in Ashkenazi individuals with multiple colorectal polyps and/or fulfill the criteria for LS.

Out of the Whirlwind Reconsidered

2020 ◽  
Vol 53 (2) ◽  
pp. 1-12
Author(s):  
Michael Berkowitz
Keyword(s):  
United States ◽  
The United States ◽  
Personal History ◽  
Historical Writing ◽  
Holocaust Literature ◽  
The Holocaust ◽  
History Of ◽  
Mutual Accountability ◽  
Union College

This article argues that Albert Friedlander’s edited book, Out of the Whirlwind (1968), should be recognised as pathbreaking. Among the first to articulate the idea of ‘Holocaust literature’, it established a body of texts and contextualised these as a way to integrate literature – as well as historical writing, music, art and poetry – as critical to an understanding of the Holocaust. This article also situates Out of the Whirlwind through the personal history of Friedlander and his wife Evelyn, who was a co-creator of the book, his colleagues from Hebrew Union College, and the illustrator, Jacob Landau. It explores the work’s connection to the expansive, humanistic development of progressive Judaism in the United States, Britain and continental Europe. It also underscores Friedlander’s study of Leo Baeck as a means to understand the importance of mutual accountability, not only between Jews, but in Jews’ engagement with the wider world.

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