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

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.

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Frequency of replication errors in colorectal cancer and their association with family history

Gut ◽

10.1136/gut.43.4.553 ◽

1998 ◽

Vol 43 (4) ◽

pp. 553-557 ◽

Cited By ~ 6

Author(s):

S R Brown ◽

P J Finan ◽

L Cawkwell ◽

P Quirke ◽

D T Bishop

Keyword(s):

Colorectal Cancer ◽

Family History ◽

Mutation Status ◽

Replication Errors ◽

Cancer Group ◽

Amsterdam Criteria ◽

History Of ◽

Regional Population ◽

Colorectal Cancer Patients

Background—Replication errors (RERs) characterise tumours of hereditary non-polyposis colorectal cancer (HNPCC). RER status may therefore improve identification of such families previously diagnosed by family history alone.Aims—To assess RER and HNPCC frequency within a population of colorectal cancer patients and a regional population of family history defined (Amsterdam criteria) HNPCC families.Methods—Family history was assessed by personal interview in a population of 479 patients with colorectal cancer attending one follow up clinic. Seven fluorescently labelled microsatellites were used to investigate RER frequency in colorectal cancers from 89 patients of this population with varying degrees of family history and 20 Amsterdam criteria positive families (four with a known germline mutation, 16 with unknown mutation status) from the regional population.Results—Only four of the follow up population (0.8%) came from families meeting the Amsterdam criteria with only one showing RERs. The frequency of RERs was similar in the early onset cancer group (less than 50 years of age), those with a family history, and those with no family history of colorectal cancer. From the regional population, RERs were identified in 4/4 families with a mutation but only 8/16 families with unknown mutation status.Conclusions—No correlation was seen between RER status and strength of family history except in HNPCC families. Results also indicate that half of the Amsterdam criteria defined families do not exhibit RERs, perhaps suggesting a different mechanism of tumorigenesis.

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Colorectal polyps, diet, alcohol, and family history of colorectal cancer: A case‐control study

Nutrition and Cancer ◽

10.1080/01635589109514137 ◽

1991 ◽

Vol 16 (1) ◽

pp. 25-30 ◽

Cited By ~ 56

Author(s):

Gabriel A. Kune ◽

Susan Kune ◽

Anthony Read ◽

Kenneth MacGowan ◽

Campbell Penfold ◽

...

Keyword(s):

Colorectal Cancer ◽

Family History ◽

Case Control Study ◽

Case Control ◽

Colorectal Polyps ◽

History Of ◽

Control Study

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HNPCC

The Professional Medical Journal ◽

10.29309/tpmj/2011.18.03.2304 ◽

2011 ◽

Vol 18 (03) ◽

pp. 344-349

Author(s):

MUTAHIR A. TUNIO ◽

ALTAF HASHMI ◽

REHAN MOHSIN ◽

Gohar Sultan

Keyword(s):

Colorectal Cancer ◽

Family History ◽

Large Sample Size ◽

Cancer History ◽

Pakistani Population ◽

Amsterdam Criteria ◽

History Of ◽

Cancer Multiple ◽

Colorectal Cancer Patients ◽

Second Degree

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary bowel cancer. Multiple generations are affected with colorectal cancer at relatively young age, between 25 and 45 years. Objective: To investigate the frequency of HNPCC in Pakistani population, due to the high incidence of colorectal cancer in younger Pakistani adults and prevalence of consanguinity in this region conducted this study. Period: November 2008 and January 2010. Methodology: Ninty histopathologically confirmed colorectal cancer patients between 12- 50 years and their families were interviewed using a detailed questionaire. The questions about family history of colorectal cancer, history of other cancers, age at diagnosis and consanguinity were asked. The pedigrees were drawn for all families based on given information. Hospital records were also reviewed to confirm cancers reported in relatives. Amsterdam criteria was used to label a family as HNPCC. Results: Seventeen patients (18.9%) had one or more first or second degree relatives under age 50 years with colorectal cancers suggestive of HNPCC. Another 15 patients (16.7%) had first or second degree relatives with a family history of other extra-colonic cancers including ovarian, breast, endometrium, lung, parotid, brain and bladder cancer. Of these 30 patients (33.3%) reported that their parents were first degree cousins. Conclusions: 1. High frequency of HNPCC is seen in Pakistani population. 2. Higher proportion of colorectal cancer is seen in young Pakistanis. Strong prevalence of consanguineous marriages could be important factors for HNPCC occurrence in Pakistan. Future studies with large sample size along with genetic testing and screening programmes are warranted.

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Mapping psychosocial interventions in familial colorectal cancer: a rapid systematic review

BMC Cancer ◽

10.1186/s12885-021-09086-8 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Andrada Ciucă ◽

Ramona Moldovan ◽

Adriana Băban

Keyword(s):

Colorectal Cancer ◽

Family History ◽

Genetic Counselling ◽

Psychosocial Interventions ◽

Rapid Review ◽

Familial Colorectal Cancer ◽

Genetic Syndrome ◽

History Of ◽

Behavioural Aspects ◽

The Impact

Abstract Background Approximately 5% of colorectal cancer (CRC) cases are part of a well-defined inherited genetic syndrome and up to approximately 30% of these cases have a clinically defined familial basis. Psychosocial interventions in familial colorectal cancer address aspects mainly focused on affective, cognitive and behavioural outcomes. The present review aims to systematically map out the available psychosocial interventions for individuals with a family history of CRC and describe the current state of the research. Methods An extensive electronic search was conducted to investigate the literature published until June 2020. Inclusion criteria consisted of quantitative studies published in English that explored the impact of psychosocial interventions for familial CRC, clearly defined the psychosocial intervention offered and included participants with a family history of CRC. Results The analysis included 52 articles. Genetic counselling, educational interventions, psychological interventions and multimodal interventions were identified across the studies. In terms of diagnoses, Lynch Syndrome, Familial Adenomatous Polyposis, Familial Colorectal Cancer were the main conditions included in the studies. Affective, cognitive, behavioural aspects and quality of life emerged as the most frequently explored outcomes. The studies included individuals with both personal and familial history of CRC or family history alone. Conclusions Our rapid review provides an overview of the literature exploring the impact of psychosocial interventions for familial CRC. The psychosocial interventions identified had an overwhelmingly positive impact across all types of outcomes measured. Genetic counselling appeared to be most beneficial, and this is expected as it is purposively designed to address genetic conditions. Further quantitative analysis of primary empirical research is needed to determine the efficacy and effectiveness of psychosocial interventions as well as the mechanisms through which they exert their effect.

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Broadening Risk Profile in Familial Colorectal Cancer Type X; increased risk for five cancer types in the national Danish cohort

10.21203/rs.2.20266/v1 ◽

2020 ◽

Author(s):

Christina Therkildsen ◽

Maria Rasmussen ◽

Lars Smith-Hansen ◽

Thomas Kallemose ◽

Lars Joachim Lindberg ◽

...

Keyword(s):

Colorectal Cancer ◽

Female Breast Cancer ◽

Hereditary Colorectal Cancer ◽

Cancer Type ◽

Familial Colorectal Cancer ◽

Specific Syndrome ◽

Increased Risk ◽

Cancer Types ◽

Rate Ratios

Abstract Background Familial colorectal cancer type X (FCCTX) is a phenotypically defined subset of hereditary colorectal cancer with unknown and potentially heterogeneous genetic aetiology. Though FCCTX has been characterized as a colorectal cancer-specific syndrome, we aimed to estimate the risk for extra-colorectal cancer in the Danish FCCTX cohort. Methods Through the national hereditary non-polyposis colorectal cancer (HNPCC) register, 213 families fulfilling the Amsterdam I criteria and showing retained mismatch repair (MMR) function were identified. In here, sex and age-specific incidence rate ratios (IRR) were calculated for 30 extra-colorectal cancer types in comparison with the general Danish population. Results In total, 494 extra-colorectal cancers developed with significantly increased risks for the urinary tract, breasts, stomach, pancreas, and eye. The age spans, during which increased risks were observed, were 30-49 years for gastric cancer, 30-69 years for female breast cancer, 50-69 years for ocular melanoma and above age 70 for pancreatic cancer and urothelial cancer. Conclusions These risk estimates suggest an increased risk of several extra-colorectal cancer types, which calls for awareness during genetic counselling and follow-up. The cancers that occur at increased risk may indicate unidentified disease-predisposing genetic variants in this phenotypically defined subset of hereditary colorectal cancer.

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.47 ◽

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.46 ◽

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.

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