Risk For Hereditary Colorectal Cancer Research Articles

Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines.

To provide recommendations on prevention, screening, genetics, treatment, and management for people at risk for hereditary colorectal cancer (CRC) syndromes. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. The Familial Risk-Colorectal Cancer: European Society for Medical Oncology Clinical Practice Guideline published in 2013 on behalf of the European Society for Medical Oncology (ESMO) Guidelines Working Group in Annals of Oncology was reviewed for developmental rigor by methodologists, with content and recommendations reviewed by an ASCO endorsement panel. The ASCO endorsement panel determined that the recommendations of the ESMO guidelines are clear, thorough, and based on the most relevant scientific evidence. The ASCO panel endorsed the ESMO guidelines and added a few qualifying statements. Approximately 5% to 6% of patient cases of CRC are associated with germline mutations that confer an inherited predisposition for cancer. The possibility of a hereditary cancer syndrome should be assessed for every patient at the time of CRC diagnosis. A diagnosis of Lynch syndrome, familial adenomatous polyposis, or another genetic syndrome can influence clinical management for patients with CRC and their family members. Screening for hereditary cancer syndromes in patients with CRC should include review of personal and family histories and testing of tumors for DNA mismatch repair deficiency and/or microsatellite instability. Formal genetic evaluation is recommended for individuals who meet defined criteria.

Next-Generation Strategies for Hereditary Colorectal Cancer Risk Assessment

Next-Generation Strategies for Hereditary Colorectal Cancer Risk Assessment

Abstract LB-295: The roles of genetic polymorphisms for susceptibility of colorectal cancer in Chinese Lynch syndrome families

Abstract Background: Lynch syndrome is associated with germ-line mutations in DNA mismatch repair (MMR) genes. Polymorphisms in candidate genes that have been implicated in sporadic colorectal cancer (CRC) risk may also play roles in hereditary CRC risk. In this retrospective analysis, we examined multiple polymorphisms (including MSH2 IVS10+12A>G, MLH1 A-93G, NAT1, GSTM1, GSTP1 Iel105Val, GSTA1 C-69T, TP53 Arg72Pro, CYP17A1 T-34C, CYP1A1*2C, CYP1A1*1F, TGFBR1 IVS7+24G>A, and TGFBR2 G-875A) to assess the genetic effect on the CRC risk in MLH1 and MSH2 mutation carriers. Material and Methods: DNA samples from 284 mutation-positive Lynch syndrome participants were genotyped by Sequenom iPLEX MassArray. Univariate and multivariate analysis was used to analyze the association between the genetic polymorphisms and CRC risk. Results: We found significant associations between the presence of variant alleles in TP53 Arg72Pro (G>C) and TGFBR2 G-875A genes and the risk of developing CRC among MLH1 and MSH2 mutation carriers. The TP53 Arg72Pro GC+CC genotypes were associated with decreased risk of CRC (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.42-0.94). However, the TGFBR2 G-875A GA+AA genotypes were associated with increased risk of CRC (HR = 1.60, 95% CI = 1.06-2.42). None of the other gene polymorphisms examined were associated with CRC risk. Conclusion: To our best knowledge, our study is the first and largest study investigating multiple genetic modifiers that may influence CRC risk in Chinese Lynch syndrome families. Our results suggested that TP53 and TGFBR2 polymorphisms may associate with CRC risk among MLH1 and MSH2 mutation carriers. Such knowledge may be helpful in identifying high-risk individuals who require more intensive surveillance. Citation Format: Chih-Ching Yeh, Reiping Tang, Huei-Tzu Chien, Chih-Hsiung Lai, Li-Ling Chiu, Tsai-Ping Lo, Kuan-Yi Hung, Chun-Yi Wang, Jeng-Fu You, Chao A. Hsiung, Ling-Ling Hsieh. The roles of genetic polymorphisms for susceptibility of colorectal cancer in Chinese Lynch syndrome families. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-295. doi:10.1158/1538-7445.AM2014-LB-295

A national survey of hereditary colorectal cancer services in the UK

ObjectivesThe British Society of Gastroenterology (BSG) Cancer Group designed a survey to determine how we might understand and improve the service for patients at elevated risk of hereditary colorectal cancer...

Identification of Patients at Risk for Hereditary Colorectal Cancer

Diagnosis of hereditary colorectal cancer syndromes requires clinical suspicion and knowledge of such syndromes. Lynch syndrome is the most common cause of hereditary colorectal cancer. Other less common causes include familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome, and others. There have been a growing number of clinical and molecular tools used to screen and test at risk individuals. Screening tools include diagnostic clinical criteria, family history, genetic prediction models, and tumor testing. Patients who are high risk based on screening should be referred for genetic testing.

Does a screening questionnaire for familial and hereditary colorectal cancer risk work in a health insurance population?

The aim of our study was to evaluate actual prevalence, uptake and first experiences with a questionnaire developed for early detection of colorectal cancer (CRC) in persons with familial/hereditary risk. A cross sectional study in an insurance population aged 30-54 years was conducted. Subjects with ICD-10 codes C00 to C97 and D37 to D48 were excluded. A standardised questionnaire was sent to 12,139 subjects. Three months later, subjects with a reported family history were followed by a second questionnaire. An additional telephone survey was performed to validate responses. Nineteen per cent met the inclusion criteria (mean age 45 ± 7 years, 38% men). Three hundred and seventy-three subjects (16%) were followed by a second questionnaire. Of these, 248 (66%) returned. Forty-four per cent were already aware of their increased risk of developing CRC. Awareness was associated with knowledge of CRC. One hundred subjects (41%) reported that they had informed their general practitioner (GP) or gastroenterologist. A colonoscopy or stool test was recommended to 92. Subjects who found out about their increased risk for the first time, reported significantly less frequent physician contact (GP: 20% vs. 34%, gastroenterologist: 8% vs. 21%). Results indicate that there is a need for a structured, person at risk-adapted, statutory early detection program.

Colorectal Cancer Survivors' Interest in Genetic Testing for Hereditary Cancer: Implications for Universal Tumor Screening

Benefits of universal tumor screening for Lynch syndrome (LS), the most common form of hereditary colorectal cancer (CRC), will be realized only if patients are interested in genetic counseling and testing. This study explores interest in genetic testing for hereditary CRC among CRC patients who have never received genetic counseling or testing. Using results from a cross-sectional survey of CRC patients (n=91) at varying categories of risk for hereditary CRC, bivariate and multivariable analyses were conducted to compare positive and negative attitudinal beliefs regarding genetic testing, risk perceptions, demographics, and tumor stage of those who were interested in genetic testing (n=61) and those who were not interested or were not sure (n=30). Although significant at the bivariate level, gender, perceived relative risk of hereditary cancer, employment status, and belief that genetic testing would help in preparing for the future were not significantly related to interest in genetic testing when controlling for all other variables in a logistic regression model. The two factors that remained significant include a single-item question measuring the belief that genetic testing is warranted based on personal/family history and a positive attitudinal scale regarding the utility of genetic testing in medical decision making and cancer prevention. Results have potential implications for policies regarding universal tumor screening for LS.

The PREMM 1,2,6 Model Predicts Risk of MLH1, MSH2, and MSH6 Germline Mutations Based on Cancer History

We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6 based on personal and family history of cancer. Data were analyzed from 4539 probands tested for mutations in MLH1, MSH2, and MSH6. A multivariable polytomous logistic regression model (PREMM(1,2,6)) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases. Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1, 250 in MSH2, and 71 in MSH6). The PREMM(1,2,6) model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.5-2.4), a CRC (4.3; 3.3-5.6), multiple CRCs (13.7; 8.5-22), endometrial cancer (6.1; 4.6-8.2), and extracolonic cancers (3.3; 2.4-4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82-0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83-0.92) for MSH2, and 0.81 (95% CI, 0.69-0.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.86-0.90) and the population-based cases (95% CI, 0.83-0.92). We developed the PREMM(1,2,6) model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1, MSH2, and MSH6. This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.

Hereditary Colorectal Cancer in the Gastroenterology Clinic

Colorectal cancer is the second leading cause of cancer deaths in the United States in both men and women and is thus a major public health problem. The American Cancer Society estimated that in 2007, approximately 153,760 people in the United States were diagnosed with colorectal cancer and about 52,180 died of the disease. Colorectal cancer is largely preventable, however, and often curable when detected early. About 80% of people with colorectal cancer seem to have sporadic disease with no evidence of inheriting the disorder, and the remaining 20% have a familial or hereditary risk. Identifying those with heritable cancers is best accomplished through a detailed family history, easily obtained by a trained nurse. With a detailed family history, risk can be assessed and further screening via colonoscopy or genetic testing may be undertaken. Unfortunately, to date, there is no universally accepted method to collect family health histories to determine the risk of hereditary colorectal cancer. This study field tested two different intake tools that collect personal and family history information for (1) evaluating their effectiveness in identifying patients at risk for hereditary colorectal cancer in a gastroenterology center; (2) determining patient, nurse, and physician satisfaction with each tool; and (3) assessing the prevalence of patients at risk for hereditary colorectal cancer in a gastroenterology center. A purposive sample of six gastroenterology practices across the United States was utilized. Eligible subjects included all patients seen in those practices over a 2-month time frame. Each intake tool was administered over a 4-week time frame. Satisfaction questionnaires were given to a random selection of subjects, as well as involved nurses and providers at each site. Overall prevalence of those at risk for hereditary colorectal cancer was 26% for all sites, ranging from 11%-39% across sites and tools. This study is significant because it revealed a fairly high percentage of people at risk for hereditary colorectal cancer and showed how an initial risk assessment can be easily done by professional nurses and other healthcare providers who are in a unique position to help reduce the incidence and mortality from colorectal cancer.

IGF1 is a modifier of disease risk in hereditary non‐polyposis colorectal cancer

Patients diagnosed with HNPCC harbouring a confirmed germline mutation in DNA mismatch repair (MMR) genes have an 80% lifetime risk of developing an epithelial malignancy. There is, however, considerable variation in the age of disease onset in these patients. Insulin-like growth factor-I (IGFI) has been implicated in colorectal cancer (CRC), and elevated plasma IGFI levels are associated with both sporadic and hereditary CRC risk. In this study, we further investigate the cytosine-adenine (CA) dinucleotide repeat polymorphism located near the promoter region of IGF1 and its relation to early onset CRC risk in 443 Australian and Polish MMR gene mutation carriers using DNA sequencing, Kaplan-Meier survival curves and Cox proportional hazard regression analysis. A significantly smaller number of IGF1 CA repeats was observed in the Polish patient population, which was associated with an earlier age of disease onset compared to the Australian patients. The threshold for the observed modifying effect was again shown to be in patients with 17 or less CA repeats compared to those with 18 or more. Furthermore, when MMR mutation group (i.e., MLH1 or MSH2), gender and family clustering were included in the final Cox model we observed a more robust trend for the role of the IGF1 CA repeat in predicting age of disease onset in HNPCC patients. In addition, this effect was shown to be equal in both MLH1 and MSH2 mutation carrier groups and not restricted to a particular MMR subgroup (p = 0.001). We conclude that the IGF1 CA repeat is an important modifier of disease onset in HNPCC and the first polymorphism to yield consistent results across different populations.

Possible new phenotypic marker for risk of hereditary colorectal cancer

Possible new phenotypic marker for risk of hereditary colorectal cancer

Racial and Gender Disparities in Hereditary Colorectal Cancer Risk Assessment: The Role of Family History

In this study, we aimed to examine racial/ethnic and gender differences in self-reported family cancer history knowledge in patients at high risk for hereditary colon cancer syndromes. We performed retrospective analysis of all referrals to the University of Chicago High Risk Colon Cancer Clinic between 1995 and 2003. We found hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis in 17% and 9% of Whites, respectively, and 6% and 0% of Blacks, respectively. Unknown paternal history was found in 6.5% of Whites and 18.9% of Blacks (23% men, 11% women). Blacks and men had significantly decreased rates of paternal history cancer knowledge.

Inherited Polyposis Syndromes: Molecular Mechanisms, Clinicopathology, and Genetic Testing

The inherited polyposis syndromes are a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gastrointestinal tract, most exhibit an increased risk of colon cancer. Benign and malignant extraintestinal tumors might also be observed. Recent elucidation of the underlying gene mutations has contributed to our understanding of the cell biology and molecular mechanisms associated with gastrointestinal tumorigenesis. Developments have also allowed genetic testing to become an integral component in accurate diagnosis, categorization, and management of inherited polyposis syndromes. In this review, we will focus on familial adenomatous polyposis, mutY human homologue-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. It is essential that both physician and patient understand the benefits and limitations of genetic testing before submission of samples to the laboratory. There are many issues accompanying molecular diagnosis of cancer syndromes, and genetic counseling is an essential prelude to genetic testing.

Genetic Testing for Inherited Colon Cancer

The genes associated with each of the inherited syndromes of colon cancer have now been identified, and genetic testing is available for diagnosis. These syndromes include familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and, possibly, Cowden's syndrome. Clinical genetic testing approaches have been developed for each of these syndromes and are now a part of accepted clinical care. Disease-causing mutations can be found in the majority of families affected with one of the inherited syndromes, and, most importantly, once a mutation is found in an index case of the family, relatives can be tested for the presence or absence of that mutation with near 100% accuracy. Cancer screening and management in syndrome families is then based on the results of genetic testing. For the physician to order and properly interpret genetic tests, a basic understanding of the types of mutations that lead to inherited disease and the methods for detecting them is vital. These issues will be presented. Additional clinical issues somewhat unique to genetic testing include genetic counseling and informed consent for genetic testing, both of which will also be reviewed. Often the most difficult aspect of genetic testing is deciding which patients and families should undergo the testing. Furthermore, this issue is quite specific for each of the syndromes. Thus, following presentation of general principles of selection for genetic testing, a detailed approach for identifying persons who should undergo testing for each of the individual syndromes will be given, together with relevant descriptions of the syndromes. Finally, the ongoing work to discover new and possibly more common but less penetrant colon cancer susceptibility genes that cause common familial colon cancer will be presented.

Accuracy of MSI testing in predicting germline mutations of MSH2 and MLH1: a case study in Bayesian meta-analysis of diagnostic tests without a gold standard

Microsatellite instability (MSI) testing is a common screening procedure used to identify families that may harbor mutations of a mismatch repair (MMR) gene and therefore may be at high risk for hereditary colorectal cancer. A reliable estimate of sensitivity and specificity of MSI for detecting germline mutations of MMR genes is critical in genetic counseling and colorectal cancer prevention. Several studies published results of both MSI and mutation analysis on the same subjects. In this article we perform a meta-analysis of these studies and obtain estimates that can be directly used in counseling and screening. In particular, we estimate the sensitivity of MSI for detecting mutations of MSH2 and MLH1 to be 0.81 (0.73-0.89). Statistically, challenges arise from the following: (a) traditional mutation analysis methods used in these studies cannot be considered a gold standard for the identification of mutations; (b) studies are heterogeneous in both the design and the populations considered; and (c) studies may include different patterns of missing data resulting from partial testing of the populations sampled. We address these challenges in the context of a Bayesian meta-analytic implementation of the Hui-Walter design, tailored to account for various forms of incomplete data. Posterior inference is handled via a Gibbs sampler.

Immunoassay for wild-type protein in lymphocytes predicts germline mutations in patients at risk for hereditary colorectal cancer

Using colorectal cancer (CRC) as an example, we present the hypothesis that quantitative immunoassays for wild-type (full-length) proteins can be used to identify carriers of traits for hereditary diseases. In the case of hereditary CRC, this involves identifying individuals with germline mutations in a mismatch-repair (MMR) gene (mainly hMSH2 or hMLH1) or in the adenomatous polyposis coli (APC) gene. Because expression of wild-type protein should reflect wild-type gene dosage, we predicted that individuals harboring a germline mutation will have a reduction of approximately 50% in expression in lymphocytes of the corresponding full-length protein. In this pilot study, we tested lymphoblastoid cell lines that had been established from controls and individuals with, or at high risk for, hereditary CRC: 9 lines from healthy, unaffected individuals; 4 from affected members in familial adenomatous polyposis families (with known germ-line APC mutation); 42 from CRC patients in our Familial CRC Registry (increased risk of hereditary nonpolyposis colon cancer as assessed by family history, age at adenoma or carcinoma diagnosis, and other clinical criteria). For MSH2 and MLH1 we used western blots; for APC we used immunoprecipitation. All familial adenomatous polyposis lines had about 50% less immunoprecipitable full-length APC protein. Some cell lines (7 of 42) from Familial CRC Registry patients showed on western blots a reduction (mean 46%) in either MSH2 or MLH1 (relative to the other protein). All 7 subsequently were proved to contain a germline MMR mutation. We conclude that (1) because most of the expected CRC-causing germ line mutations are truncation-causing, immunoassays for wild-type protein should be able to identify most individuals with hereditary CRC-causing traits; (2) these assays, which are more practical and inexpensive than current mutation-detecting tests for hereditary CRC traits, have the potential for commercial development into broad-based population screens of high-risk patients and their families and the potential to save both lives and health-care dollars; (3) this strategy may be useful for other hereditary cancers and even other hereditary diseases; (4) our approach has the potential to greatly benefit public-health programs for cancer control.

The utility of brief questionnaire in assessment of risk for hereditary colorectal cancer in a clinic setting

The utility of brief questionnaire in assessment of risk for hereditary colorectal cancer in a clinic setting

Immunoassay predicts DNA mismatch repair (MMR) and APC germiline mutation in lymphocytes from patients at risk for hereditary colorectal cancer (CRC)

Immunoassay predicts DNA mismatch repair (MMR) and APC germiline mutation in lymphocytes from patients at risk for hereditary colorectal cancer (CRC)

The utility of brief questionnaire in assessment of risk for hereditary colorectal cancer in a clinic setting

The utility of brief questionnaire in assessment of risk for hereditary colorectal cancer in a clinic setting

Immunoassay predicts DNA mismatch repair (MMR) and APC germiline mutation in lymphocytes from patients at risk for hereditary colorectal cancer (CRC)

Immunoassay predicts DNA mismatch repair (MMR) and APC germiline mutation in lymphocytes from patients at risk for hereditary colorectal cancer (CRC)