Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers

Cancer Epidemiology Centre, Victorian Cancer Registry, Carlton, Victoria, Australia.
CancerSpectrum Knowledge Environment (Impact Factor: 15.16). 12/2009; 102(3):193-201. DOI: 10.1093/jnci/djp473
Source: PubMed

ABSTRACT Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain.
We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment.
For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7).
We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.

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Available from: Graham G Giles, Jul 30, 2015
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    • "Germline mutations in one of the mismatch repair genes (MLH1, MSH2, MSH6, PMS2) predispose people to colorectal cancer (CRC), endometrial cancer and some other cancers known as Lynch syndrome (Lynch and Chapelle 2003). Carriers of mutations in these genes have an approximate 30–60 % lifetime risk (to age 70 years) of CRC and 30–50 % lifetime risk of endometrial cancer depending on age and gender of carriers and the type of gene that is mutated (Baglietto et al. 2010; Bonadona et al. 2011; Senter et al. 2008). The only way to determine if unaffected people in families with a mismatch repair gene mutation have or have not inherited that mutation is genetic testing. "
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    ABSTRACT: People carrying germline mutations in mismatch repair genes are at high risk of colorectal cancer (CRC), yet about half of people from mutation-carrying families decline genetic counselling and/or testing to identify mutation status. We studied the association of quantitative measures of risk perception, risk prediction and self-reported screening colonoscopy in this elusive yet high-risk group. The sample of 26 participants (mean age 43.1 years, 14 women) in the Australasian Colorectal Cancer Family Registry were relatives of mutation carriers; had not been diagnosed with any cancer at the time of recruitment and had declined an invitation to attend genetic counselling and/or testing. A structured elicitation protocol captured perceived CRC risk over the next 10 years. Self-reported colonoscopy screening was elicited during a 45-minute semi-structured interview. Predicted 10-year CRC risk based on age, gender, known mutation status and family history was calculated using "MMRpro." Mean perceived 10-year risk of CRC was 31 % [95 % CI 21, 40], compared with mean predicted risk of 4 % [2, 7] (p < 0.001); this was independent of age and sex (p = 0.9). Among those reporting any medical advice and any screening colonoscopy (n = 18), those with higher risk perception had less frequent colonoscopy (Pearson's r = 0.49 [0.02, 0.79]). People who decline genetic testing for CRC susceptibility mutations perceive themselves to be at substantially higher risk than they really are. Those with high perceived risk do not undertake screening colonoscopy more often than those who perceive themselves to be at average risk.
    Journal of Genetic Counseling 06/2013; DOI:10.1007/s10897-013-9614-2 · 1.75 Impact Factor
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    • "Early publications on Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC) syndrome, cited 44–45 years as the average age of onset of colorectal cancer (Fitzgibbons et al. 1987; Lynch 1999). As germline molecular testing has become widely available, it has become evident that not all individuals present at a young age (Hampel et al. 2005b) and the risk may vary according to genotype (Baglietto et al. 2010; Barrow et al. 2008; Ramsoekh et al. 2009; Senter et al. 2008; Stoffel et al. 2009). Likewise, the average age of onset of endometrial cancer among individuals with Lynch syndrome has been shown to be 54.6 years (Hampel et al. 2006) and a prospective study of newly diagnosed endometrial tumors under age 70 found no difference in age of onset between those likely to have Lynch syndrome based on tumor screening results and those with sporadic tumors (Leenen et al. 2012). "
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    ABSTRACT: An electronic survey of the National Society of Genetic Counselors Cancer Special Interest Group was conducted in July 2011 to assess Lynch syndrome tumor screening programs and identify barriers to implementation. Over half of respondents (52.8 %) reported having a routine Lynch syndrome tumor screening protocol for newly diagnosed colon and/or endometrial cancers, and approximately half of these used a universal approach. There was an increase in the number of those screening over time, especially in the past 3 years. Tumor screening methods varied; 34/53 (64.2 %) started with immunohistochemistry, 11/53 (20.8 %) started with microsatellite instability testing and 8/53 (15.1 %) performed both on newly diagnosed colorectal tumors. Just 21.7 % (23/106) of respondents indicated they have a tumor screening program in place for newly diagnosed endometrial cancers. Written consent is rarely obtained (7.1 %) and the method of how results were returned to the patient was variable among respondents. Prevalent barriers to implementation were concern about cost, bringing key players together and convincing medical staff of the necessity. Use of Lynch syndrome tumor screening is in clinical practice, but protocols vary widely. This survey provides a glimpse of current practices and common barriers, and identifies the need for tumor screening algorithms with outcomes data.
    Journal of Genetic Counseling 05/2013; 23(1). DOI:10.1007/s10897-013-9603-5 · 1.75 Impact Factor
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    • "This is unlike sporadic CRC for which the general population has a 5–6% lifetime risk, has an average age at diagnosis of 65 years and a modest left-sided predilection. Of note, the lifetime risk of CRC in those with LS may be lower and the average age of onset may be older with mutations in the MSH6 and PMS2 genes (Baglietto et al. 2009; Plaschke et al. 2004; Senter et al. 2008) when compared to mutations in the MLH1 and MSH2 genes. CRCs in LS are associated with evidence of a host immune response including lymphocytic infiltrates and a Crohn's-like reaction. "
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    ABSTRACT: Identifying individuals who have Lynch syndrome (LS) involves a complex diagnostic work up that includes taking a detailed family history and a combination of various genetic and immunohistochemical tests. The National Society of Genetic Counselors (NSGC) and the Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC) have come together to publish this clinical practice testing guideline for the evaluation of LS. The purpose of this practice guideline is to provide guidance and a testing algorithm for LS as well as recommendations on when to offer testing. This guideline does not replace a consultation with a genetics professional. This guideline includes explanations in support of this and a summary of background data. While this guideline is not intended to serve as a review of LS, it includes a discussion of background information on LS, and cites a number of key publications which should be reviewed for a more in-depth understanding of LS. These guidelines are intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses and other healthcare providers who evaluate patients for LS.
    Journal of Genetic Counseling 12/2011; 21(4):484-93. DOI:10.1007/s10897-011-9465-7 · 1.75 Impact Factor
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