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Risk of pancreatic cancer in families with Lynch syndrome.

ABSTRACT: Lynch syndrome is an inherited cause of colorectal cancer caused by mutations of DNA mismatch repair (MMR) genes. A number of extracolonic tumors have been associated with the disorder, including pancreatic cancer; however, the risk of pancreatic cancer in Lynch syndrome is uncertain and not quantified.To estimate pancreatic cancer risk in families with germline MMR gene mutations.Cancer histories of probands and their relatives were evaluated in MMR gene mutation carriers in the familial cancer registries of the Dana-Farber Cancer Institute (n = 80), Boston, Massachusetts, and University of Michigan Comprehensive Cancer Center (n = 67), Ann Arbor, Michigan. Families enrolled before the study start date (June 2008) were eligible. Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk were calculated and compared with the general population using modified segregation analysis, with correction for ascertainment.Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk.Data on 6342 individuals from 147 families with MMR gene mutations were analyzed. Thirty-one families (21.1%) reported at least 1 case of pancreatic cancer. Forty-seven pancreatic cancers were reported (21 men and 26 women), with no sex-related difference in age of diagnosis (51.5 vs 56.5 years for men and women, respectively). The cumulative risk of pancreatic cancer in these families with gene mutations was 1.31% (95% confidence interval [CI], 0.31%-2.32%) up to age 50 years and 3.68% (95% CI, 1.45%-5.88%) up to age 70 years, which represents an 8.6-fold increase (95% CI, 4.7-15.7) compared with the general population.Among 147 families with germline MMR gene mutations, the risk of pancreatic cancer was increased compared with the US population. Individuals with MMR gene mutations and a family history of pancreatic cancer are appropriate to include in studies to further define the risk of premalignant and malignant pancreatic neoplasms and potential benefits and limitations of surveillance.

SUBMITTER: Kastrinos F

PROVIDER: S-EPMC4091624 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Risk of pancreatic cancer in families with Lynch syndrome.

Kastrinos Fay F Mukherjee Bhramar B Tayob Nabihah N Wang Fei F Sparr Jennifer J Raymond Victoria M VM Bandipalliam Prathap P Stoffel Elena M EM Gruber Stephen B SB Syngal Sapna S

JAMA 20091001 16

<h4>Context</h4>Lynch syndrome is an inherited cause of colorectal cancer caused by mutations of DNA mismatch repair (MMR) genes. A number of extracolonic tumors have been associated with the disorder, including pancreatic cancer; however, the risk of pancreatic cancer in Lynch syndrome is uncertain and not quantified.<h4>Objective</h4>To estimate pancreatic cancer risk in families with germline MMR gene mutations.<h4>Design, setting, and patients</h4>Cancer histories of probands and their relat ...[more]

PMID: 19861671

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Project description:ImportanceThe data describing cancer risks associated with Lynch syndrome are variable.ObjectivesTo quantify the prevalence of families that fulfill the Amsterdam I or II criteria for Lynch syndrome in the Utah population and investigate the risk of colonic and extracolonic cancers in family members and their relatives.Design, setting, and participantsIn a population-based study, 202 families with Amsterdam I and II criteria–positive pedigrees in the Utah Population Database were identified. Of these, all cancer diagnoses in members of families with Amsterdam criteria and their first-degree, second-degree, and first-cousin relatives were located through linkage to the Utah Cancer Registry. The study was conducted from May 1 to June 30, 2016.Main outcomes and measuresStandardized morbidity ratios (SMRs) were estimated by comparing the observed rates of cancer in relatives with population-expected rates estimated internally from the Utah Population Database.ResultsA total of 202 families meeting Amsterdam criteria for Lynch syndrome accounted for 2.6% of all colorectal cancers in the state; of these, 59 met both the Amsterdam I and Amsterdam II criteria. Cancers observed in significant excess in the first-degree relatives of Amsterdam criteria pedigrees included colorectal (SMR, 10.10; 95% CI, 9.43-10.81), endometrial (SMR, 5.89; 95% CI, 5.09-6.78), stomach (SMR, 2.90; 95% CI, 2.02-4.03), small intestine (SMR, 7.72; 95% CI, 5.17-11.08), prostate (SMR, 1.94; 95% CI, 1.73-2.17), kidney (SMR, 3.22; 95% CI, 2.45-4.16), urinary bladder (SMR, 1.62; 95% CI, 1.22-2.12), thyroid (SMR, 2.26; 95% CI, 1.55-3.17), and non-Hodgkin lymphoma (SMR, 2.10; 95% CI, 1.64-2.65). Risks of colorectal and endometrial cancers were also found to be elevated in second-degree (SMR, 4.31; 95% CI, 3.98-4.65 and SMR, 2.70; 95% CI, 2.30-3.14, respectively) and first-cousin (SMR, 1.85; 95% CI, 1.70-2.00 and SMR, 1.50; 95% CI, 1.29-1.73, respectively) relatives of families with Amsterdam criteria.Conclusions and relevanceIn this population-based study of cancer risk in families fulfilling the Amsterdam criteria, many of the cancers previously reported to be associated with Lynch syndrome were observed, several previously unreported cancer associations were noted, and the risk of colorectal and endometrial cancer were markedly increased in first-, second-, and even third-degree relatives of these families. This study provides clinicians with population-based, unbiased data to counsel members of families meeting the Amsterdam criteria regarding their elevated risks of cancer and the importance of cancer screening.

Project description:BackgroundExisting clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence.MethodsIn this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.Findings5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p<0·0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A>T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%.InterpretationOur study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome.FundingNational Health and Medical Research Council, Australia.

Project description:IntroductionLynch syndrome is an autosomal dominantly inherited disorder of cancer susceptibility caused by germline mutations in the DNA mismatch repair (MMR) genes. Mutation carriers have a substantial burden of increased risks of cancers of the colon, rectum, endometrium and several other organs which generally occur at younger ages than for the general population. The issue of whether breast cancer risk is increased for MMR gene mutation carriers has been debated with evidence for and against this association.MethodsUsing the PUBMED, we identified all relevant studies of breast cancer associated with Lynch syndrome that were published by 15 December 2012. In the review, we included: (i) molecular studies that reported microsatellite instability and/or immunohistochemistry in breast cancer tumors of MMR gene mutation carriers; and (ii) risk studies that investigated risk of breast cancer for confirmed MMR gene mutation carriers or families or clinically and/or pathologically defined Lynch syndrome families.ResultsWe identified 15 molecular studies and, when combined, observed 62 of 122 (51%; 95% CI 42 to 60%) breast cancers in MMR gene mutation carriers were MMR-deficient. Of the 21 risk studies identified, 13 did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome while 8 studies found an increased risk of breast cancer ranging from 2- to 18-fold compared with the general population (or non-carriers). There is only one prospective study demonstrating an elevated risk of breast cancer for MMR gene mutation carriers compared with the general population (standardized incidence ratio 3.95; 95% CI 1.59, 8.13).ConclusionsSince breast cancer is a relatively common disease in the general population, more precise estimates of risk and gene-specific risks will need to utilize large prospective cohort studies with a long follow-up. While current data are inconclusive at a population level, individual tumor testing results suggest that MMR deficiency is involved with breast cancers in some individuals with Lynch syndrome.

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Risk of pancreatic cancer in families with Lynch syndrome.

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Risk of pancreatic cancer in families with Lynch syndrome.

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