Explaining the Familial Colorectal Cancer Risk Associated with Mismatch Repair (MMR)-Deficient and MMR-Stable Tumors

Abstract

Purpose: There is a paucity of data quantifying the familial risk of colorectal cancer associated with mismatch repair (MMR)-deficient and MMR-stable tumors. To address this, we analyzed a population-based series of 1,042 colorectal cancer probands with verified family histories. Experimental Design: Constitutional DNA from probands was systematically screened for MYH variants and those with cancers displaying microsatellite instability (MSI) for germ-line MMR mutations; diagnoses of familial adenomatous polyposis and juvenile polyposis were established based on clinical phenotype and mutational analysis. Familial colorectal cancer risks were enumerated from age-, sex-, and calendar-specific population incidence rates. Segregation analysis was conducted to derive a model of the residual familial aggregation of colorectal cancer. Results: Germ-line predisposition to colorectal cancer was identified in 37 probands [3.4%; 95% confidence interval (95% CI), 2.4-4.6]: 29 with MLH1/MSH2 mutations, 2 with familial adenomatous polyposis, 1 with juvenile polyposis, and 5 with biallelic MYH variants. The risk of colorectal cancer in first-degree relatives of probands with MSI and MMR-stable cancers was increased 5.01-fold (95% CI, 3.73-6.59) and 1.31-fold (95% CI, 1.07-1.59), respectively. MSH2/ MLH1 mutations were responsible for 50% of the overall excess familial risk and 80% of the risk associated with MSI cancers but 32% of the familial risk was unaccounted for by known loci. Genetic models based on major gene loci did not provide a better explanation of the residual familial aggregation than a simple polygenic model. Conclusions:The information from our analyses should be useful in quantifying familial risks in clinical practice and in the design of studies to identify novel disease alleles.Family history is acknowledged to be one of the strongest risk factors for the development of colorectal cancer. Numerous studies have documented that f15% of individuals with colorectal cancer report a close relative also affected by the disease (1 -3). A meta-analysis of epidemiologic studies we conducted showed that having a first-degree relative with colorectal cancer approximately doubled the risk of colorectal cancer, and if the affected relative was diagnosed before the age of 45 years, the risk was increased f4-fold (4).Germ-line mutations in APC, SMAD4, ALK3, STK11/LKB1, MYH, and the mismatch repair (MMR) genes have all been shown to be predispose to syndromic forms of colorectal cancer: familial adenomatous polyposis (FAP; Mendelian inheritance in man 175100), 5 juvenile polyposis (Mendelian inheritance in man 174900), Peutz-Jeghers syndromes (Mendelian inheritance in man 175200), recessive polyposis (MYH; Mendelian inheritance in man 608456), and hereditary nonpolyposis colorectal cancer (HNPCC; Mendelian inheritance in man 120435-6), respectively (5). Aside from the substantive risk associated with HNPCC (6, 7), germ-line mutations in the MMR genes are thought to contribute significantly to the overall burden o...

Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

“…4 Fulfillment of the Amsterdam criteria I. 5 The relationship of the two family members from which the tumors were analyzed in this study. FDR, first-degree relative; TDR, third-degree relative.…”

“…4 Moreover, it has been estimated that $32% of the excess CRC risk that is associated with a positive family history of CRC remains unexplained by known genes. 5 In these families, it is likely that other high penetrance genetic risk factors play a role. Analysis of the incidence of cancer in these families showed that they have an increased risk of CRC compared with the general population, albeit to a lesser extent than Lynch syndrome families.…”

“…Analysis of the incidence of cancer in these families showed that they have an increased risk of CRC compared with the general population, albeit to a lesser extent than Lynch syndrome families. [5][6][7] Lindor et al observed that MMR-proficient AC-I positive families have an increased risk for CRC but not for other cancers. Furthermore, members of MMRproficient AC-I positive families tend to develop CRC at an older age than individuals in MMR-deficient AC-I positive families.…”

“…6 Aaltonen et al estimated that first-degree relatives (FDRs) of probands with microsatellite stable (MSS) cancer had a 1.3-fold increase in CRC risk. 5 In addition, a recent study reported that FDRs of CRC patients with MSS tumors had an increased risk for CRC and observed a strong correlation between the risk of CRC and the number of affected FDRs. 7 Linkage analysis in CRC pedigrees and affected siblings has been performed to identify novel high-penetrance risk factors.…”

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

“…Genetic factors play important roles in colorectal cancer development and account for approximately 35% of colorectal cancer risk (2). Highly penetrant germline mutations in APC, SMAD4, BMPR1A, MUTYH, STK11, and DNA mismatch repair genes are estimated to account for approximately 6% of all colorectal cancer cases (3). In addition to these rare variants, much of colorectal cancer inherited susceptibility is likely attributable to multiple low penetrance common variants.…”