Risk for CRC in Lynch Syndrome May Be Lower Than We Thought: Prevalence of Alterations in DNA Mismatch Repair Genes in Patients With Young-Onset Colorectal Cancer

full-text and related information ► Risk for CRC in Lynch Syndrome May Be Lower Than We Thought: Prevalence of Alterations in DNA Mismatch Repair Genes in Patients With Young-Onset Colorectal Cancer: "From Medscape Genomic Medicine > Viewpoints in Genomic Medicine
Risk for CRC in Lynch Syndrome May Be Lower Than We Thought

Gil Y. Melmed, MD; Dermot P. B. McGovern, MD, PhD

Summary

Lynch syndrome (LS) accounts for 3%-5% of colorectal cancer (CRC) cases, and young-onset (< 50 years old) CRC typically develops in individuals with LS. Approximately 95% of LS cases result from defects in the DNA mismatch repair genes MLH1, MSH2, or MSH6.[1] Once LS is recognized in a given family, affected family members can be identified, counseled, and screened with heightened frequency for CRC and other LS-associated cancers, such as endometrial cancer. However, the true increase in cancer risk is unknown, as previous studies suffered from selection and ascertainment bias. Furthermore, risk for cancer may vary among specific gene mutations.

Three recently published studies shed some light on this issue. Limburg and colleagues examined the prevalence of LS mutations in North American population-based samples of patients with young-onset CRC. They randomly selected cases of CRC from 3 colon cancer registries, and assessed for variants in MLH1, MSH2, and MSH6 using genetic sequencing. These results were compared against clinical (Amsterdam II) criteria[2] and immunohistochemistry of tissue specimens.

Their results indicated that only about 5% of young-onset CRC cases had confirmed deleterious or suspected deleterious mutations. Of note, most of these would not have been identified using Amsterdam II criteria alone, which had a sensitivity of 36% and specificity of 97%; using immunohistochemistry, these values were 86% and 92%, respectively.

In a separate study, Mukherjee and colleagues sought to quantify the specific risk of cancer attributable to a mutation in MSH2 A636P, which was previously detected in up to 7% of patients with early-onset CRC in Ashkenazi Jews, and may account for up to one third of LS cases in this population.[3] Using a powerful combination of both a population-based cohort and a registry-based cohort, they studied 27 families, which included a total of 74 cases of CRC and 28 cases of endometrial cancer, and estimated the cumulative risk of CRC by age 70 at 62% for men and 61% for women.

Finally, in a third study, Bonadona and colleagues estimated the risk for cancer for each of the 3 common mutations, MLH1, MSH2, and MSH6, in a large French cohort of 537 families and used rigorous statistical methods to overcome ascertainment bias. They found that the risk for colon cancer did not seem to increase until age 30. The estimated cumulative risks for cancer by age 70 were 41% for MLH1 mutation carriers, 48% for MSH2, and 12% for MSH6.
Viewpoint

Before the availability of genetic susceptibility testing, families with LS were identified using the Amsterdam criteria, which required 3 individuals with CRC in 2 generations, with 1 case diagnosed at younger than 50 years. Subsequently, with the availability of genetic testing, the Bethesda criteria have expanded the identification of LS in additional families.[4] However, these clinically-based algorithms are suboptimal, failing to identify many subjects with LS mutations. This raises the question of whether population-based screening of CRC cases would be appropriate.

These 3 studies highlight the importance of identifying LS mutations and quantifying risk to implement appropriate screening strategies for cancer. The finding by Limburg and colleagues of only a small proportion of deleterious or suspected deleterious mutations even in a high-risk population suggests the need for comparative effectiveness research to determine the most appropriate screening strategy for LS among patients with young-onset CRC. The findings by Bonadona and colleagues similarly suggest that the risk for CRC among those with LS mutations may be lower than previously thought. Yet the significantly increased risk of CRC in the study from Mukherjee and colleagues seems to support aggressive screening in individuals with LS specifically with the MSH2 A636P mutation, consistent with current guidelines to begin colonoscopy screening at age 20-25 with 1- to 2-year follow-up intervals.[5]

Clearly, as we develop more accurate estimates of risks associated with specific mutations, personalized screening methods and intervals will need to be further clarified among those with LS. Although it appears that the overall risk for CRC among those with LS may be lower than previously thought, there are likely to be specific mutations that confer a higher risk and require more intensive screening protocols.

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