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Subset of Colorectal Cancer Cases in Younger Individuals Linked to Rare Germline Methylation

In a paper appearing in the Journal of the National Comprehensive Cancer Network, an international team led by investigators at Cedars-Sinai Medical Center uncovers ties between germline methylation of the MLH1 gene and a form of colorectal cancer (CRC) that tends to turn up in individuals under the age of 55 — results that help to bridge the missing heritability gap for these mismatch repair-deficient (MRRd), MLH1-methylated CRC cases. Because many sporadic MMRd CRC cases involve somatic MLH1 methylation, the team says, cases involving this alteration are typically not tested for germline alterations. In an effort to understand the potential germline role for MLH1 methylation in CRC development, the authors used pyrosequencing, real-time PCR, and bisulfite sequencing to search for germline MLH1 methylation in a retrospective set of almost 400 MLH1-methylated MMRd cases treated at sites in Ohio, focusing in on eight cases involving relatively young patients with constitutional or mosaic MLH1 methylation. "Although rare overall," they write, "a significant proportion of younger patients with MLH1-methylated CRC had underlying constitutional MLH1 methylation," suggesting that "[r]outine testing for this high-risk mechanism is warranted in patients aged [55 or younger] for a timely and accurate molecular diagnosis that will significantly alter their clinical management while minimizing additional testing."