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Colorectal cancer (CRC) is uncommon in individuals <50 years old. Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes and associated with early-onset CRC, but little is known about the proportion of young patients with apparently sporadic CRC who actually have Lynch syndrome. We examined patterns of microsatellite instability (MSI) and MMR genes among patients <50 years old with non-familial CRC (patients with not more than 1 family member with CRC).Tissue specimens were collected from 75 CRC patients <50 years old (mean age, 34.5 years) and analyzed using immunohistochemical analyses of MLH1, MSH2, MSH6, and PMS2. MSI and mutations in BRAF and KRAS were also analyzed.Most cancers (72%) arose in the distal colon. MSI was detected in 21% of the samples, and loss of 1 or more MMR proteins was observed in 21%. Interestingly, only 38% of the MMR-deficient CRCs lost either MLH1 or MSH2, whereas 63% of the MMR-deficient CRC samples lost either PMS2 or MSH6. All 11 CRC samples that had lost MSH2, MLH1, or PMS2 had MSI, but only 2 of the 5 tumors that lost only MSH6 had MSI. There were no BRAF mutations in any tumor.In young patients with apparently sporadic CRC, most tumors arise in the distal colon; only 21% have features of Lynch syndrome. Loss of MSH6 or PMS2 occurred in 13.3% of these tumors. Most tumors that lose MSH6 will not be detected in screens for MSI; CRC screening might be modified to identify more patients with Lynch syndrome.