Background & Aims: It is not clear what proportion of synchronous or metachronous colorectal cancers (CRCs) are associated with DNA mismatch repair (MMR) alterations or unsuspected Lynch syndrome. On the basis of tissue analyses, the aims were to evaluate DNA MMR expression in metachronous, synchronous, and isolated sporadic CRCs and to assess within-patient concordance of MMR expression in metachronous and synchronous CRCs. Methods: Tissue was evaluated from 34 patients with metachronous CRC, 34 matched solitary CRC patients, and 40 patients with synchronous CRCs. Subjects with known hereditary CRC were excluded. Immunohistochemical staining for MLH1 and MSH2 was performed on all tissues. Results: Absent MLH1 or MSH2 staining of the initial metachronous tumor was observed in 27% compared with 21% of control CRCs, P = .58. The odds of metachronicity with absent immunostaining were 1.33 (95% confidence interval, 0.46-3.84). Loss of MMR expression was observed in at least one cancer in 30% of patients with synchronous CRC. MMR expression loss was discordant in 70% of metachronous CRCs and 50% of synchronous CRCs. Lynch syndrome was subsequently diagnosed in 2 patients with synchronous CRCs, both with concordant tumor MMR loss but in no patient with metachronous CRC. Conclusions: Among those without known Lynch syndrome, development of multiple primary CRCs appears to be due largely to somatic events and often occurs via different molecular pathways within the same patient. Altered MMR expression in sporadic CRC has low predictive value for metachronicity. MMR expression analysis in cases of multiple primary CRC might identify a small number of patients with unsuspected Lynch syndrome.
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