MSH3 protein expression and nodal status in MLH1-deficient colorectal cancers

Purpose: Patients with colorectal cancers (CRC) and high microsatellite instability (MSI) have a better outcome than their chromosome-unstable counterpart. Given the heterogeneity of microsatellite-unstable CRCs, we wanted to see whether any MSI-associated molecular features are specifically associated with prognosis. Experimental Design: One hundred and nine MSI-high CRCs were typed for primary mismatch repair (MMR) defect and for secondary loss of MMR proteins. Frameshifts at seven target genes, mutations in the RAS pathway, and methylation at MLH1/CDKN2A promoters were also searched. The interplay of molecular findings with clinicopathologic features and patient survival was analyzed. Results: Of 84 MLH1-deficient CRCs, 31 (36.9%) had MSH3 and 11 (13.1%) had MSH6 loss (P <0.001), biallelic frameshift mutations at mononucleotide repeats accounting for most (78%) MSH3 losses. As compared with MSH3-retaining cancers, MLH1-deficient tumors with MSH3 loss showed a higher number of mutated target genes (3.94±1.56 vs. 2.79±1.75; P=0.001), absence of nodal involvement at pathology [N0; OR, 0.11; 95% confidence interval (CI), 0.04-0.43, P <0.001], and better disease-free survival (P = 0.06). No prognostic value was observed for KRAS status and for MLH1/CDKN2A promoter methylation. The association between MSH3 loss and N0 was confirmed in an independent cohort of 71 MLH1-deficient CRCs (OR, 0.23; 95% CI, 0.06-0.83, P = 0.02). Conclusions: MLH1-deficient CRCs not expressing MSH3 have a more severe MSI, a lower rate of nodal involvement, and a better postsurgical outcome.