MLH1-deficient colorectal carcinoma

Between 10% and 15% of colorectal carcinomas demonstrate sporadic DNA mismatch-repair protein deficiency as a result of MLH1 promoter methylation and are thought to arise from sessile serrated adenomas (SSA/P), termed the " serrated neoplasia pathway ".

Although the presence of the BRAF-V600E mutation is indicative of a sporadic cancer, up to 30% to 50% of colorectal carcinomas with MLH1 promoter hypermethylation will lack a BRAF mutation.

A study reported the clinicopathologic and molecular features of " MLH1-deficient colorectal carcinoma " with wild-type BRAF and MLH1 promoter hypermethylation (referred to as " MLH1-hypermethylated BRAF wild-type colorectal carcinoma ", n=36) in comparison with " MLH1-deficient BRAF-mutated colorectal carcinoma " (n=113) and " Lynch syndrome-associated colorectal carcinoma " (n=36).

KRAS mutations were identified in 31% of MLH1-hypermethylated BRAF wild-type colorectal carcinomas compared with 0% of MLH1-deficient BRAF-mutated colorectal carcinomas and 37% of Lynch syndrome-associated colorectal carcinomas.

When a precursor polyp was identified, MLH1-hypermethylated BRAF wild-type colorectal carcinomas arose from precursor polyps resembling conventional tubular/tubulovillous adenomas in contrast to MLH1-deficient BRAF-mutated colorectal carcinomas, which arose from precursor sessile serrated adenomas (P@<@0.001).

Both MLH1-hypermethylated BRAF wild-type colorectal carcinoma and MLH1-deficient BRAF-mutated colorectal carcinoma had a predilection for the right colon compared with Lynch syndrome-associated colorectal carcinoma (86% vs. 92% vs. 49%, P@<@0.001).> 0.05).

These results indicate that MLH1-hypermethylated BRAF wild-type colorectal carcinomas can harbor KRAS mutations and arise from precursor polyps resembling conventional tubular adenoma / tubulovillous adenoma .

Paywall references

 MLH1-deficient Colorectal Carcinoma With Wild-type BRAF and MLH1 Promoter Hypermethylation Harbor KRAS Mutations and Arise From Conventional Adenomas.
Farchoukh L, Kuan SF, Dudley B, Brand R, Nikiforova M, Pai RK. Am J Surg Pathol. 2016 Oct;40(10):1390-9. doi : 10.1097/PAS.0000000000000695 PMID: 27438990