Evolving approach and clinical significance of detecting DNA mismatch repair deficiency in colorectal carcinoma

Abstract

The last two decades have seen significant advancement in our understanding of colorectal tumors with DNA mismatch repair (MMR) deficiency. The ever-emerging revelations of new molecular and genetic alterations in various clinical conditions have necessitated constant refinement of disease terminology and classification. Thus, a case with the clinical condition of hereditary non-polyposis colorectal cancer as defined by the Amsterdam criteria may be one of Lynch syndrome characterized by a germline defect in one of the several MMR genes, one of the yet-to-be-defined "Lynch-like syndrome" if there is evidence of MMR deficiency in the tumor but no detectable germline MMR defect or tumor MLH1 promoter methylation, or "familial colorectal cancer type X" if there is no evidence of MMR deficiency. The detection of these conditions carries significant clinical implications. The detection tools and strategies are constantly evolving. The Bethesda guidelines symbolize a selective approach that uses clinical information and tumor histology as the basis to select high-risk individuals. Such a selective approach has subsequently been found to have limited sensitivity, and is thus gradually giving way to the alternative universal approach that tests all newly diagnosed colorectal cancers. Notably, the universal approach also has its own limitations; its cost-effectiveness in real practice, in particular, remains to be determined. Meanwhile, technological advances such as the next-generation sequencing are offering the promise of direct genetic testing for MMR deficiency at an affordable cost probably in the near future. This article reviews the up-to-date molecular definitions of the various conditions related to MMR deficiency, and discusses the tools and strategies that have been used in detecting these conditions. Special emphasis will be placed on the evolving nature and the clinical importance of the disease definitions and the detection strategies.

Keywords: CMMR-D; Lynch syndrome; Lynch-like syndrome; MMR IHC; Microsatellite instability; Sporadic MSI cancer.

Fig. 1

Subclassification of colorectal cancer cases associated with “hereditary nonpolyposis colorectal cancer” and microsatellite instability. AC, Amsterdam criteria; HNPCC, hereditary nonpolyposis colorectal cancer; MMR, mismatch repair; CMMR-D, constitutional MMR deficiency; CRC, colorectal cancer; MAP, MUTYH associated polyposis. *May present with LS type cancers in early adulthood, **WHO term “probably Lynch syndrome.”

Fig. 2

An algorithmic detection schema utilizing screening tests to select at-risk patients for germline mutation testing for diagnosing Lynch syndrome. CRC, colorectal cancer; MMR, mismatch repair; IHC, immunohistochemistry; MSI, microsatellite instability testing; Methyl, methylation; Mut, mutation; LS, Lynch syndrome; LLS, Lynch-like syndrome.