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.

Landscape of Microsatellite Instability Across 39 Cancer Types

“…1 Microsatellites occur at microsatellite loci, which are widely dispersed throughout the human genome. In normal cells, repeat count of microsatellites is verified and maintained during cell division by the mismatch repair (MMR) system, 2,3 one of many cellular DNA repair mechanisms. Impairment of the MMR system can render cells unable to regulate the lengths of their microsatellites during cell division, termed MSI.…”

“…Mismatch repair deficiency is known to occur in some tumors, 2 either by somatic hypermutation of MMR genes, most commonly, MLH1 4,5 ; an inherited germline MMR pathway mutation, such as in Lynch syndrome 6,7 ; or double somatic mutations in MMR genes. MSI has been frequently observed within several types of cancer, most commonly in colorectal, endometrial, and gastric adenocarcinomas.…”

Morphological characterization of colorectal cancers in The Cancer Genome Atlas reveals distinct morphology–molecular associations: clinical and biological implications

“…(3, 6) What has not been fully integrated into the analysis, however, is tumor morphology. While an association of morphology with the DNA mismatch-repair pathway in colorectal cancer is well known and this knowledge has shown significant clinical and biological importance,(7, 8) it remains to be determined whether there exist additional relevant associations between tumor morphology and the newly understood genomic alterations.…”

Microsatellite instability in glioblastoma: is it really relevant in tumor prognosis?

“…None of these tumors were treated with neoadjuvant therapy. A total of 41 (43%) tumors showed loss of expression of at least one MMR risk for colorectal cancer and certain other malignancies in thekidney, ovary, bladder, brain, stomach, pancreas, and lung (1)(2)(3)12,16,24,34). MLH1, MSH2, MSH6, and PMS2 are the main proteins involved in this MMR system, and they interact as heterodimers: MSH2 couples with MSH6, and MLH1 couples with PMS2 (3,10,14,18).…”