A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer

Abstract

Ovarian cancer ranks fifth in both cancer incidence and mortality among women in the United States. Defects in the mismatch-repair (MMR) pathway that arise through genetic and/or epigenetic mechanisms may be important etiologically in a reasonable proportion of ovarian cancers. Genetic mechanisms of MMR dysfunction include germline and somatic mutations in the MMR proteins. Germline mutations cause hereditary nonpolyposis colorectal cancer (HNPCC), which is the third most common cause of inherited ovarian cancer after BRCA1 and BRCA2 mutations. An epigenetic mechanism known to cause inactivation of the MMR system is promoter hypermethylation of 1 of the MMR genes, mutL homolog 1 (MLH1). Various laboratory methods, in addition to clinical and histopathologic criteria, can be used to identify MMR-deficient ovarian cancers. Such methods include microsatellite instability analysis, immunohistochemistry, MLH1 promoter hypermethylation testing, and germline mutation analysis. In this review, the authors describe the existing literature regarding the molecular, clinical, and histologic characteristics of MMR-deficient ovarian cancers along with the possible effect on survival and treatment response. By further defining the profile of MMR-deficient ovarian cancers and their associated etiologic mechanisms, there may be a greater potential to distinguish between those of hereditary and sporadic etiology. The ability to make such distinctions may be of diagnostic, prognostic, and therapeutic utility.

FIGURE 1

Schematic representation of the human mismatch-repair system. T indicates thymine; G, guanine; MLH1, mutL homolog 1; PMS2, postmeiotic segregation increased 2; MLH3, mutL homolog 3; MSH2, mutS homolog 2; MSH3, mutS homolog 3; MSH6, mutS homolog 6; C, cytosine. (Adapted from Polato F, Broggini M. Microsatellite instability and genetic alterations in ovarian cancer. Minerva Ginecol. 2003;55:129−138.)

FIGURE 2

Genetic versus epigenetic pathways leading to the high-level microsatellite instability (MSI-H) phenotype and subsequent tumorigenesis. The epigenetic type of MSI-H cancers frequently are accompanied by the B-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation. MMR indicates mismatch repair; HNPCC, hereditary nonpolyposis colorectal cancer; MLH1, mutL homolog 1. (Adapted from Imai K, Yamamoto H. Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis. 2007 Oct 17;[Epub ahead of print].)