Molecular wanderings through the DNA damage response and risk for ovarian cancer.

Large-scale genomic analyses and smaller targeted studies have collectively reinforced our appreciation of the DNA damage response and homologous recombination deficits as important early mutational events in the biology of high-grade serous cancer (HGSC) arising from the ovary and associated gynecologic sites, including the distal fallopian tube, peritoneal cavity, and endome-trium. The near-universal loss of functional p53 occurs at the earliest stages of cancer development, including immunohistochemical and molecular identification of clonal p53 mutations or deletions in noninvasive precursor lesions. Loss of p53 contributes to a picture of " genomic instability " characterized by a large number of amplifications, mutations, and deletions present at diagnosis before initiation of chemotherapy. In addition, at least 50% of HGSCs harbor mutations or altered expression of components involved in DNA repair. Homologous recombination deficits–associated changes include loss of BRCA1, BRCA2, and RAD51, with the potential for molecular targeting through inhibition of poly-ADP-ribose polymerase, which is being explored in large randomized trials. Although the majority of HGSCs are initially sensitive to platinum-based chemotherapy, these tumors are adept in the development of resistance through multiple mechanisms, including increased damage tolerance. In this issue of the Journal, Akbari et al. (1) provide data to extend and confirm a recent study (2) demonstrating that truncat-ing mutations in protein phosphatase magnesium-dependent 1 δ (PPM1D) are associated with an increased risk of ovarian cancer. PPM1D appears to function as a negative regulator of p53 (3) and could generate an internal knockdown of p53 function, contributing to platinum resistance in tumors that retain p53 (4). Both studies identified truncating mutations located exclusively in the last of six exons. The truncated mRNA is transcribed, and there is in vitro evidence to suggest that these modified proteins have increased biologic activity compared with wild-type full-length products. Of interest, analysis of peripheral blood mononuclear cells demonstrated simultaneous (mosaic) expression of the truncated and normal proteins, suggesting that biologic activity of the truncated protein is dominant. In addition, mutations were not found in family members, and there is no evidence of mutation inheritance. At first review, it is surprising that molecular analysis of two ovarian tumor specimens that developed in patients with PPM1D mutations did not contain the mutation (1). However, there is frequent loss of chromosome 17q in ovarian cancer, which could contribute to loss of the mutated alleles. More important, this may offer a veiled clue regarding the role and timing of PPM1D …