Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary

Abstract

Numerous studies have tested the association between TP53 mutations in ovarian cancer and prognosis but these have been consistently confounded by limitations in study design, methodology, and/or heterogeneity in the sample cohort. High-grade serous (HGS) carcinoma is the most clinically important histological subtype of ovarian cancer. As these tumours may arise from the ovary, Fallopian tube or peritoneum, they are collectively referred to as high-grade pelvic serous carcinoma (HGPSC). To identify the true prevalence of TP53 mutations in HGPSC, we sequenced exons 2-11 and intron-exon boundaries in tumour DNA from 145 patients. HGPSC cases were defined as having histological grade 2 or 3 and FIGO stage III or IV. Surprisingly, pathogenic TP53 mutations were identified in 96.7% (n = 119/123) of HGPSC cases. Molecular and pathological review of mutation-negative cases showed evidence of p53 dysfunction associated with copy number gain of MDM2 or MDM4, or indicated the exclusion of samples as being low-grade serous tumours or carcinoma of uncertain primary site. Overall, p53 dysfunction rate approached 100% of confirmed HGPSCs. No association between TP53 mutation and progression-free or overall survival was found. From this first comprehensive mapping of TP53 mutation rate in a homogeneous group of HGPSC patients, we conclude that mutant TP53 is a driver mutation in the pathogenesis of HGPSC cancers. Because TP53 mutation is almost invariably present in HGPSC, it is not of substantial prognostic or predictive significance.

Figure 1

Characterization of TP53 mutation-negative cancer samples. (A) Summary plots of whole genome DNA copy number data for seven mutation-negative samples. Red indicates chromosomal gain and blue shows regions of chromosomal loss. (B) High-resolution DNA copy number analysis of MDM2, MDM4, and TP53 loci in each sample. The dotted line indicates the position of the gene within the region. Samples with chromosomal gain or loss are marked with a red or blue asterisk, respectively. (C) Confirmation of MDM2 and MDM4 copy number gain using quantitative PCR of tumour DNA. Samples with gain are indicated in red. (D) Immunohistochemical staining of p53 protein in the following selected mutation-negative cases: case 41358; case 60258 (MDM2 gain); case 22029 (MDM4 gain); and case 60049 (MDM4 gain).