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. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells

“…TP53 mutations occur in almost every type of cancer at rates varying between 10% in hematopoietic malignancies [38] and 98% in high-grade serous carcinoma of the ovary [39]. Unlike the majority of tumor suppressor genes, which are inactivated by deletions or truncated mutations, TP53 mostly undergoes missense mutations [40].…”

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

“…A large majority of high-grade serous ovarian cancers have TP53 mutations, which appear to occur as an early event in disease progression. 16,17 Tumors from women with high-grade serous cancers frequently show a host immune response, and the presence of cytotoxic T lymphocytes, and T-regulatory cells is consistently associated with favorable prognosis. [18][19][20][21][22][23][24] Germline mutations in BRCA1 and BRCA2 are present in B18% of ovarian cancer patients with high-grade serous carcinoma.…”

Overexpression of S100A14 in human serous ovarian carcinoma

“…In addition, S100A14 controls cell invasion through the regulation of matrix metalloproteinase-2 (MMP2), and the regulation of MMP2 by S100A14 is dependent on p53 (29). It has been reported that SOC demonstrates the highest frequency of p53 mutation in any solid cancer (30), and a previous study confirmed that TP53 was mutated in 303 out of 316 ovarian cancer samples (31). At present, the role and mechanism of S100A14 in the invasion and metastasis of epithelial ovarian cancer remains unclear.…”