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Title: Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures
Authors: Ow, Ghim Siong
Ivshina, Anna V.
Fuentes, Gloria
Kuznetsov, Vladimir A.
Keywords: RPS6KA2
Cancer driver mutation
High-grade serous ovarian carcinoma
Cancer sub-type
Gene signature
Survival analysis
Patient’s stratification
Chemotherapy resistance
Issue Date: 2014
Source: Ow, G. S., Ivshina, A. V., Fuentes, G., & Kuznetsov, V. A. (2014). Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures. Cell Cycle, 13(14), 2262-2280.
Series/Report no.: Cell Cycle
Abstract: High-grade serous ovarian cancer (HG-SOC), a major histologic type of epithelial ovarian cancer (EOC), is a poorly-characterized, heterogeneous and lethal disease where somatic mutations of TP53 are common and inherited loss-of-function mutations in BRCA1/2 predispose to cancer in 9.5–13% of EOC patients. However, the overall burden of disease due to either inherited or sporadic mutations is not known. We performed bioinformatics analyses of mutational and clinical data of 334 HG-SOC tumor samples from The Cancer Genome Atlas to identify novel tumor-driving mutations, survival-significant patient subgroups and tumor subtypes potentially driven by either hereditary or sporadic factors. We identified a sub-cluster of high-frequency mutations in 22 patients and 58 genes associated with DNA damage repair, apoptosis and cell cycle. Mutations of CHEK2, observed with the highest intensity, were associated with poor therapy response and overall survival (OS) of these patients (P = 8.00e-05), possibly due to detrimental effect of mutations at the nuclear localization signal. A 21-gene mutational prognostic signature significantly stratifies patients into relatively low or high-risk subgroups with 5-y OS of 37% or 6%, respectively (P = 7.31e-08). Further analysis of these genes and high-risk subgroup revealed 2 distinct classes of tumors characterized by either germline mutations of genes such as CHEK2, RPS6KA2 and MLL4, or somatic mutations of other genes in the signature. Our results could provide improvement in prediction and clinical management of HG-SOC, facilitate our understanding of this complex disease, guide the design of targeted therapeutics and improve screening efforts to identify women at high-risk of hereditary ovarian cancers distinct from those associated with BRCA1/2 mutations.
ISSN: 1538-410
DOI: 10.4161/cc.29271
Schools: School of Computer Engineering 
Rights: © 2014 Landes Bioscience. This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited. Permission is granted subject to the terms of the License under which the work was published. Please check the License conditions for the work which you wish to reuse. Full and appropriate attribution must be given. This permission does not cover any third party copyrighted material which may appear in the work requested.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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