Abstract
High-grade serous ovarian cancer (HGSOC) is the most aggressive histological type of epithelial ovarian cancer, which is characterized by a high frequency of somatic TP53 mutations. We performed exome analyses of tumors and matched normal tissues of 34 Japanese patients with HGSOC and observed a substantial number of patients without TP53 mutation (24%, 8/34). Combined with the results of copy number variation analyses, we subdivided the 34 patients with HGSOC into subtypes designated ST1 and ST2. ST1 showed intact p53 pathway and was characterized by fewer somatic mutations and copy number alterations. In contrast, the p53 pathway was impaired in ST2, which is characterized by abundant somatic mutations and copy number alterations. Gene expression profiles combined with analyses using the Gene Ontology resource indicate the involvement of specific biological processes (mitosis and DNA helicase) that are relevant to genomic stability and cancer etiology. In particular we demonstrate the presence of a novel subtype of patients with HGSOC that is characterized by an intact p53 pathway, with limited genomic alterations and specific gene expression profiles.
Highlights
The age adjusted rates of ovarian and other uterine adnexa cancers in 2002 were 10.6 per 100,000, and 5.2 per 100,000 person-years in USA and Japan, respectively [1]
We identified 88 genes related to progression-free survival in 110 Japanese patients with advanced-stage serous ovarian cancer [7], as well as 126 genes related to overall survival in 260 Japanese patients with advanced-stage highgrade serous ovarian cancer (HGSOC) [8]
Gene ontology (GO) analysis showed that differentially expressed genes were significantly enriched in the mitosis and DNA helicase GO groups that may be involved in genomic instability and tumorigenesis of HGSOC. These findings provide new insights into the molecular characteristics and novel biological processes that contribute to the pathogenesis of HGSOC, in patients with an intact p53 pathway
Summary
The age adjusted rates of ovarian and other uterine adnexa cancers in 2002 were 10.6 per 100,000, and 5.2 per 100,000 person-years in USA and Japan, respectively [1]. Subclassification of HGSOC histological types such as high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous cancers [2, 3]. Ovarian cancers are divided into Type I and Type II tumors [2, 4]; Type I tumors include low-grade serous, low-grade endometrioid, clear-cell, and mucinous carcinomas. These tumors poorly respond to platinum-based therapy, harbor a high frequency of mutations in genes that encode components of the RAS signaling pathway, and are relatively stable in genomic structure. The mutation status of TP53 is associated with stages, gene expression patterns, and the survival of patients with serous ovarian cancer [6]
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