Abstract
Ovarian cancer is the most lethal gynecological malignancy in the western world. Despite recent efforts to characterize ovarian cancer using molecular profiling, few targeted treatment options are currently available. Here, we examined genetic variants, fusion transcripts, SNP genotyping, and gene expression patterns for early-stage (I and II) ovarian carcinomas (n=96) in relation to clinicopathological characteristics and clinical outcome, thereby identifying novel genetic features of ovarian carcinomas. Furthermore, mutation frequencies of specific genetic variants and/or their gene expression patterns were associated with histotype and overall survival, e.g. SLC28A2 (mucinous ovarian carcinoma histotype), ARCN1 (low expression in 0-2 year survival group), and tumor suppressor MTUS1 (mutation status and overall survival). The long non-coding RNA MALAT1 was identified as a highly promiscuous fusion transcript in ovarian carcinoma. Moreover, gene expression deregulation for 23 genes was associated with tumor aggressiveness. Taken together, the novel biomarkers identified here may improve ovarian carcinoma subclassification and patient stratification according to histotype and overall survival.
Highlights
Recent advances in our understanding of ovarian carcinoma contributed to the reclassification of the disease into five major histotypes (high-grade serous (HGSC), low-grade serous (LGSC), endometrioid (EC), mucinous (MC) and clear cell (CCC) carcinomas) based on differences in origin, morphology, and clinical and biological behavior [1–3]
Whole-transcriptome RNA sequencing and whole-genome SNP genotyping analysis were performed on early-stage ovarian tumors in relation to clinicopathological features and clinical outcome to identify novel prognostic and/or diagnostic biomarkers, and improve histotype classification and patient stratification
This study presents an important addition to existing research due to its complete genome characterization of a large sample size of early-stage ovarian carcinoma specimens since few studies have previously characterized histotype-specific genetic features in early-stage ovarian carcinomas [9–11]
Summary
Recent advances in our understanding of ovarian carcinoma contributed to the reclassification of the disease into five major histotypes (high-grade serous (HGSC), low-grade serous (LGSC), endometrioid (EC), mucinous (MC) and clear cell (CCC) carcinomas) based on differences in origin, morphology, and clinical and biological behavior [1–3]. The majority of ovarian cancer patients are still currently treated with conventional treatment based on tumor stage and grade, regardless of histotype or other biological characteristics. There is a profound need for novel biomarkers with improved prognostic and diagnostic value that may guide the selection of therapeutic targets and thereby improve personalized medicine based on an individual ovarian carcinoma patient’s clinicopathological and tumor characteristics [8]. Since the introduction of the revised 2014 World Health Organization (WHO) criteria for histotype diagnoses, few efforts have been made to identify novel molecular biomarkers that stratify ovarian carcinomas according to clinical outcome and the current histotypes. Relatively few studies have characterized histotype-specific genetic features in early-stage ovarian carcinomas (I and II) [9–11]. Few studies have previously been performed on early-stage ovarian carcinomas to identify novel prognostic biomarkers [12]. One reason may be that the majority of all ovarian carcinomas are diagnosed at advanced stages III and IV [13]
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