Elsevier

Gynecologic Oncology

Volume 148, Issue 2, February 2018, Pages 375-382
Gynecologic Oncology

Genomic landscape of ovarian clear cell carcinoma via whole exome sequencing

https://doi.org/10.1016/j.ygyno.2017.12.005Get rights and content

Highlights

  • 14 genes, including PIK3CA, ARID1A and KRAS, were mutated in multiple Korean OCCCs.

  • 53 somatic mutations (27 novel) were identified in fresh Korean OCCC tissue.

  • Genomic landscape (somatic mutations and CNVs) expands our understanding of OCCCs.

  • Genetic alteration frequencies were similar in OCCCs with or without endometriosis.

Abstract

Objective

To analyze whole exome sequencing (WES) data on ovarian clear cell carcinoma (OCCC) in Korean patients via the technique of next generation sequencing (NGS). Genomic profiles were compared between endometriosis-associated OCCC (EMS-OCCC) and Non-EMS-OCCC.

Methods

We used serum samples and cancer tissues, stored at the Seoul National University Hospital Human Biobank, that were initially collected from women diagnosed with OCCC between 2012 and 2016. In total, 15 patients were enrolled: 5 with pathologically confirmed EMS-OCCC and 10 with Non-EMS-OCCC. We performed NGS WES on 15 fresh frozen OCCC tissues and matched serum samples, enabling comprehensive genomic characterization of OCCC.

Results

OCCC was characterized by complex genomic alterations, with a median of 178 exonic mutations (range, 111-25,798) and a median of 343 somatic copy number variations (range, 43-1,820) per tumor sample. In all, 54 somatic mutations were discovered across 14 genes, including PIK3CA (40%), ARID1A (40%), and KRAS (20%) in the 15 Korean OCCCs. Copy number gains in NTRK1 (33%), MYC (40%), and GNAS (47%) and copy number losses in TET2 (73%), TSC1 (67%), BRCA2 (60%), and SMAD4 (47%) were frequent. The significantly altered pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 87% of OCCCs and with chromatin remodeling in 47% of OCCCs. No significant differences in frequencies of genetic alterations were detected between EMS-OCCC and Non-EMS-OCCC groups.

Conclusion

We successfully characterized the genomic landscape of 15 Korean patients with OCCC. We identified potential therapeutic targets for the treatment of this malignancy.

Introduction

Ovarian cancer, the most lethal gynecologic malignancy, imposes a global burden in both developed and developing countries [1]. In Korea, the incidence of ovarian cancer has been gradually increasing and is expected to reach 2.5% (2,618) of new cancer cases and 3.8% (1,168) of all cancer deaths among women in 2017 [2], [3]. Of the histologic types, the majority (90%) of ovarian cancers are epithelial ovarian cancers (EOCs), which are further grouped into different histologic subtypes [4].

Ovarian clear cell carcinoma (OCCC), a subtype of EOC, is known to be less sensitive to chemotherapy and has a poorer prognosis than other histologic EOC subtypes, such as serous or endometrioid adenocarcinomas [5]. OCCC is associated with endometriosis (EMS), which is a common benign condition in reproductive-age women [6], [7]. Interestingly, OCCC is more common in East Asian women than in Western women: it accounts for 24% of EOCs in Japan but only a small portion of EOCs in Western countries [8]. In Korea, OCCC is the fourth most common histologic subtype, which accounts for 10.3% of EOCs, and the incidence of OCCC has increased markedly across all age groups since 1999 [9].

In accordance with the era of precision medicine, it is obvious that reliable genetic diagnosis is essential for providing individualized treatment for patients with OCCC. In OCCC, both a clinical approach, considering the presence of underlying EMS, and a genomic approach, such as those conducted by The Cancer Genome Analysis (TCGA) Group, may be necessary [10]. However, the low incidence of OCCC hinders such integrative genomic analyses. To date, only small genomic studies of OCCC have been reported from some East Asian countries; the genomic landscape of Korean OCCC has not yet been investigated.

The aim of this study was to obtain whole exome sequencing (WES) data of Korean OCCC via the next generation sequencing (NGS) technique. Genomic profiles were compared between EMS-associated OCCC (EMS-OCCC) and Non-EMS-OCCC.

Section snippets

Materials and methods

This retrospective case-control study, using genomic analyses, was conducted after obtaining approval from the Institutional Review Board of Seoul National University Hospital (IRB No. 1609-081-792).

Characteristics of 15 Korean patients with OCCC

The patients' clinicopathologic characteristics are depicted in Table 1. Their median age was 51.1 years. The numbers of patients with stage I, II, and III disease were 9, 2, and 4, respectively. All patients underwent PDS, which was followed by adjuvant chemotherapy in all except two patients. During the median observation period of 23.4 months, two patients had a recurrence and received second-line chemotherapy. Of these, one patient eventually died despite treatment at 19.0 months after

Discussion

In the present study, we successfully characterized the genomic landscape of 15 Korean patients with OCCC. This cancer featured complex genomic alterations. To our knowledge, this is the first report of an NGS WES study in Korean patients with OCCC, as well as the first attempt to compare genomic profiles of OCCC according to the presence or absence of EMS. As TCGA Research Network emphasizes, genomic analyses and identification of alterations will provide new therapeutic approaches and allow

Conflict of interest

No conflicts of interest, relevant to this manuscript, exist.

Ackwnowledgments

This work was supported by a grant from the Seoul National University Hospital Research Fund (Grant No. 04-2016-0310). The biospecimens for this study were provided by the Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea, which is supported by the Ministry of Health and Welfare. All samples, derived from the National Biobank of Korea, were obtained with informed consent under institutional review board-approved protocols.

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