Genomic analysis of ovarian clear cell carcinomas and uterine corpus endometrial carcinomas using next generation sequencing

Abstract

Gynecologic Cancer, occurred in reproductive organs, including the cervix, ovaries, uterus, fallopian tubes, vagina and vulva, is one of the cancers that women have most often been affected. Especially, ovarian cancer and uterine corpus cancer of gynecologic cancers are in the 10 leading types of estimated new cancer cases and death in 2017. In accordance with the era of precision medicine, reliable genetic diagnosis is essential for providing individualized treatment of the cancers. Recently, many groups including The Cancer Genome Atlas have been researched for the genetic profiling of this cancers to broaden the understanding of gynecologic cancer. However, in the cases of ovarian clear cell carcinoma (OCCC) and uterine corpus endometrial carcinoma (UCEC), only small genomic studies have been reported, and the genetic understandings of these cancers are not fully elucidated until now. <br/> <br/> In the first chapter, comprehensive genomic characterization of OCCCs was performed and analyzed via whole exome sequencing (WES) with blood samples and fresh cancer tissues. The samples were collected from the fifteen patients with ovarian clear cell carcinoma (OCCC) from 2012 to 2016, and stored at the Seoul National University Hospital Human Biobank. The sequencing data of the fresh OCCC tissues was characterized by analyzing genomic alterations (somatic mutations and somatic copy number variations). A median of 178 exonic mutations (111-25,798) and a median of 343 somatic copy number variations (43-1,820) were found per tumor sample. In all, 54 somatic mutations including PIK3CA, ARID1A, and KRAS were found in the 15 Korean OCCCs. Copy number amplifications in NTRK1, MYC, and GNAS and copy number deletions in TET2, TSC1, BRCA2, and SMAD4 were frequently detected in 15 OCCCs. The somatically altered pathways were associated with proliferation and survival pathways (including the PI3K/AKT, ERBB2, and TP53 pathways) in 87% of OCCCs, and with chromatin remodeling pathway in 47% of OCCCs. No significant differences in frequencies of genetic alterations were detected between OCCC with endometriosis and OCCC groups without endometriosis. <br/> <br/> In the second chapter, clinical characteristics and corresponding genomic data were analyzed via sequencing data of 370 patients with UCEC from The Cancer Genome Atlas (TCGA) database, and factors associated with survival outcomes were also investigated. The analyses suggest that the LYL1 gene amplification was observed in 22 patients (5.9%) with UCEC. Patients with LYL1 gene amplification were significantly older at the time of diagnosis and more often were marked by non-endometrioid, high-grade, or advanced disease. Multivariate analyses, adjusted for tumor histologic type, grade, and stage, did not confirm LYL1 gene amplification as an independent prognostic factor for either progression-free survival (PFS) or overall survival (OS) clearly. However, in survival analyses, PFS and OS rates (3-year PFS: 34.4% vs. 79.9%, P=0.031