Exome Sequencing Landscape Analysis in Ovarian Clear Cell Carcinoma Shed Light on Key Chromosomal Regions and Mutation Gene Networks

Abstract

Previous studies have reported genome-wide mutation profile analyses in ovarian clear cell carcinomas (OCCCs). This study aims to identify specific novel molecular alterations by combined analyses of somatic mutation and copy number variation. We performed whole exome sequencing of 39 OCCC samples with 16 matching blood tissue samples. Four hundred twenty-six genes had recurrent somatic mutations. Among the 39 samples, ARID1A (62%) and PIK3CA (51%) were frequently mutated, as were genes such as KRAS (10%), PPP2R1A (10%), and PTEN (5%), that have been reported in previous OCCC studies. We also detected mutations in MLL3 (15%), ARID1B (10%), and PIK3R1 (8%), which are associations not previously reported. Gene interaction analysis and functional assessment revealed that mutated genes were clustered into groups pertaining to chromatin remodeling, cell proliferation, DNA repair and cell cycle checkpointing, and cytoskeletal organization. Copy number variation analysis identified frequent amplification in chr8q (64%), chr20q (54%), and chr17q (46%) loci as well as deletion in chr19p (41%), chr13q (28%), chr9q (21%), and chr18q (21%) loci. Integration of the analyses uncovered that frequently mutated or amplified/deleted genes were involved in the KRAS/phosphatidylinositol 3-kinase (82%) and MYC/retinoblastoma (75%) pathways as well as the critical chromatin remodeling complex switch/sucrose nonfermentable (85%). The individual and integrated analyses contribute details about the OCCC genomic landscape, which could lead to enhanced diagnostics and therapeutic options.

A Clinical and Molecular Phase II Trial of Oral ENMD-2076 in Ovarian Clear Cell Carcinoma (OCCC): A Study of the Princess Margaret Phase II Consortium

“…There was no PTEN variant (SNVs and indels; refer to methods section) detected by NGS in our analyses, consistent with previous observations in a whole exome study [31]. In this study, the mutations that both lead to an elevated signalling through the PI3K pathway [31].…”

“…In this study, the mutations that both lead to an elevated signalling through the PI3K pathway [31]. These results indicate that other mechanisms rather than sequence mutations are involved in activating the pathway for OCCC with wild-type PIK3CA.…”

Establishment and characterization of patient‐derived organoids from a young patient with cervical clear cell carcinoma

“…Given the low number of studies with cCCC, we referred to studies in ovarian CCC, which is the second most common ovarian epithelial cancer in Japan . For example, chromosomal gains and losses identified in cCCC resembled those of ovarian CCC previously documented . In addition, copy number gain of MET and protein overexpression of MET in cCCC were previously documented in ovarian CCC .…”

Clear cell carcinomas of the ovary and kidney: clarity through genomics

“…Focal amplification of chromosomes 3q12–29 and 8p23 was observed in a cohort of Japanese and Chinese CCOCs . Exome sequencing and array comparative genomic hybridization also identified frequent arm‐level copy number changes, including amplification in chromosomes 8p (64%), 20q (54%), 17q (46%), and 3p (26%), which contain genes for CCOC‐associated proteins such as MYC , ZNF217 , HNF1b , and PIK3CA , respectively . Whole genome sequencing of seven CCOC tumours identified deletions in chromosomes housing RB1 , NOTCH1 , and a few genes encoding members of the SWI–SNF complex .…”