Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing

Abstract

Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian cancer and more prevalent in Japanese than Caucasians (25% and 5% of all ovarian cancer, respectively). The aim of this study is to discover the genomic alterations that may cause OCCC and effective molecular targets for chemotherapy. Paired genomic DNAs of 48 OCCC tissues and corresponding noncancerous tissues were extracted from formalin-fixed, paraffin embedded specimens collected between 2007 and 2015 at Tohoku University Hospital. All specimens underwent exome sequencing and the somatic genetic alterations were identified. We divided the cases into three clusters based on the mutation spectra. Clinical characteristics such as age of onset and endometriosis are similar among the clusters but one cluster shows mutations related to APOBEC activation, indicating its contribution to subset of OCCC cases. There are three hypermutated cases (showing 12-fold or higher somatic mutations than the other 45 cases) and they have germline and somatic mismatch repair gene alterations. The frequently mutated genes are ARID1A (66.7%), PIK3CA (50%), PPP2R1A (18.8%), and KRAS (16.7%). Somatic mutations important for selection of chemotherapeutic agents, such as BRAF, ERBB2, PDGFRB, PGR, and KRAS are found in 27.1% of OCCC cases, indicating clinical importance of exome analysis for OCCC. Our study suggests that the genetic instability caused by either mismatch repair defect or activation of APOBEC play critical roles in OCCC carcinogenesis.

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

“…Mutations in the SWI/SNF (SWItch/Sucrose Non‐Fermentable) chromatin‐remodeling complex genes, the PI3K/Akt signaling pathway, and the receptor tyrosine kinase (RTK)/Ras signaling pathway are the major molecular aberrations observed in nearly 50%, 40%, and 29% of OCCCs, respectively. Among the SWI/SNF subunits, AT‐rich interaction domain 1A ( ARID1A ) is the most frequently mutated gene, detected in 40% to 67% of OCCCs . In the PI3K signaling pathway, activating mutations in PIK3 catalytic subunit α ( PIK3CA ) (33%) and loss of phosphatase and tensin homolog ( PTEN ) (37%) are the most common aberrations .…”

Identification of novel mutations of ovarian cancer-related genes from RNA-sequencing data for Japanese epithelial ovarian cancer patients

“…In CCC, mutations of the AT-rich interactive domain A (ARID1A) and/or phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit α (PIK3CA) are commonly observed in Caucasian [11]. Japanese ovarian CCC patients were reported to have higher mutation ratio of ARID1A (67-78%) compared to Caucasian, while similar or lower mutation ratio of PIK3CA (11-50%) compared to Caucasian [12,13]. In EC, aberrations have been reported in the Wnt signaling pathway involving the somatic mutations of catenin β1 (CTNNB1) and phosphatase and tensin homologue (PTEN) [14].…”

“…MC is thought to be malignantly transformed from borderline mucinous tumor, and the most common molecular lesions are observed in the proto-oncogene KRAS (a GTPase [KRAS] mutation); this has been consistently identified in 50-65% of patients with MC [16,17]. Among Japanse patients, KRAS mutation ratio in MC cases was similar to that among Caucasian whereas that in CCC cases (25.9%) was much higher than Caucasian (7%) [12,18].…”

Endometriosis and cancerogenesis of the ovaries (a review)

“…Предполагается, что мутация в гене ARID1A происходит в начале опухолевого генеза; это в сочетании с другой генетической мутацией приводит к болезни. Мутации ARID1A обнаружены у 41-57% пациентов со светлоклеточной опухолью яичников, у 30-48%с эндометриоидной опухолью яичников, приблизительно у 40% -при эндометриозе и у 15-20% с доброкачественной эндометриоидной овариальной кистой [27].…”

“…В исследовании Y. Shibuya и соавт. [27] с помощью секвенирования генома изучен характер соматических мутаций при светлоклеточном раке яичников. Наиболее часто были подвержены мутациям гены: ARID1A, PIK3CA, PPP2R1A, KRAS.…”