Homologous recombination inquiry through ovarian malignancy investigations: JGOG3025 Study

Abstract

The Cancer Genome Atlas (TCGA) network has clarified that ~50% of high-grade serous ovarian cancers show homologous recombination deficiency (HRD). However, the frequency of HRD in Japanese patients with ovarian cancer remains unclear. We aimed to identify the frequency of HR-associated gene mutations in Japanese patients with ovarian cancer. The JGOG3025 study is a multicenter collaborative prospective observational study involving 65 study sites throughout Japan. We recruited 996 patients who were clinically diagnosed with ovarian cancer before surgery from March 2017 to March 2019, and 701 patients were eligible according to the criteria. We used frozen tumor tissues to extract DNA and performed next-generation sequencing for

Identification of ovarian high-grade endometrioid-type tumors through multi-omics analysis: JGOG3025-TR2 study

“…In the JGOG3025 study, the Japanese Gynecologic Oncology Group (JGOG) collected clinical information and targeted DNA sequencing data for 51 genes in 710 cases of epithelial ovarian cancer, including 298 high-grade serous carcinoma (HGSC) and 24 high-grade (grade 3) endometrioid carcinoma (HGEC) (#7).…”

“…As previously reported (#7), the central pathological review (CPR) was performed by three independent pathologists (Professor Yuko Sasajima, Professor Miki Kushima, and Dr. Masaharu Fukunaga) assigned by the JGOG. Evaluation and diagnosis were based on the WHO classification of tumors of female reproductive organs using only the representative hematoxylin and eosin staining (HE) slides of tumors without any reference to the results of immunohistochemistry (IHC) staining.…”

“…The following were defined as genes associated with homologous recombination repair pathways: ATM, ATR, ATRX, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCL, MLE11, NBN, PALB2, RAD 21, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RECQL4 , and XRCC2 . Since it was unclear whether mutations in these genes cause HRD in the absence of locus-specific loss-of-heterozygosity (LOH) (#7), variants were retained as significant only when the copy number of the minor allele at the locus was 0.…”

“…Epithelial ovarian cancer, which accounts for approximately 90% of ovarian malignancies, includes several major histologic types, including high-grade serous carcinoma (HGSC), low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma (#2). These different histologic types are related to molecular characteristics, including gene expression, DNA methylation, gene mutations, and copy number variations, which influence clinical presentation and response to drug treatment (#4, #5, #6, #7, #8, #9). HGSC is the predominant histologic type, accounting for approximately 70% of epithelial ovarian cancers, and most cases are diagnosed as advanced cases with peritoneal dissemination (#2).…”

Genomic landscape of endometrial, ovarian and cervical cancers in Japan from database in the Center for Cancer Genomics and Advanced Therapeutics

“…In cervical cancers, genomic alterations of PIK3CA are the most common (26%), followed by EP300 (11%) and FBXW7 (11%) 8 . In ovarian cancers, genomic alterations of BRCA1 / 2 (both germline and somatic) and TP53 are common in high-grade serous ovarian carcinomas 9,10 . Genomic alterations of ARID1A and PIK3CA are detected at 30-60% in endometriosis-associated ovarian carcinomas, i.e., endometrioid and clear cell ovarian carcinomas 11 .…”