Comprehensive genomic profiling of high‐grade serous ovarian carcinoma from Chinese patients identifies co‐occurring mutations in the Ras/Raf pathway with TP53

Abstract

High‐grade serous ovarian carcinoma (HGSOC) is a major form of ovarian epithelial tumor that is often diagnosed only at an advanced stage when it is already highly aggressive. We performed comprehensive genomic profiling using an analytically validated clinical next‐generation sequencing assay to identify genomic alterations in 450 cancer‐related genes in a cohort of 88 Chinese HGSOC patients. Overall, we detected 547 genomic alterations with an average of 6.2 alterations per tumor. Most of these HGSOC tumors had low tumor mutation burden and were microsatellite stable. Consistent with earlier studies, TP53 mutations were present in the majority (96.6%) of the tumors studied, and mutations in BRCA1/2 that affect DNA repair were also detected frequently in 20.5% of the tumors. However, we observed a 10.2% of mutated genes in the Ras/Raf pathway, all co‐occurring with TP53 mutations in the same tumor, which was unrecognized previously. Our results show that in HGSOC patients, there may be an unrecognized co‐occurrence of TP53 mutations with mutations in Ras/Raf pathway.

Somatic Mutational Profile of High-Grade Serous Ovarian Carcinoma and Triple-Negative Breast Carcinoma in Young and Elderly Patients: Similarities and Divergences

“…Similarly, Azim and colleagues reported a higher frequency of KMT2C variants in elderly breast cancer patients as well as higher frequencies of KMT2D , another member of the lysine methyltransferase family [ 65 , 76 ]. Alterations affecting the lysine-transferase family genes were also observed in high-grade ovarian cancer patients, ( KMT2A = 2; KMT2C = 3), which is in accordance with a prior study (Zhang, 2021), where alterations in KMT2C were specifically identified in elderly patients, suggesting that these might be biomarkers that are related to the patient’s age [ 62 , 75 ].…”

“…Even though alterations in the RAS and PIK3CA pathways are mostly related to low-grade serous ovarian carcinomas [ 72 , 73 , 74 ], we were able to detect mutations in those genes in 14.3% and 15% of young and elderly HGSOC, respectively. NF1 , which was altered in 5%, and 9.5% of young and elderly patients in the currently presented cohort, usually appears as one of most mutated genes in HGSOC analysis and occurs at higher frequencies of 16%-17% when age is not taken into account [ 62 , 75 ]. However, NF1 may also be altered through structural variants [ 66 ], which were not assessed in this study.…”

Role of RAS signaling in ovarian cancer

“…110 In the comprehensive genomic profiling study, Zhong et al reported that KRAS mutation was a characteristic feature of LGSOC. 108 A report from Zuo et al suggests that KRAS mutations are significantly associated with invasive implants of borderline serous tumor. They found that KRAS mutation is a significant prognostic indicator for tumor recurrence as higher recurrence rate of 71% was observed with patients carrying KRAS mutation wherein it was as low as 21% in patients without KRAS mutation.…”

Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence

“…Intensive preclinical researches have led to identifying Raf kinase inhibitors, as well as inhibitors of its downstream effector MEK kinase. [274][275][276] The results of the completed phase II trials, which evaluated the efficacy of the Ras/Raf/MEK pathway inhibitors in treating gynecological cancers, are summarized in Table 9.…”