Background: Ovarian cancer is the seventh most common cancer in women worldwide among which the most frequently occurred histological type is serous ovarian cancer (SOC). Since efficacious treatments for SOC have not advanced beyond platinum-based combination chemotherapy and more than 75% of high-grade SOC will relapse after first-line therapy, it is urgent to observe the genomic abnormalities and identify novel therapeutic targets and prognosis biomarkers. Methods: In order to comprehensively identify molecular features of serous ovarian cancer, we performed targeted sequencing with 425 cancer-related genes on four serous ovarian tumor (SOT) cohorts, classified as ovarian serous adenoma (OSA), ovarian serous borderline tumor (OSBT), low-grade serous cancer (LGSC) and high-grade serous cancer (HGSC). The association between genetic alterations and patients’ overall survival (OS) was analyzed. Results: Genomic profiling revealed distinct molecular features among these four cohorts. The frequency of genetic alterations in OSA was relatively low, and in OSBT cohort, the predominantly mutated genes, BRAF and KRAS, were identified at prevalence of 52.6% (10/19) and 36.8% (7/19) respectively with two patients harbored both these two mutations. In LGSC cohort, alterations of KRAS still occupied the highest percentage of patients which was up to 50.0% (5/10) while BRAF was not common (1/10, 10.0%). The most frequently mutated gene was TP53 in HGSC (46/47, 97.9%), whereas BRAF or KRAS mutation was rare. Meanwhile, a higher prevalence of gene copy gains in PTK2 (12/47, 25.5%), MYC (9/47, 19.1%), MDM4 (5/47, 10.6%) and ZNF217 (5/47, 10.6%) were identified only in HGSC group which indicated cancer progression promoted by chromosomal instability in this group. The median tumor mutational burden (TMB) and chromosome instability score (CIS) in cases with LGSC and HGSC higher than that in OSBT. Additionally, analysis of DNA damage repair (DDR) relevant genes showed most altered genes enriched in homologous recombination (HR) pathway in HGSC. Finally, we correlated genomic profiles with overall survival (OS) and found that PIK3CA wildtype or chromosome instability score (CIS) low patients had significantly longer OS in HGSC. Conclusion: In this study, we revealed the comprehensive genomic profiling among four SOT cohorts. Additionally, we correlated PIK3CA status and first associated chromosome instability with clinical outcomes of patients and found them to be useful clinical biomarkers in HGSC prognosis.
Chromosome instability is prevalent and dynamic in high-grade serous ovarian cancer patient samples
