Abstract
ObjectiveEpithelial ovarian cancer (EOC) is a heterogeneous disease with diverse clinicopathological features and behaviors, and its heterogeneity may be concerned with the accumulation of multiple somatic oncogenic mutations. The major goals of this study are to systematically perform the comprehensive mutational profiling in EOC patients, and investigate the associations between somatic mutations and clinicopathological characteristics.MethodsA total of 80 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery, and genomic DNAs were extracted from fresh-frozen tissues. We investigated mutational status in hot spot regions of 50 cancer-related genes by targeted next-generation sequencing using an Ion AmpliSeq Cancer Hotspot Panel v2 Kit.ResultsValidated mutations were detected in 66 of the 80 tumors (82.5%). The five most frequently mutated genes were TP53 (43.8%), PIK3CA (27.5%), KRAS (23.8%), PTEN (10%) and CTNNB1 (10%). PTEN and CTNNB1 mutations were associated with younger age. PIK3CA1, KRAS and CTNNB1 mutations were observed in early-stage, whereas TP53 mutations were more common in advanced stage. Significant associations were observed between TP53 mutation and serous carcinoma, and between KRAS mutation and mucinous carcinoma. Both PIK3CA mutation and CTNNB1 mutation were also significantly associated with endometrioid and clear cell carcinoma. The patients with PIK3CA and KRAS mutations were significantly associated with favorable progression free survival (PFS). In particular, PIK3CA mutations had more significant associations with favorable PFS than PIK3CA wild-type in the endometrioid subtype (P = 0.012). Patients with mutations only in TP53 were significantly associated with worse PFS.ConclusionEOCs were heterogeneous at the genomic level and harbored somatic oncogenic mutations. Our molecular profiling may have the potential for becoming a novel stratification within histological subtypes of EOC. Further studies are needed to define molecular classification for improved clinical outcomes and treatment of EOC patients in future.
Highlights
Epithelial ovarian cancer (EOC) is the seventh most common cancer in women and the eighth most common cause of death from cancer in women worldwide [1, 2]
Recurrence was detected during the follow-up period in 43 (53.8%) patients: 17 (21.3%) patients were alive with disease; 24 (30%) patients died due to tumor progression
TP53 mutations did not influence the EOC survival, in the subgroup analysis, patients with mutations only in TP53 were significantly associated with worse progression free survival (PFS) compared to those with TP53 WT (P = 0.008) or those with TP53 mutation with other mutations (P = 0.006) (Fig. 3d) Regarding overall survival (OS), as shown in Table 3, a significant association was only found with stage (P < 0.001), and age, histology, and mutations of TP53, PIK3CA, KRAS, PTEN and CTNNB1 had no significant associations
Summary
Epithelial ovarian cancer (EOC) is the seventh most common cancer in women and the eighth most common cause of death from cancer in women worldwide [1, 2]. Type I cancers include low-grade serous cancer, endometrioid cancer, mucinous cancer, and clear cell cancer, which harbor somatic mutations such as BRAF, KRAS and PTEN, often with microsatellite instability (MSI). They are characterized by an indolent behavior diagnosed in early-stage, and arise in a stepwise process from borderline neoplasms [5,6,7]. The classification of type I and II tumors better reflects the molecular diversity of EOC, the molecular biological heterogeneity of type I and II tumors has yet to be revealed
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