Identification and clinical significance of somatic oncogenic mutations in epithelial ovarian cancer

Abstract

Objective Epithelial 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. Methods A 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. Results Validated 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. Conclusion EOCs 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.

Cancer‑associated gene analysis of cervical cytology samples and liquid‑based cytology significantly improve endometrial cancer diagnosis sensitivity

“…no. 4475346; Thermo Fisher Scientific, Inc.), which covers ~2,800 mutational hotspot regions from 50 cancer-associated genes, as previously described (13)(14)(15). Endometrioid carcinoma is preferentially associated with mutations in PTEN, KRAS, AT-rich interaction domain 1A (ARID1A), catenin β1 (CTNNB1) and PI3K catalytic subunit α (PIK3CA) as well as microsatellite instability, whereas serous (non-endometrioid, type II) carcinoma exhibits HER2 amplification and TP53 and PPP2R1A mutations (16), which were assessed in the present study.…”

Landscape of somatic mutated genes and inherited susceptibility genes in gynecological cancer

“…The frequency of PIK3CA mutations varies across different histological subtypes of OC; while these mutations are rare in high‐grade ovarian serous carcinoma (HG‐OSC) and ovarian mucinous carcinoma (OMC), they have been observed in >40% of cases of ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC) 27–29 . PI3K pathway activation including the PIK3CA mutation was associated with favorable prognosis in OCCC 30,31 .…”

“…PI3K pathway activation including the PIK3CA mutation was associated with favorable prognosis in OCCC 30,31 . A recent study reported that PIK3CA mutations were significantly associated with favorable progression‐free survival (PFS) in OC, especially in the OEC subtype 29 . Although larger prospective cohort studies are needed for evaluation, activation of PIK3CA may be a useful biomarker.…”

Role of RAS signaling in ovarian cancer

“…Very few also harbor mutant PPP2R1A. 77 , 111 , 112 , 132 An elevated frequency of KRAS mutation in the human tissue specimens was hypothesized as the rationale for the chemoresistance and aggressiveness of EnOC. 133 A previous study also demonstrated the significant prevalence of the overexpression and amplification of KRAS gene in the aggressive phenotypes compared to the primary lesions.…”