High Frequency of PIK3CA Mutations in Low-Grade Serous Ovarian Carcinomas of Japanese Patients.

Tomoka Ishibashi,Satoru Kyo,Satoru Nakayama,Masako Ishikawa,Kohei Nakamura,Noriyoshi Ishikawa,Kentaro Nakayama,Sultana Razia,Hitomi Yamashita,Koji Iida,Hiroko Kurioka,Yoshiro Otsuki,Puja Dey

doi:10.3390/diagnostics10010013

Abstract

The frequency of KRAS/BRAF mutations associated with low-grade serous ovarian carcinoma (LGSC)/serous borderline tumors (SBTs) in Japan is unknown. We aimed to identify genetic variations in KRAS, BRAF, PIK3CA, and ERBB2 in LGSC/SBT/serous cystadenomas (SCAs) in a Japanese population. We performed a mutation analysis (by Sanger sequencing) of 33 cases of LGSC/SBT/SCA and 4 cases of LGSC with synchronous SBTs using microdissected paraffin-embedded sections. Immunohistochemistry of p53 and ARID1A was also performed. The frequency of oncogenic mutations in PIK3CA was 60.0% (6/10) in LGSCs, 63.6% (7/11) in SBTs, and 8.3% (1/12) in SCAs. All cases harbored wild-type KRAS. The frequency of BRAF mutations was 20.0% (2/10) in LGSCs, whereas all SBTs and SCAs harbored the wild-type allele. The frequency of ERBB2 mutations was 30.0% (3/10) in LGSCs, 0.0% (0/11) in SBTs, and 16.7% (2/12) in SCAs. ARID1A staining was positive in all cases. p53 staining was positive in 0% (0/10) LGSCs, 9.1% (1/11) SBTs, and 0.0% (0/12) SCAs. One LGSC case had two PIK3CA mutations (G1633A and G3149A) in both LGSC and SBT lesions, but a BRAF mutation was detected only in an LGSC lesion. These results suggest that, compared with the values in Western populations (16–54%), the KRAS mutation frequency in LGSCs/SBTs is lower and that of PIK3CA mutations in LGSCs/SBTs is much higher in Japanese populations. Therefore, the main carcinogenesis signaling pathways may be different between Japanese and Western LGSCs. Molecular therapies targeting the PIK3CA/AKT pathway may be effective in LGSCs in Japan.

Highlights

Ovarian cancer is the leading cause of death owing to gynecologic malignancies in the world [1].Recently, ovarian cancer was subdivided into two categories, Type I and Type II [2]
We evaluated the prevalence of KRAS, BRAF, PIK3CA, and ERBB2 mutations in Japanese low-grade serous ovarian carcinoma (LGSC), clarifying the genetic drivers of these mutations and the difference in mechanisms of carcinogenesis between Japanese and European LGSCs
Wild-type KRAS was found in all Japanese LGSC, SBT, and SCA cases

Summary

Introduction

Ovarian cancer is the leading cause of death owing to gynecologic malignancies in the world [1]. Ovarian cancer was subdivided into two categories, Type I and Type II [2]. Type II tumors mainly include high-grade serous carcinomas (HGSCs) with TP53 mutations and show an aggressive clinical course. Type I tumors include low-grade serous carcinomas (LGSCs), mucinous. LGSCs are more common in younger patients and associated with chemoresistance than HGSCs. Previous reports from Western countries have indicated that LGSCs have a higher frequency of KRAS (16–54%) or BRAF (2–33%) mutations [3,4,5]. KRAS/BRAF/ERK signaling pathways are thought to be essential in the carcinogenesis of LGSC in Europe

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