Frequency of mutations and polymorphisms in borderline ovarian tumors of known cancer genes

Abstract

Borderline ovarian tumors represent an understudied subset of ovarian tumors. Most studies investigating aberrations in borderline tumors have focused on KRAS/BRAF mutations. In this study, we conducted an extensive analysis of mutations and single-nucleotide polymorphisms (SNPs) in borderline ovarian tumors. Using the Sequenom MassArray platform, we investigated 160 mutations/polymorphisms in 33 genes involved in cell signaling, apoptosis, angiogenesis, cell cycle regulation and cellular senescence. Of 52 tumors analyzed, 33 were serous, 18 mucinous and 1 endometrioid. KRAS c.35G>A p.Gly12Asp mutations were detected in eight tumors (six serous and two mucinous), BRAF V600E mutations in two serous tumors, and PIK3CA H1047Y and PIK3CA E542K mutations in a serous and an endometrioid BOT, respectively. CTNNB1 mutation was detected in a serous tumor. Potentially functional polymorphisms were found in vascular endothelial growth factor (VEGF), ABCB1, FGFR2 and PHLPP2. VEGF polymorphisms were the most common and detected at four loci. PHLPP2 polymorphisms were more frequent in mucinous as compared with serous tumors (P=0.04), with allelic imbalance in one case. This study represents the largest and most comprehensive analysis of mutations and functional SNPs in borderline ovarian tumors to date. At least 25% of borderline ovarian tumors harbor somatic mutations associated with potential response to targeted therapeutics.

Figure 1. Expression of beta catenin in a serous borderline ovarian tumour with beta-catenin mutation

In the serous borderline tumour with beta-catenin mutation there is cytoplasmic and notable nuclear localisation with absence of membranous staining (A: X400). This is in contrast to distinct membranous localisation and absence of nuclear localisation in a serous borderline ovarian tumor with wild type beta-catenin (B: X100).

Figure 2. Pyrosequencing results for PHLPP2 polymorphisms

A) Normal female genomic DNA homozygous for PHLPP2 major allele, B) Borderline ovarian tumor heterozygous for major and minor alleles, C) Borderline ovarian tumor with allelic imbalance for the minor allele.