592 INPP4B gene is frequently deregulated via copy number alteration and underexpression in ovarian cancer

Introduction/Background* The PI3K/AKT signaling pathway is activated in a wide spectrum of human cancers. INPP4B is a tumor suppressor gene encoding lipid phosphatase type II - a negative regulator of the PI3K signaling. We aimed to determine mechanisms of INPP4B inactivation in ovarian cancer. Methodology Among 194 ovarian cancers studied, there were 126 serous, 23 endometrioid, 18 clear cell, 10 mucinous and 17 other type carcinomas. INPP4B mutations were analyzed in 52 carcinomas using Sanger sequencing method. Analyses of copy number alteration (CNA), mRNA expression and promoter methylation were performed with the use of quantitative PCR (qPCR) method for 194, 144 and 125 ovarian carcinomas, respectively. Five specimens of noncancerous fallopian tube constituted a control group. Statistical analyses were done with Fisher’s exact test, χ2 and Mann-Whitney U tests. Result(s)* One INPP4B missense mutation, c.1659G>A, p.(Gly554Ser), was detected in two carcinomas (3.8%, 2/52) of clear cell and serous type. The INPP4B CNA was found in 82 out of 194 (42.3%) ovarian cancers. There were 25.3% (49/194) allelic losses and 17% (33/194) amplifications at the INPP4B locus. Allelic loss was associated with high-grade (P = 0.031) and advanced FIGO stage (P = 0.011) tumors. Reduced copy number was more common in carcinomas with PIK3CA amplification (P = 0.014) and PIK3R1 allelic loss (P = 0.001). The INPP4B copy loss was mutually exclusive with PTEN mutations (P = 0.035). The INPP4B mRNA expression was significantly decreased in ovarian cancers compared with control tissues (P = 0.004). The difference in mean expressions between carcinomas and normal tissues was 57% (0.099 ± 0.12 vs 0.231 ± 0.11). We did not observe an association between decreased mRNA level and copy number loss of the gene. Lower levels of INPP4B mRNA were more frequent in cancers with wt PTEN, PIK3R1 and KRAS genes (P = 0.038). INPP4B promoter wasn’t methylated in any of 125 ovarian carcinomas. Conclusion* A part of ovarian cancers have a reduced INPP4B copy number and mRNA expression. This may be an alternative pathway of PI3K activation in these tumors. Copy number loss is more common in cancers with aggressive tumor phenotype. This study was supported by the grant no. 2016/23/B/NZ5/00572 of the National Science Centre, Poland