Abstract 4927: Identification of novel candidate of driver genes on chromosome 7 in colorectal cancer

Abstract

Abstract Background Colorectal cancer(CRC) is one of the most common types of cancer worldwide. Its high mortality rate is serious problems. Hence it is urgently necessary to identify novel molecular target to improve it. Gain of chromosome 7 is frequently found in CRC, and it has been considered to harbour driver genes that promote tumorigenesis or tumor progression by the gain of function. The aim of this study is to identify novel candidate driver genes on chromosome 7 and to clarify the clinical significance of their expression in CRC. Material and Methods 1. We have selected the candidate genes which satisfied the following criteria using CRC data from The Cancer Genome Atlas (TCGA), 1) their DNA copy number and the mRNA expression is positively correlated with each other, 2) overexpressed in tumor tissues compared to normal tissues. 2. We measured the mRNA expression of the candidate genes in 125 surgically-resected primary CRC tissues and the paired normal colon tissues in our hospital by quantitative RT-PCR. Difference of mRNA expression between CRC tissues and normal colon tissues was analyzed by Mann Whitney U-test. 3. Survival analysis between high and low expression group of the candidate genes was performed by Kaplan-Meier method. Correlation between the mRNA expression of the candidate genes and clinicopathological factors were analyzed by Fisher's exact test. 4. We performed Gene Set Enrichment Analysis (GSEA) in CRC data from TCGA to elucidate the correlation between the candidate genes and gene sets that are associated with tumorigenesis or tumor progression. Results We focused on phosphoserine phosphatase(PSPH), the rate-limiting enzyme in serine biosynthesis pathway(SSP), as a novel candidate driver gene on chromosome 7 in CRC. PSPH expression was significantly higher in CRC tissues than in normal colon tissues (p<0.005). PSPH expression positively correlated with depth of invasion (p<0.05), venous invasion (p<0.05), and distant metastasis (p<0.05). The high PSPH expression group had a significantly poorer prognosis than the low expression group (p<0.001). On multivariate analysis, high PSPH expression was an independent prognostic factor affecting 5-years OS (p<0.005) with hazard ratios (95% CI) of 4.85(1.77-16.2) among conventional clinicopathological factors. The high PSPH expression group in TCGA data set also had poorer prognosis than the low expression group (p<0.05). GSEA showed that PSPH expression was positively correlated with expression of gene set of c-Myc-downstream. Conclusions We identified PSPH as a promising candidate driver gene on chromosome 7. Moreover, PSPH expression was a prognostic factor in CRC. It has been reported that c-Myc upregulates expression of SSP enzymes including PSPH. Therefore, PSPH is suggested to be involved in tumorigenesis or tumor progression as a downstream molecule of c-Myc in CRC. PSPH should be an important gene on chromosome 7 to promote the progression of CRC. Citation Format: Kuniaki Sato, Qingjiang Hu, Shinya Kidogami, Yushi Ogawa, Tomoko Saito, Sho Nambara, Hisateru Komatsu, Hidenari Hirata, Shotaro Sakimura, Ryutaro Uchi, Naoki Hayashi, Tomohiro Iguchi, Hidetoshi Eguchi, Shuhei Ito, Takaaki Masuda, Takashi Nakagawa, Koshi Mimori. Identification of novel candidate of driver genes on chromosome 7 in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4927.