Age-related differences in gene expression in colorectal cancer (CRC).

Abstract

654 Background: Colorectal cancer (CRC) in young patients is increasing in incidence and is associated with worse outcomes than CRC in older patients. While distinct molecular subtypes of CRC have been recently characterized, it is unclear whether there are molecular differences between the tumors of young and old patients. We sought to identify differences in gene expression of CRC between these two groups. Our discovery analysis identified a gene signature of several differentially expressed RNAs, from which we validated PEG10. The PEG10 gene on chromosome 7q21.3 has been implicated in liver, gallbladder, thyroid, and blood cancers, and is thought to play a role in cancer cell survival and regulation of apoptosis. In hepatocellular carcinoma, increased PEG10 expression has been associated with younger patient age. Methods: RNA sequencing data was obtained from The Cancer Genome Atlas (TCGA) and analyzed for differences in gene expression between patients ≤ 45 years old and those ≥ 65 years old. The identified differentially expressed genes were then validated with qPCR using human CRC tissue from patients ≤ 45 years old and those ≥ 65 years old. Results: RNA sequencing data from patients ≤ 45 years old (n = 29) and patients ≥ 65 years old (n = 299) identified seven genes with increased expression in younger patients: ZNF334 (log2 [fold change] = 2.30), DSC3 (1.78), PEG10 (1.67), CACNA1I (1.54), PKIA (1.33), MAP9 (1.27), and EPHX3 (1.17) (p < 0.07). Validation with qPCR for PEG10 was most promising, and was performed on both young (n = 10, mean age = 39) and old patient samples ( n= 8, mean age = 72). Two cancers (20%) in the young group received radiation treatment and five (50%) received chemotherapy. One cancer (12.5%) in the old group received radiation and two (25%) received chemotherapy. PEG10 had increased expression in the young group with log2 [fold change] = 3.16 (p < 0.02). Conclusions: We have identified a potentially unique gene expression signature for CRC in young patients, which includes PEG10. Functional analysis of PEG10 and other genes is underway using in vitro cell culture, archived human tumor tissue, and mouse tumor models.