1033 Genetic and Epigenetic Features in Synchronous Colorectal Cancer Cases Versus Solitary Cancers, Utilizing 1243 Colorectal Cancer Patients From Two Large Prospective Cohort Studies

Abstract

Background & Aims: Synchronous colorectal cancers refer to two or more primary colorectal carcinomas detected in a single individual at the time of the first diagnosis of colorectal cancer. Synchronous neoplasias, which arise in a background of common etiologic (genetic or environmental) factors, can provide a unique model to examine molecular aberrations. Previous studies have reported several molecular features in synchronous colorectal cancers. However, in all of these studies, control solitary cases were retrospectively selected, thereby subject to potential selection bias. In this study, we analyzed data collected from 32 patients with synchronous colorectal cancers and 1211 solitary cancers (controls) in 2 well-characterized, large prospective cohort studies. Methods: Tumor tissue specimens were analyzed for methylation in LINE-1 and 16 CpG islands (CACNA1G, CDKN2A [p16], CRABP1, IGF2, MLH1, NEUROG1, RUNX3, SOCS1, CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14 [CDKN2A/ARF], and WRN); microsatellite instability (MSI) status; CpG island methylator phenotype (CIMP) status; KRAS, BRAF, and PIK3CA mutations; and expressions of DNA methyltransferase-3B (DNMT3B) and JC virus T-antigen (JCVT). Results: BRAF mutations were significantly more common in synchronous cancers (30%=9/30; p=0.0080) than in solitary cancers (13%=158/1198). Likewise, synchronous cancers were more commonly CIMP-high (p=0.047) and MSI-high (p=0.030), compared to solitary controls, whereas no association was found between tumor synchronicity and other molecular markers. Considering the confounding effect by age, we constructed a logistic regression model including age, BRAF mutation, CIMP-high, MSI-high and synchronicity status as an outcome variable. As a result, the association between BRAF mutation (p=0.010), CIMP-high (p=0.038), MSIhigh (p=0.033) and tumor synchronicity persisted, while age was no longer associated with tumor synchronicity. Among the 32 synchronous cancer cases, 12 synchronous cases could provide cancer tissues from both of two cancers in synchronous pairs. We found that methylation levels of LINE-1 (Spearman r=0.76; p=0.0062) and levels of CpG island methylation (p<0.0001) correlated between synchronous pairs from the same individuals. Conclusions: Compared with solitary cancers, synchronous colorectal cancers more commonly show BRAF mutations, CIMP-high, and MSI-high. In addition, synchronous colorectal cancer pairs exhibit a significant correlation of LINE-1 methylation levels and concordance in CpG island methylation. Our study may be an important one step forward to elucidate clinical and molecular characteristics of synchronous colorectal cancers.