Abstract IA26: Mechanistic differences in early-onset colorectal cancer

Abstract

Abstract African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared to other US populations. AAs present with more right-sided, microsatellite stable disease, and they are diagnosed at earlier ages compared to non-Hispanic whites (NHWs). Data from the Chicago Colorectal Cancer Consortium (CCCC) suggest that the right-sided and early-onset CRCs are distinct diseases, because early-onset CRC arises more often in the distal colon (1). In addition, analysis of stage at presentation data from the SEER database suggests that early-onset CRC is on average a more rapidly developing disease that is less likely to be prevented by colonoscopy (2). To better understand these trends, we conducted exome sequencing (n=45), copy number (n=33), and methylation analysis (n=11) of microsatellite stable AA CRCs. Results were compared to data from The Cancer Genome Atlas (TCGA). In the 43 non-hypermutable tumors, only 27 (63%) contained loss-of-function mutations in APC as compared to 80% of TCGA NHW CRCs. Importantly, APC mutation-negative CRCs were associated with an earlier age of onset of CRC (p=0.01). In the TCGA, APC mutation-negative CRCs were also associated with an earlier age of onset of CRC (p=10−5). In CCCC CRCs, APC mutation-negative CRCs were also associated with previous cancer, lower overall mutation burden, and fewer copy number variants. We conducted an analysis of DNA methylation patterns and found an epigenetic signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease, referred to as CIMP. Included in the list of genes that were differentially hypermethylated in APC mutation-negative CRCs were genes that regulate the WNT signaling pathway, such as SOX9, GATA6, TET1, GLIS1, and FAT1. Using the most variable differentially methylated regions from the CCCC data, we found that these regions similarly clustered in APC mutation-negative CRCs from the TCGA. These data strongly suggest that a novel epigenetic mechanism accounts for cancer development in early-onset CRCs. Contrary to the mechanism that predominates in later-onset CRC, the early-onset mechanism does not depend on mutation in the APC gene but is associated with differential methylation of WNT pathway regulating genes instead. Our data support the claim that early-onset CRC is driven by a distinct subtype of CRC that is associated with lack of APC mutation, microsatellite and chromosome stability, lower mutation burden, and distinctive DNA methylation changes. CRC driven by epigenetic changes is consistent with the epidemiologic data suggesting that early-onset CRC develops as a more rapidly advancing disease. A deeper understanding is needed of the pathways affected by the epigenetic changes and the exposures that drive those changes in order to develop therapeutic approaches to early-onset CRC.