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- Lack of APC somatic mutation is associated with early-onset colorectal cancer in African Americans.
- Paper ID
- Department of Medicine and Cancer Center, Yale University, CT.
PMID: 30239619 (view at PubMed or Europe PMC)
- African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared to other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared to non-Hispanic whites (NHWs). To gain insight into 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). Two of the 45 tumors contained POLE mutations. In the remaining 43 tumors, only 27 (63%) contained loss-of-function mutations in APC compared to 80% of TCGA NHW CRCs. APC mutation-negative CRCs were associated with an earlier onset of CRC (p=0.01) and with previous cancer (p=0.06). They were also associated with lower overall mutation burden, fewer copy number variants, and a DNA methylation signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease. Three of the APC mutation-negative CRCs had loss-of-function mutations in BCL9L. Mutations in driver genes identified by TCGA exome analysis were less frequent in AA colorectal cancer cases than TCGA NHWs. Genes that regulate the WNT signaling pathway, including SOX9, GATA6, TET1, GLIS1, and FAT1, were differentially hypermethylated in APC mutation-negative CRCs, suggesting a novel mechanism for cancer development in these tumors. In summary, we have identified a subtype of CRC that is associated with younger age of diagnosis, lack of APC mutation, microsatellite and chromosome stability, lower mutation burden, and distinctive methylation changes.
- Paper Status