Lack ofAPCsomatic mutation is associated with early-onset colorectal cancer in African Americans

Abstract

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.

Decreased copy‐neutral loss of heterozygosity in African American colorectal cancers

“…No other comparison of chromosome losses was significantly different. Together, these results confirm findings of other studies 2‐4 that chromosome‐arm copy number gains and losses occur at similar frequencies in African American and White CRCs.…”

“…We are not the first to suggest a mechanistic difference in the development of CRC in African Americans. Work by our and the Cleveland group identified SNVs in genes in African American CRCs that are rarely observed in White CRCs 4,11,12 . These independent studies present evidence that the tumorigenic processes may differ by ethnic group, but interpretation of results is limited because the sample size of these studies are relatively small and therefore possibly subject to selection bias.…”

“…In each case, tumor heterozygosity was retained outside of the si‐cnLOH but lost inside the segment affected by si‐cnLOH (Table 4). Two of the five CRCs that exhibited si‐cnLOH events overlapped with CRCs from which we had mutation data from our previous exome sequencing study 4 . Although the 24 regions encompassed by si‐cnLOH events overlapped with some gene and promoter regions (Tables S5 and S6), there were no mutations in the two CRCs from which we had exome sequence data that overlapped with regions affected by si‐cnLOH events.…”

“…Fresh CRC tissue samples in the CCCC were collected from five major medical centers in Chicago between 2011 and 2012 6 . Race was assigned by self report and African ancestry was confirmed by ancestry informative markers as described earlier 4 . Tumor samples and noninvolved mucosal samples were obtained during surgery or endoscopy.…”

“…Previous studies have investigated large‐scale CNVs (ie, chromosome gains and losses) in African American CRCs. These studies found that large‐scale CNVs occur at similar frequencies in CRCs in African American and White 2‐4 . However, there is a source of chromosomal instability that has not yet been investigated, namely, copy‐neutral loss of heterozygosity (cnLOH).…”