Abstract
Background: Recent reports have shown that chromosomal copy number gains and losses associated with the development of colorectal cancer (CRC) occur at similar frequencies in Whites and African Americans (AAs), but no studies have compared copy-neutral loss of heterozygosity (cnLOH) between these two populations. cnLOH can arise by at least two different mechanisms. One involves recombination between homologous chromosomes, but cnLOH most commonly arises from mis-segregation of chromosomes via a mitotic form of uniparental disomy. Preliminary analysis of copy number data from Chicago AA CRC cases by our lab suggested that cnLOH occurred less frequently in AA CRCs. The present study aimed to use publicly available data from The Cancer Genome Atlas (TCGA) to test whether cnLOH was less frequent in AA CRC cases in the TCGA.
Methods: Raw Affymetrix GenomeWide SNP Array 6.0 files were obtained from TCGA Data Portal and processed using R package Rawcopy and PennCNV to determine segments of loss, gain, and cnLOH. Samples from AAs and Whites were processed separately, using normals from their respective populations as reference. cnLOH events involving less than 20 markers were removed, and the proportion of each chromosome arm affected by cnLOH was calculated for each tumor. Chromosome arms with over 50% cnLOH were counted as cnLOH events. Linear regression models were used to determine associations between the number of chromosome arm events and clinical variables. AA and White cases were identified per TCGA clinical data. Additionally, logistic regression models were used to determine associations between affected and unaffected tumors, defining affected as a tumor with > 2 cnLOH events. The value of 2 was chosen because it was the median value of cnLOH events per tumor among all samples. Chromosome arm-specific differences were tested by Fisher exact tests, using a Bonferroni correction to adjust for multiple testing.
Results: Data from 56 AA and 210 White CRCs were analyzed. Race was associated with a decreased number of cnLOH events per tumor, with AA CRCs on average having significantly fewer chromosome arms affected than White CRCs (p = 0.01). This difference remained significant after correction for age at diagnosis, sex, stage, and BMI. Additionally, AA CRCs were half as likely to have developed more than two cnLOH events compared to White CRCs. In AA CRCs, the frequency of cnLOH events was lower on 32 of the 39 chromosome arms compared to frequency of cnLOH events in White CRCs. Chromosomes 17p and 5q were the arms most frequently subject to cnLOH, comprising 13% of all cnLOH events in White tumors and 15% of all cnLOH events in AA tumors. 19.6% and 17.9% of AA CRC cases had cnLOH events on 17p and 5p, respectively, whereas 24.8% and 24.3% of White CRC cases had events on 17p and 5p. These differences were not significant. cnLOH of chromosome 6p was nominally significantly different (3% of AA cases vs 17% of White cases, p = 0.009); however, that difference did not remain significant after adjustment for multiple testing. No other differences were significant. No differences were found in chromosome arm gains or losses.
Conclusions: The results in our present study show that cnLOH affects AA CRCs less than White CRCs. cnLOH is not a rare event in CRC. Only 64 of 266 CRCs examined from TCGA (~24%) had zero chromosome arms affected. This mechanism of genomic instability is more frequent for certain chromosome arms, specifically chromosomes 5q and 17p, where the known tumor suppressors APC and TP53 are located. In AA CRCs, the majority of chromosome arms showed lower levels of cnLOH, suggesting that the difference in the frequency of cnLOH events is the result of a reduced susceptibility to cnLOH and not of the selective action of different cancer driver genes. Taken together, these results suggest that there is a racial difference in mechanisms that drive genomic instability as it affects and drives CRC.
Citation Format: Gaius J. Augustus, Nathan A. Ellis. Copy-neutral loss of heterozygosity is decreased in African American colorectal cancers [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B52.
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