Abstract PR02: Homologous recombination drives African American colorectal carcinogenesis

Background: African Americans (AAs) have the highest incidence and mortality rates of colorectal cancer (CRC) cases in the United States, with higher levels of early-onset and right-sided CRC, yet there are little data on carcinogenesis in AA CRC. Copy number variations (CNVs) affect large portions of the cancer genome, and they provide information about mechanisms of cancer initiation and progression. Given the unique clinical-pathological features of AA CRC, we hypothesized that different mechanisms operate in colorectal carcinogenesis in AAs. To test this hypothesis, we evaluated CNVs in AA CRC as compared to publically available data on CRC from the TCGA. Methods: Tumor DNA samples from 46 AA CRC cases were available through the Chicago Colorectal Cancer Consortium. Determinations of CNVs were performed using the Affymetrix Cytoscan HD platform, which provides data from 2.67 million copy number probes and 750,000 genotype probes for analysis of loss of heterozygosity (LOH) with and without copy number change. Whole chromosome-arm gains and losses were defined as the gain or loss of >50% of probes on an arm. Gains and losses were tabulated and compared to data from the TCGA. Statistical analyses of arm losses and gains were performed with Fisher exact tests, adjusting for multiple testing using a Bonferroni correction. Statistical analysis of total chromosome number alterations was performed with the chi-square test. Results: Overall, significantly fewer chromosome-arm gains and losses occurred in AA CRC cases than in TCGA CRC cases with 10% of gains and losses in AA and 34% of gains and losses from TCGA (p The difference in chromosome-arm gain and loss was not the result of segmental gain or loss. However, analysis of genotype data revealed that copy-number neutral LOH in AA CRC cases substantially compensates for the lower frequency of chromosome-arm losses and focal amplifications for the lower frequency of gains. For example, in AAs, for chromosomal region 17p where TP53 localizes, 24% of cases exhibited 17p loss and 26% exhibited copy-number neutral LOH, for a total of 50% TP53 loss. For chromosomal region 13q where CDK8 localizes, 26% of cases exhibited 13q gain and 28% exhibited focal gains around CDK8, for a total of 54% CDK8 gain. The total frequency of tumor-suppressor gene losses and oncogene gains was similar in AA CRC and TCGA cases. Conclusion: These data show that, although the major carcinogenesis genes (as identified by LOH and gene amplification) appear to be similar in AA and TCGA CRC cases, the mechanisms of genomic instability that generate these genetic changes are different. Chromosome-arm losses are more frequent in TCGA CRC cases whereas AA CRC is driven by homologous recombination and segregation resulting in copy-number neutral LOH. Chromosome-arm gains are more frequent in TCGA CRC cases whereas AA CRC is driven by focal amplification, which could result from unequal sister chromatid exchange. Thus, these CNV differences could reflect variation in the regulation of fundamental genomic integrity mechanisms in AAs. More studies are needed to confirm these results and elucidate the mechanisms of carcinogenesis in AA CRC. This abstract is also presented as Poster A62. Citation Format: Gaius J. Augustus, Rosa Xicola, Arthur R. Brothman, Xavier Llor, Nathan A. Ellis. Homologous recombination drives African American colorectal carcinogenesis. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr PR02.