Common Genetic Polymorphisms Contribute to the Association between Non-Melanoma Skin Cancer and Chronic Lymphocytic Leukemia

Introduction: Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with numerous traits and diseases. The analysis of shared genetic associations between diseases can help explain previously found epidemiological associations and provide better insight into disease etiology. Epidemiological studies have demonstrated a consistent positive association between chronic lymphocytic leukemia (CLL) and non-melanoma skin cancers (NMSC); however, the reasons for this association are not well understood. We explored the hypothesis that shared genetic risk factors between CLL and NMSC could contribute to the epidemiological association observed between these diseases.

Methods: We identified established loci associated with CLL or NMSC with p<5x10^-8 based on published results. Single nucleotide polymorphisms (SNPs) were considered independent if they were ≥500 kb apart and had r²<0.05. We examined the association between NMSC loci and CLL risk in a pooled GWAS of CLL including 3,100 cases and 7,667 controls of European ancestry. In parallel, we investigated the association between CLL loci and NMSC risk in a study of 4,242 basal cell carcinoma (BCC) cases and 12,802 controls and also 825 squamous cell carcinoma (SCC) cases and 11,518 controls. Weighted genetic risk scores (wGRS) were constructed separately for each disease. For each SNP, the odds ratios (OR) for the association with NMSC or CLL was extracted from existing literature. In the wGRS, the number of risk alleles was multiplied by the log-OR of that SNP as reported in the literature. We estimated the OR and 95% confidence interval (95% CI) for the associations with individual SNPs and with the wGRS for both CLL and NMSC using logistic regression, adjusting for age, sex, and principal components to account for population substructure.

Results: Six of the established genetic loci for CLL and NMSC overlapped such that at least SNPs associated with CLL and NMSC were within a 1 Mb: 2q33.1, 3q28, 5p15, 6p21, 6p25 and 9q21.

Of the reported NMSC loci, 4 index SNPs were nominally associated with CLL risk after adjustment for multiple testing (P_FDR-adjusted≤0.05): rs12203592 and rs12210050 at 6p25 (IRF4/EXOC2), rs78378222 at 17p13.1 (TP53), and rs191177147 at 3q28 (LPP). The most significant associations were at 6p25.3 region in the IRF4/EXOC2 locus: rs12203592 (OR: 1.41, 95% CI: 1.29-1.54, P=7.34 x 10^-14) and rs12210050 (OR=1.23, 95% CI: 1.12-1.35, P=1.97 x 10^-5). Using the wGRS from SCC SNPs, we found a pattern of increasing risk of CLL with increasing quartile, reaching statistical significance for quartile 4 vs. quartile 1 (OR=1.26, 95% CI: 1.14-1.39, P=0.001). After excluding the IRF4 polymorphism rs12203592, the association between the wGRS and CLL was no longer significant (OR=1.02, 95% CI: 0.90-1.45, P=0.81).

Of the reported CLL SNPs, five were associated with NMSC risk after adjustment for multiple testing (P_FDR-adjusted≤0.05): rs9815073 at 3q28 (LPP), rs3769825 at 2q33 (CASP10/CASP8), rs17246404 at 7q31 (POT1), rs4368253 at 18q21 (PMAIP1) and rs872071 at 6p25 (IRF4/EXOC2). The wGRS based on the CLL SNPs was associated with BCC risk (P=0.004) but not with SCC risk (P=0.12), possibly due to a lack of statistical power. Of note, after exclusion of the IRF4 polymorphism, the association between the wGRS and BCC remained statistically significant (P=0.02).

Conclusion: We report here a novel and statistically significant association between the genetic burden for risk of NMSC and of CLL. Finally, we uncovered that polymorphisms in the Interferon Regulatory Factor 4 (IRF4) gene appear to contribute to the association between CLL and NMSC. IRF4, also known as multiple myeloma oncogene-1 (MUM1), is a transcriptional regulator expressed in lymphocytes and in melanocytes. Further studies are needed to understand the common biological mechanisms that lead to this association. Overall, these findings highlight the pleiotropic effect of genes in the pathogeneses of these cancers and suggest that they have a partially shared genetic etiology.