Genome-wide association studies (GWAS) have emerged as a powerful approach for identifying susceptibility loci associated with polygenetic diseases such as type 2 diabetes mellitus (T2DM). However, it is still a daunting task to prioritize single nucleotide polymorphisms (SNPs) from GWAS for further replication in different population. Several recent studies have shown that genetic variation often affects gene-expression at proximal (cis) as well as distal (trans) genomic locations by different mechanisms such as altering rate of transcription or splicing or transcript stability.

Pancreatic cancer is a highly lethal cancer with limited diagnostic and therapeutic modalities. To begin to explore the genomic landscape of pancreatic cancer, we used massively parallel sequencing to catalog and compare transcribed regions and potential regulatory elements in two human cell lines derived from normal and cancerous pancreas. By RNA-sequencing, we identified 2,146 differentially expressed genes in these cell lines that were enriched in cancer related pathways and biological processes that include cell adhesion, growth factor and receptor activity, signaling, transcription and differentiation. Our high throughput Chromatin immunoprecipitation (ChIP) sequence analysis furthermore identified over 100,000 regions enriched in epigenetic marks, showing either positive (H3K4me1, H3K4me3, RNA Pol II) or negative (H3K27me3) correlation with gene expression. Notably, an overall enrichment of RNA Pol II binding and depletion of H3K27me3 binding were seen in the cancer derived cell line as compared to the normal derived cell line. By selecting genes for further assessment based on this difference, we confirmed enhanced expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in two larger sets of pancreatic cancer cell lines and in tumor tissues as compared to normal derived tissues. As aldehyde dehydrogenase (ALDH) activity is a key feature of cancer stem cells, our results indicate that a member of the ALDH superfamily, ALDH1A3, may be upregulated in pancreatic cancer, where it could mark pancreatic cancer stem cells.

Background: Genome-wide association studies (GWAS) have identified several SNPs that are independently associated with prostate cancer (PrCa) in Caucasian men. Population isolates with unique allele frequencies are likely to have different sets of risk alleles for PrCa constituting personalized population risk stratification in addition to individual risk profiles. Methods: To test this hypothesis, we examined associations between 31 GWAS SNPs and PrCa among 979 cases and 1,251 controls of Ashkenazic descent. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated for each SNP using logistic regression models adjusted for age. We also investigated risk in strata by age at diagnosis, pathological features of PrCa, as well as family history of PrCa and other cancers. Results: Of 31 SNPs, 19 (62%) were associated with PrCa at p<0.05 in one or more genetic risk models. The strongest associations with PrCa were for rs6983267 at 8q24 (OR=1.78, p=5.7 x 10⁻⁷;comparison of GG vs. TT genotype), and rs1465618 at 2p21 (OR=2.19; p=0.003; AA vs. AG/GG). Six SNPs were associated with aggressive PrCa, while six others with less aggressive cancer. Four SNPs showed statistically significant interactions between PrCa and family history of PrCa (rs8102476 at 19q13), lung cancer (rs17021918 at 4q22), colorectal cancer (rs6983267 at 8q24), and breast cancer (rs10896449 at 11q13). Conclusion: These data define a specific set of risk alleles associated with PrCa in Ashkenazic men. Results demonstrate differences between men of European and Ashkenazic ancestry in relation to genetic susceptibility of PrCa. Interactions of genetic variants with family history of specific cancers indicate a complex network of inherited cancer risk syndromes still to be defined. Use of genetic markers to identify men at higher risk of PrCa will provide an opportunity for personalized care of PrCa prevention through screening of high-risk individuals, independent of family history information. Citation Format: Ilir Agalliu, Zhaoming Wang, Anne Dunn, Hemang Parikh, Timothy Myers, Robert Burk, Laufey Amundadottir. Characterization of SNPs associated with prostate cancer in men of Ashkenazic descent from the set of GWAS identified SNPs: Impact of cancer family history. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 28.