Analysis of HLA Region Polymorphisms Analysis of HLA Region Polymorphisms Associated with CancerAssociated with Cancer

Amy E. KENNEDY, Sandeep K. SINGH, Karina VILLALBA, M. Tevfik DORAK

Department of EpidemiologyRobert Stempel College of Public Health and Social Work

Florida International University Miami, Florida

U.S.A.

BACKGROUNDBACKGROUND

Earlier animal studies suggested a strong influence of HLA polymorphisms on cancer susceptibility Candidate gene studies reported a number of associations, but most have not been replicated Genome-wide association studies have identified numerous risk markers even in non-virus-related cancers Whether these markers are proxies for HLA alleles or likely to be causal markers are unknown

BACKGROUNDBACKGROUNDUnique Features of the HLA region

Most gene-dense, most polymorphic region in the genome with the highest deleterious variant proportion, and strong linkage disequilibrium Strongest cis-eQTL in the genome Strongest trans-eQTL in the genome Gene content is enriched in embryo-expressed genes, and genes related to transcriptional/ translational machinery, stress response and genome surveillance

ASHI 2012: 148-PASHI 2012: 148-P

Correlations of Complex Disease-associated HLA Region SNPs with HLA AllelesCorrelations of Complex Disease-associated HLA Region SNPs with HLA AllelesAmy E. Kennedy, Sandeep K. Singh, Malaroviyam Samikkannu, M. Tevfik Dorak

Department of Environmental and Occupational Health, Robert Stempel College of Public Health and Social Work, Florida International University, Miami 33199, USA

Correlations of Complex Disease-associated HLA Region SNPs with HLA AllelesCorrelations of Complex Disease-associated HLA Region SNPs with HLA AllelesAmy E. Kennedy, Sandeep K. Singh, Malaroviyam Samikkannu, M. Tevfik Dorak

Department of Environmental and Occupational Health, Robert Stempel College of Public Health and Social Work, Florida International University, Miami 33199, USA

ASHI 2011: 184-P ASHI 2011: 184-P

ASHI 2013: 79-PASHI 2013: 79-P

AIMAIM

To gain mechanistic insight into the reported cancer associations in GWAS and selected candidate gene studies

To delineate correlations between these markers and HLA alleles

MATERIAL MATERIAL andand METHODSMETHODS

NHGRI-GWAS catalog to compile cancer associations

CGEMS results from dbGAP (HLA region only) and WTCCC results for HLA and breast cancer associations from supplementary data file

103 HLA-typed IHWG reference cell lines

Bioinformatics suits for functional analysis (RegulomeDB, F-SNP, GTeX, GWAS Central, GWASdb)

RESULTSRESULTSCorrelations with HLA

Most SNPs were not exclusive to HLA alleles/haplotypes/lineages, but the SNPs associated with lymphoid malignancies, nasopharyngeal cancer, lung

cancer, and prostate cancer showed some correlations.

HLA-DRA rs2395185 ~ HLA-DRB4 lineage (Hodgkin lymphoma, lung cancer)

BAG6 rs3117582 ~ HLA-A1-B8-DR3 (lung cancer)

BTNL2 rs28362675 ~ HLA-B52-DR15 (prostate cancer)

* * *

HLA-DPB1 rs2281389 ~ HLA-DPB1*0301 (Hodgkin lymphoma)

RESULTSRESULTSBioinformatics: RegulomeDB

RESULTSRESULTSBioinformatics: RegulomeDB

Five of the eight European-origin samples homozygous for the variant allele of this SNP are DPB1*0301 homozygous in the IHWG panel.

Two Asian samples are DPB1*0901 homozygous in the IHWG panel.

RESULTSRESULTSBioinformatics: F-SNP

BTNL2 SNP associated with prostate cancer risk (Fitzgerald, 2013).

RESULTSRESULTSBioinformatics: F-SNP

This SNP creates a stop codon in BTNL2

Another BTNL2 SNP is associated with lung cancer risk

A splice site variant in BTNL2 is associated with sarcoidosis susceptibility

RESULTSRESULTSBioinformatics: F-SNP

EHMT2 SNP associated with breast cancer risk (Cebrian, 2006). No HLA correlation data.

CONCLUSIONSCONCLUSIONS

By using one of the most underutilized resources in immunogenetics, we have generated useful information for HLA and cancer connection

HLA complex harbors genetic variants that modify cancer susceptibility

If individual SNP analyses have revealed associations in GWAS, more associations can be

unmasked by considering the special features of the HLA complex

FUTURE PROSPECTSFUTURE PROSPECTS

False negatives in GWAS

Unfaithfullness in the HLA region

Lack of consideration of effect modification