Mortality due to cervical cancer in the United States has declined substantially over the past 40 years, largely due to increased cervical screening. Although this trend is encouraging, cervical cancer remains one of the most common types of cancer diagnosed among women worldwide. Cervical infection by certain high-risk types of human papillomavirus (HPV) is known to cause cervical cancer. HPV causes nearly 100% of cervical cancer cases. Approximately 80% of sexually active people have been exposed to HPV, but paradoxically, only 1% of HPV-infected women develop cervical cancer. These statistics suggest that additional factors likely contribute to the development of HPV-associated cervical cancer. Indeed, several studies conducted over the past decade have shed light on the role of genetic variation in susceptibility to cervical neoplasia. Some of these previous studies revealed strong associations between allelic variation human leukocyte antigen (HLA) genes of the major histocompatibility complex (MHC) and cervical cancer. HLA proteins are integral components of the immune system. In the case of HPV infection, class I and class II HLA proteins present viral peptides to T cells leading to an immune response.
Population-based genomic studies are increasingly employed to assist in the identification of genetic variants associated with disease risk, and Dr. Margaret Madeleine of the Public Health Sciences Division at Fred Hutch co-lead a recently published study in PLoS Genetics that provides new insight on allelic variation of HLA genes that confer risk for, or protection from, cervical cancer. Dr. Madeleine indicated that a strength of the new study lies in the consortium approach the authors took, which allowed them to analyze samples from ten different study populations that spanned five countries. With samples from 2,866 cervical cancer cases and 6,762 controls, this study was well poised to provide high resolution of allelic variation associated with cervical neoplasia and cancer. Over 10 million single nucleotide polymorphisms (SNPs) were genotyped and analyzed for association with disease risk. Consistent with previous work, this genome-wide association analysis identified and confirmed several SNPs in the MHC region of chromosome 6 that are significantly associated with cervical cancer. In this region, both risk and protective HLA alleles were identified.
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The authors also utilized a computer program that combined the SNP analysis with HLA typing to predict HLA amino acids; this allowed them to identify site-specific amino acid positions of HLA proteins that may play key roles in how HLA allelic variation differentially affects cervical cancer susceptibility. An exciting finding from these analyses was that the researchers discovered two amino acid positions, 13 and 71, of HLA-DRB1 that strongly associate with cervical cancer risk (see figure). Says Dr. Madeleine, “We identified specific amino acids in two alleles that account for almost all of the really strong genetic signal.” These results build upon previous work by Dr. Madeleine and colleagues, in which they conducted high-resolution HLA typing and found that co-occurring HLA alleles associated with cervical cancer risk may be stronger predictors than the individual alleles (1). Finally, the authors also calculated genetic risk scores for the development of cervical cancer for all individuals and found that women in the lower 50% of risk have a less than 0.6% percent chance of developing cervical neoplasia while women in the top 5% have a substantially higher risk with a 22% chance of developing cervical cancer.
Even with the advances from this new study, much about the interaction between HLA allelic variation and HPV-associated cancer risk remains unknown, and new questions have emerged that may be addressed in future studies. As stated by Dr. Madeleine, “I think that the next step would be to investigate whether HLA associations at other HPV-related cancer sites were similar.” While work by others recently demonstrated similarly strong HLA associations for oropharyngeal cancer (2), Dr. Madeleine questions, “what about vulvar and anal cancers? Is it possible to come up with a treatment vaccine, for those who do not receive the safe and effective prophylactic vaccine? Understanding more about how HPV interacts with the HLA region genes might help with new vaccines or other treatments.” Despite the existence of highly efficacious HPV vaccines, the global burden of cervical cancer remains quite high, as many women, particularly in developing countries, do not have access to the vaccine. Dr. Madeleine notes that “perhaps information about HPV and HLA interactions might help with future treatment for people already infected.”
Also contributing to this project from the Fred Hutch were Drs. Stephen Schwartz and Lisa Johnson.
Leo PJ, Madeleine MM, Wang S, Schwartz SM, Newell F, Kymmer U, Hemminki K, Hallmans G, Tiews S, Steinberg W, Rader JS, Castro F, Safaeian M, Franco EL, Coutlee F, Ohlsson C, Cortes A, Marshall M, Mukhopadhyay P, Cremin K, Johnson LG, Garland S, Tabrizi SN, Wentzensen N, Sitas F, Little J, Cruickshank M, Frazer IH, Hildesheim A, Brown MA. 2017. Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study. PLoS Genet 13(8), e1006866. doi: 10.1371/journal.pgen.1006866.
1. Madeleine MM, Johnson LG, Smith AG, et al. 2008. Comprehensive analysis of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci and squamous cell cervical cancer risk. Cancer Res. 68(9):3532-3539.
2. Lesseur C, Diergaarde B, Olshan AF, et al. 2016. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. Nat Genet. 48:1544-1550.
Funding for this study was provided by the National Health and Medical Research Council (Australia), the Australian Cancer Research Foundation, the National Institutes of Health (US), the Canadian Institutes of Health Research, the Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg and Umeå, the Lundberg Foundation, the Torsten and Ragnar Söderberg's Foundation, the Novo Nordisk Foundation, the European Commission, the Swedish Society of Medicine, the Kempe-Foundation, the Medical Faculty of Umeå University, and the County Council of Västerbotten.