Genital infection by genus alpha human papillomavirus (HPV) types is the necessary cause of cervicalcancer and a large proportion of vulvar carcinomas. Accumulating evidence suggests that genus beta HPVtypes contribute to the development of squamous cell skin carcinoma (SCSC), particularly in organtransplant recipients (OTR). Although the molecular mechanisms through which HPV oncoproteins influencethe development of anogenital and SCSC differ, an immunologic milieu that allows the virus and/or nascenttumor cells to escape host surveillance likely plays a key role in the etiology of these cancers. Our long-termgoal is to clarify the role of immunogenetic factors in the etiology of HPV-related cancers. In the first specificaim, we will test the hypothesis that the risk of cervical and vulvar carcinoma is increased among personscarrying variant alleles of genes involved in the Toll-like receptor (TLR) pathway (TLR3, TLR4, TLR7, TLR9,TICAM1, T1CAM2, TIRAP, IRAKI, IRAK4, TOLLIP, TRAF6, TBK1, IKBKE, IRF3), a key component of theinnate immune response.
This aim will use resourcesDNA specimens and interview data from population-based cases of squamous cell cervical cancer (n=391), cervical adenocarcinomas (n=508), squamous cellvulvar carcinomas (n=535), and population controls (n=1,318)accumulated in the prior funding periods ofthe Program Project Grant. In the second specific aim, we will test the hypothesis that the risk of SCSC inOTR is increased among persons carrying variant alleles of genes involved in the immune response to HPV,tumor antigens, and/or UV light: human leukocyte antigen (HLA) (DRB1, DQB1, A, B, C, and G); TLRpathway (TLR4, TLR7, TICAM1, TICAM2, IRAKI, IRAK4, TOLLIP, TRAF6, TBK1, IKBKE, IRF3),immunomodulatory cytokines (IL10, IL12A, IL12B, IL6, IFNG and TNF), and nucleotide excision repairenzymes (XPB, XPC, XPD, XPF, XPG, and ERCC1).
This aim will use DNA specimens and other dataobtained from 250 SCSC cases and 250 controls recruited into Project 1. For the candidate genes other thanthe classical HLA-DRB1-DQB1, -A, -B, -C loci, we will capture the major patterns of genomic variation bychoosing and assaying for tagging single nucleotide polymorphisms (tagSNPs). Analytic methods formultilocus genotype data will be used to estimate the associations with individual polymorphisms andinferred haplotypes. This project will provide new information about the role of inherited variation in immuneresponse systems in the development of HPV-related cancers.LAY SUMMARY: Infection with cancer-causing human papillomaviruses (HPV) is common, but manyinfected persons do not develop cancer. This study will determine whether a person's genetic make-upinfluences whether HPV-related cancers occur, and could provide clues as to how such cancers might beprevented in the future.
Showing the most recent 10 out of 127 publications
