Comprehensive analysis of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci and squamous cell cervical cancer risk.
Variation in human major histocompatibility genes may influence the risk of squamous cell cervical cancer (SCC) by altering the efficiency of the T-cell-mediated immune response to human papillomavirus (HPV) antigens. We used high-resolution methods to genotype human leukocyte antigen (HLA) class I (A, B, and Cw) and class II (DRB1 and DQB1) loci in 544 women with SCC and 542 controls. Recognizing that HLA molecules are codominantly expressed, we focused on co-occurring alleles. Among 137 allele combinations present at >5% in the case or control groups, 36 were significantly associated with SCC risk. All but one of the 30 combinations that increased risk included DQB1*0301, and 23 included subsets of A*0201-B*4402-Cw*0501-DRB1*0401-DQB1*0301. Another combination, B*4402-DRB1*1101-DQB1*0301, conferred a strong risk of SCC (odds ratio, 10.0; 95% confidence interval, 3.0-33.3). Among the six combinations that conferred a decreased risk of SCC, four included Cw*0701 or DQB1*02. Most multilocus results were similar for SCC that contained HPV16; a notable exception was A*0101-B*0801-Cw*0701-DRB1*0301-DQB1*0201 and its subsets, which were associated with HPV16-positive SCC (odds ratio, 0.5; 95% confidence interval, 0.3-0.9). The main multilocus associations were replicated in studies of cervical adenocarcinoma and vulvar cancer. These data confirm that T helper and cytotoxic T-cell responses are both important cofactors with HPV in cervical cancer etiology and indicate that co-occurring HLA alleles across loci seem to be more important than individual alleles. Thus, certain co-occurring alleles may be markers of disease risk that have clinical value as biomarkers for targeted screening or development of new therapies.
Madeleine
Margaret M
MM
Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. mmadelei@fhcrc.org
Johnson
Lisa G
LG
Smith
Anajane G
AG
Hansen
John A
JA
Nisperos
Brenda B
BB
Li
Sue
S
Zhao
Lue-Ping
LP
Daling
Janet R
JR
Schwartz
Stephen M
SM
Galloway
Denise A
DA
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000032:analysis / Q000235:genetics*; D015235:HLA-B Antigens / Q000032:analysis / Q000235:genetics*; D015236:HLA-C Antigens / Q000032:analysis / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000032:analysis / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000032:analysis / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D008875:Middle Aged; D015995:Prevalence; D012307:Risk Factors; D012747:Sexual Partners; D012907:Smoking / Q000453:epidemiology; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology / Q000235:genetics*
D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C553505:HLA-DRB1*04:01 antigen; D008562:Membrane Glycoproteins