title: The HLA class III subregion is responsible for an increased breast cancer risk.
abstract: BRCA1 and BRCA2 germline mutations account for <5% of breast cancer cases. Less penetrant breast cancer susceptibility genes are likely to exist. Earlier studies have suggested involvement of the HLA region. The HLA region was genotyped with 24 microsatellite markers and markers for two single nucleotide polymorphisms (SNPs) in TNFalpha and TNFbeta, in germline DNA from 956 breast cancer patients and 1271 family-based controls. Association analyses and the haplotype sharing statistic (HSS) were used to search for differences in haplotype sharing between patients and controls. Based on criteria known to influence genetic breast cancer risk, patients were divided into groups of high, moderate and low risk. The HSS revealed a significant difference in mean haplotype sharing between patients and controls for four consecutive markers (D6S2671, TNFa, D6S2672 and MICA), the highest being at D6S2671 (P=0.017). Subgroup analyses showed that moderate-risk patients were responsible for this difference, with the strongest association for D6S2672 (P=0.0009). A single haplotype was more frequent and longer in moderate-risk patients than in controls. The results were confirmed with association analyses. Individuals homozygous for haplotype 110-184 (D6S2672-MICA) were observed in 9.0% of moderate-risk patients and 1.5% of controls [odds ratio (OR)=7.14], while heterozygotes were at a lower risk (OR=1.41), suggesting a recessive effect. No association was observed between the two SNPs in TNFalpha (-308) and TNFbeta (intron 1) and breast cancer risk. The results reveal a potential role of the HLA class III subregion in susceptibility to breast cancer in patients at moderate familial risk.
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Mirjam M
authors.initials: MM
authors.lastname: de Jong
authors.forename: Ilja M
authors.initials: IM
authors.lastname: Nolte
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Michael
authors.initials: M
authors.lastname: Schaapveld
authors.forename: Jan H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: Elvira
authors.initials: E
authors.lastname: Oosterom
authors.forename: Jan C
authors.initials: JC
authors.lastname: Oosterwijk
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: van der Hout
authors.forename: Gerrit
authors.initials: G
authors.lastname: van der Steege
authors.forename: Marcel
authors.initials: M
authors.lastname: Bruinenberg
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Te Meerman
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001943:Breast Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D005190:Family; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats; D008875:Middle Aged; D009426:Netherlands; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D012307:Risk Factors; D044465:White People
chemical_list: D005819:Genetic Markers; D006680:HLA Antigens