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Human Molecular Genetics Advance Access originally published online on July 22, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 18 2311-2319
DOI: 10.1093/hmg/ddg245
© 2003 Oxford University Press

The HLA class III subregion is responsible for an increased breast cancer risk

Mirjam M. de Jong1,2,3, Ilja M. Nolte2,4, Elisabeth G. E. de Vries1, Michael Schaapveld6, Jan H. Kleibeuker3, Elvira Oosterom4, Jan C. Oosterwijk2, Annemarie H. van der Hout2, Gerrit van der Steege4, Marcel Bruinenberg4, H. Marike Boezen5, Gerard J. te Meerman2 and Winette T. A. van der Graaf1,*

1Department of Medical Oncology, 2Department of Medical Genetics, 3Department of Gastroenterology, 4Department of Medical Biology and 5Department of Epidemiology, University Medical Center, Groningen, The Netherlands and 6Comprehensive Cancer Center Northern Netherlands, Groningen, The Netherlands

Received April 17, 2003; Accepted July 10, 2003

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 TNF{alpha} and TNFß, 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 TNF{alpha} (-308) and TNFß (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.

* To whom correspondence should be addressed at: Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB, Groningen, The Netherlands. Tel: +31 503612821; Fax: +31 503614862; Email: w.t.a.van.der.graaf{at}int.azg.nl


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