Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer

被引:49
作者
Wirtenberger, Michael
Frank, Bernd
Hemminki, Kari
Klaes, Ruediger
Schmutzler, Rita K.
Wappenschmidt, Barbara
Meindl, Alfons
Kiechle, Marion
Arnold, Norbert
Weber, Bernhard H. F.
Niederacher, Dieter
Bartram, Claus R.
Burwinkel, Barbara
机构
[1] German Canc Res Ctr, DKFZ, Div Mol Genet Epidemiol, D-69120 Heidelberg, Germany
[2] Karolinska Inst, Novum, Dept Biosci, Huddinge, Sweden
[3] Heidelberg Univ, Inst Human Genet, Heidelberg, Germany
[4] Univ Hosp Cologne, CMMC, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany
[5] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, D-8000 Munich, Germany
[6] Univ Hosp Schleswig Holstein, Dept Obstet & Gynaecol, Div Oncol, Kiel, Germany
[7] Univ Regensburg, Inst Human Genet, D-8400 Regensburg, Germany
[8] Univ Dusseldorf, Ctr Clin, Dept Obstet & Gynaecol, Div Mol Genet, Dusseldorf, Germany
[9] Helmholtz Univ, Grp Mol Epidemiol, DKFZ, Heidelberg, Germany
关键词
D O I
10.1093/carcin/bgi374
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature ageing and cancer predisposition. We tested the hypothesis whether three polymorphic, non-conservative amino acid exchanges in WRN and BLM act as low-penetrance familial breast cancer risk factors. Moreover, we examined the putative impact of p53 MspI 1798G > A, which is completely linked to p53PIN3, a 16 bp insertion/duplication that has been associated with reduced p53 expression, on familial breast cancer risk. Genotyping analyses, performed on 816 BRCA1/2 mutation-negative German familial breast cancer patients and 1012 German controls, revealed a significant association of the WRN Cys1367Arg polymorphism with familial breast cancer (OR = 1.28, 95% CI 1.06-1.54) and high-risk familial breast cancer (OR = 1.32, 95 % CI 1.06-1.65). The analysis of p53 MspI 1798G > A, which is completely linked to p53PIN3, showed a significantly increased familial breast cancer risk for carriers of the 16 bp insertion/duplication, following a recessive mode (OR = 2.15, 95% CI = 1.124.11). WRN Cys1367Arg, located in the C-terminus, the binding site of p53, is predicted to be damaging. The joint effect of WRN Cys1367Arg and p53 MspI resulted in an increased breast cancer risk compared to the single polymorphisms (OR = 3.39, 95% CI 1.19-9.71). In conclusion, our study indicates the importance of inherited variants in the WRN and p53 genes for familial breast cancer susceptibility.
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收藏
页码:1655 / 1660
页数:6
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