Wirtenberger Michael, Frank Bernd, Hemminki Kari, Klaes Rüdiger, Schmutzler Rita K, Wappenschmidt Barbara, Meindl Alfons, Kiechle Marion, Arnold Norbert, Weber Bernhard H F, Niederacher Dieter, Bartram Claus R, Burwinkel Barbara
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
Carcinogenesis. 2006 Aug;27(8):1655-60. doi: 10.1093/carcin/bgi374. Epub 2006 Feb 25.
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 = 1.12-4.11). 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.
人类RecQ解旋酶基因WRN和BLM的突变会导致罕见的常染色体隐性疾病，即沃纳综合征和布卢姆综合征，这些疾病与早衰和癌症易感性相关。我们检验了以下假设：WRN和BLM中三个多态性、非保守氨基酸交换是否作为低外显率的家族性乳腺癌风险因素。此外，我们研究了p53 MspI 1798G>A（其与p53PIN3完全连锁，p53PIN3是一个16 bp的插入/重复，与p53表达降低相关）对家族性乳腺癌风险的假定影响。对816名BRCA1/2突变阴性的德国家族性乳腺癌患者和1012名德国对照进行基因分型分析，结果显示WRN Cys1367Arg多态性与家族性乳腺癌（OR = 1.28，95% CI 1.06 - 1.54）和高危家族性乳腺癌（OR = 1.32，95% CI 1.06 - 1.65）存在显著关联。对与p53PIN3完全连锁的p53 MspI 1798G>A的分析表明，16 bp插入/重复携带者的家族性乳腺癌风险显著增加，呈隐性模式（OR = 2.15，95% CI = 1.12 - 4.11）。位于C端（p53的结合位点）的WRN Cys1367Arg预计具有损害性。与单一多态性相比，WRN Cys1367Arg和p53 MspI的联合作用导致乳腺癌风险增加（OR = 3.39，95% CI 1.19 - 9.71）。总之，我们的研究表明WRN和p53基因中的遗传变异对家族性乳腺癌易感性具有重要意义。
