Frank Bernd, Hemminki Kari, Wirtenberger Michael, Bermejo Justo Lorenzo, Bugert Peter, Klaes Rüdiger, Schmutzler Rita K, Wappenschmidt Barbara, Bartram Claus R, Burwinkel Barbara
Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
Carcinogenesis. 2005 Mar;26(3):643-7. doi: 10.1093/carcin/bgh342. Epub 2004 Nov 18.
Overexpression of the proto-oncogene ERBB2 (HER2/NEU) has been observed in 20-30% of breast cancers involving poor prognosis. Genetic alterations within ERBB2 have been shown to induce carcinogenesis and metastasis. We investigated eight annotated single nucleotide polymorphisms for occurrence in familial breast cancer samples. The confirmed variants Ile654Val, Ile655Val and Ala1170Pro were analysed in subsequent epidemiological studies on familial breast cancer risk. While Ala1170Pro resides within a C-terminally located regulatory domain, the two adjacent polymorphisms Ile654Val and Ile655Val are part of the transmembrane domain. A case-control study analysing a cohort of 348 German familial breast cancer cases and 960 corresponding controls showed no significant association of either Ile655Val (OR = 1.05, 95% CI = 0.82-1.34, P = 0.728) or Ala1170Pro (OR = 0.94, 95% CI = 0.74-1.20, P = 0.632) with familial breast cancer risk. Differences in haplotype frequencies between cases and controls could also not be detected. The ERBB2 variant Ile654Val, however, revealed an increased risk for carriers of the heterozygous Val654 allele (OR = 2.56, 95% CI = 1.08-6.08, P = 0.028). The rare Val654 variant is linked with the more frequent Val655, resulting in two consecutive valine instead of two isoleucine residues within the transmembrane domain. Computational analyses suggest that the Val654-Val655 allele provokes receptor dimerization and activation, thus stimulating kinase activity and cell transformation. We hypothesize that ERBB2 Val654 represents an oncogenic variant which might, in addition, influence clinical outcome and predict a worse prognosis.
在20%-30%预后较差的乳腺癌中已观察到原癌基因ERBB2（HER2/NEU）的过表达。ERBB2内的基因改变已被证明可诱导致癌作用和转移。我们研究了8个注释的单核苷酸多态性在家族性乳腺癌样本中的出现情况。在随后关于家族性乳腺癌风险的流行病学研究中，对已确认的变异体Ile654Val、Ile655Val和Ala1170Pro进行了分析。虽然Ala1170Pro位于C末端的调节域内，但相邻的两个多态性Ile654Val和Ile655Val是跨膜域的一部分。一项病例对照研究分析了348例德国家族性乳腺癌病例和960例相应对照组成的队列，结果显示Ile655Val（比值比=1.05，95%置信区间=0.82-1.34，P=0.728）或Ala1170Pro（比值比=0.94，95%置信区间=0.74-1.20，P=0.632）与家族性乳腺癌风险均无显著关联。病例组和对照组之间的单倍型频率差异也未被检测到。然而，ERBB2变异体Ile654Val显示，杂合Val654等位基因携带者的风险增加（比值比=2.56，95%置信区间=1.08-6.08，P=0.028）。罕见的Val654变异与更常见的Val655相关联，导致跨膜域内出现两个连续的缬氨酸而非两个异亮氨酸残基。计算分析表明，Val654-Val655等位基因可引发受体二聚化和激活，从而刺激激酶活性和细胞转化。我们推测，ERBB2 Val654代表一种致癌变异体，此外，它可能会影响临床结局并预示预后更差。
