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Polymorphisms of the estrogen receptor gene in familial breast cancer

家族性乳腺癌雌激素受体基因多态性

基本信息

批准号：
08457311
负责人：
KOBAYASHI Shunzo
金额：
$ 0.7万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457311/
关键词：
familial breast cancer estrogen receptor gene mutation polymorphism ERbeta methylation 生殖細胞変異エストロゲンレセプター BRCA1 BRCA2 LOH

项目摘要

1)Possible linkage to the estrogen receptor geneWe demonstrated a possible linkage to the estrogen receptor (ER) gene in four Japanese breast cancer families, using three genetic markers (ESR,point variations of codon 10,325) in the ER gene and four markers (D17S250, D17S846, D17S855, D17S579) in the BRCA1 region. In two of the four families, the affected women shared allele type of the ER gene, but did not share BRCA1 allele types. Unfortunately, we could not find out any mutation of the ER gene in the families.2)Estrogen receptor gene and breast cancer susceptibilityWe previously found 2 types of sequence variants in exon 1 and exon 4, indicated two silent mutations in codon 10 (TCT to TCC) and codon 325 (CCC to CCG), respectively. Although the frequency of these polymorphic sites were not correlated with hormone receptor status and other clinico-pathologic factors, the variant in codon 325 tended to be seen more frequently in breast cancer patients than in non-cancer control cases (P=0.057). Since codon 325 is located in the hormone binding domain, this polymorphic site which appears to correlate with breast cancer susceptibility may affect ER function. Alternatively, this polymorphism may be in linkage disequilibrium with a coding or undetectable regulatory mutation.3)Loss of hormone dependency and alterations of the ER geneIt is a substantial problem that hormone independence may occur during breast cancer treatment. However, genetic alterations of the ER gene, such as missense, nonsense mutations, could not affect the loss of ER function. DNA methylation frequently occurred in the patients with ER negative tumor. It has been suggested that the epigenetic changes, alternative splice variants and DNA methylation of the ER gene, may affect ER function. Additionally, a novel estrogen receptor, ERbeta, was recently cloned, so ERbeta may affect the classical ER (ER*) function. We will focus these area in the future.

1）与雌激素受体基因的可能连锁我们使用ER基因中的三个遗传标记（ESR，密码子10,325的点变异）和BRCA1区域中的四个标记（D17S250、D17S846、D17S855、D17S579）证明了四个日本乳腺癌家族中与雌激素受体（ER）基因可能的连锁。在四个家庭中的两个家庭中，受影响的女性具有 ER 基因的等位基因类型，但不具有 BRCA1 等位基因类型。不幸的是，我们未能发现家系中ER基因的任何突变。2）雌激素受体基因与乳腺癌易感性我们之前在外显子1和外显子4中发现了两种类型的序列变异，分别表明密码子10（TCT到TCC）和密码子325（CCC到CCG）的两个沉默突变。尽管这些多态性位点的频率与激素受体状态和其他临床病理因素无关，但密码子 325 的变异在乳腺癌患者中比在非癌症对照病例中更常见 (P=0.057)。由于密码子 325 位于激素结合域，该多态性位点似乎与乳腺癌易感性相关，可能会影响 ER 功能。或者，这种多态性可能与编码或不可检测的调节突变连锁不平衡。3)激素依赖性的丧失和ER基因的改变乳腺癌治疗过程中可能发生激素独立性是一个重大问题。然而，ER基因的遗传改变，例如错义、无义突变，不会影响ER功能的丧失。 DNA甲基化常发生在ER阴性肿瘤患者中。有人认为，ER 基因的表观遗传变化、选择性剪接变异和 DNA 甲基化可能会影响 ER 功能。此外，最近克隆了一种新型雌激素受体 ERbeta，因此 ERbeta 可能会影响经典的 ER (ER*) 功能。未来我们会重点关注这些领域。