Feng Jinong, Yan Jin, Chen Jiesheng, Schlake Gudrun, Jiang Zefei, Buzin Carolyn H, Sommer Steve S, Dritschilo Anatoly
Department of Molecular Genetics, City of Hope National Medical Center, Duarte, CA 91010, USA.
Cancer Genet Cytogenet. 2003 Sep;145(2):179-82. doi: 10.1016/s0165-4608(03)00120-1.
Accumulating evidence indicates that germline missense mutations in the ATM gene predispose to breast cancer. To investigate the potential role of somatic ATM mutations in the tumorigenesis of breast cancer, the ATM gene was scanned in 58 mammary carcinomas using DOVAM-S (detection of virtually all mutations-SSCP [single-strand conformation polymorphism]), a robotically enhanced, highly redundant form of SSCP that detects virtually all mutations. A total of 1.65 megabases of tumor DNA sequence was scanned and 16 structural variants were identified, including one novel nonsense mutation, four novel missense mutations, and a common missense change in African-Americans. Sequencing from microdissected normal cells reveals that all variants were present in the germline. Thus, the ATM gene may be similar to the BRCA1/BRCA2 genes in that germline mutations are important in cancer predisposition, but somatic mutations are seldom present in tumors. Loss of heterozygosity (LOH) is common in these tumors, but ATM missense mutations occur with similar frequencies when LOH is present or absent (P=0.73). If germline ATM missense mutations predispose to breast cancer, the unmasking of a recessive missense allele by LOH does not seem to be a critical step in breast neoplasia.
越来越多的证据表明，ATM基因的种系错义突变易患乳腺癌。为了研究体细胞ATM突变在乳腺癌发生中的潜在作用，使用DOVAM-S（几乎检测所有突变的单链构象多态性检测）对58例乳腺癌中的ATM基因进行扫描，DOVAM-S是一种经机器人增强的、高度冗余的单链构象多态性形式，几乎能检测所有突变。共扫描了165万个碱基对的肿瘤DNA序列，鉴定出16个结构变异，包括1个新的无义突变、4个新的错义突变以及非裔美国人中一个常见的错义变化。对显微切割的正常细胞进行测序显示，所有变异均存在于种系中。因此，ATM基因可能与BRCA1/BRCA2基因类似，即种系突变在癌症易感性中很重要，但肿瘤中很少出现体细胞突变。杂合性缺失（LOH）在这些肿瘤中很常见，但无论有无LOH，ATM错义突变的发生频率相似（P=0.73）。如果种系ATM错义突变易患乳腺癌，那么通过LOH揭示隐性错义等位基因似乎不是乳腺肿瘤形成的关键步骤。
