Campbell Ian G, Phillips Wayne A, Choong David Y H
Victorian Breast Cancer Research Consortium Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, 8006, Australia.
Clin Cancer Res. 2006 Jun 15;12(12):3713-5. doi: 10.1158/1078-0432.CCR-06-0800.
A very high frequency of somatic mutations in the transforming growth factor-beta signaling component km23 has been reported in a small series of ovarian cancers (8 of 19, 42%). Functional studies showed that some mutations disrupt km23 function, resulting in aberrant transforming growth factor-beta signaling and presumably enhanced tumorigenicity. If verified, this would elevate mutation of km23 as the single most frequent somatic event in ovarian cancer.
We sought to verify the frequency of silencing of km23 among 104 primary ovarian cancers (49 serous, 18 mucinous, 29 endometrioid/clear cell, and 8 undifferentiated) as well as 72 breast and 61 colorectal cancers by undertaking both somatic mutation and promoter methylation analyses. All four exons of km23 were individually amplified from genomic DNA with primers complementary to surrounding intronic sequences and analyzed by single-stranded conformational polymorphism analysis.
Two germ line polymorphisms were identified, but none of the 237 tumors analyzed harbored somatic km23 mutations. In addition, promoter methylation analysis showed that in all cases, the 5' CpG island was unmethylated.
Our data suggest that silencing of km23, either through somatic genetic mutation or promoter hypermethylation, is rare in ovarian, breast, and colorectal cancers.
在一小部分卵巢癌病例（19例中有8例，占42%）中，已报道转化生长因子-β信号传导成分km23的体细胞突变频率非常高。功能研究表明，一些突变会破坏km23的功能，导致转化生长因子-β信号传导异常，并可能增强致瘤性。如果得到证实，这将使km23突变成为卵巢癌中最常见的体细胞事件。
我们通过进行体细胞突变和启动子甲基化分析，试图验证104例原发性卵巢癌（49例浆液性、18例黏液性、29例子宫内膜样/透明细胞癌和8例未分化癌）以及72例乳腺癌和61例结直肠癌中km23沉默的频率。使用与周围内含子序列互补的引物从基因组DNA中分别扩增km23的所有四个外显子，并通过单链构象多态性分析进行检测。
鉴定出两个种系多态性，但在分析的237个肿瘤中均未发现体细胞km23突变。此外，启动子甲基化分析表明，在所有病例中，5' CpG岛均未甲基化。
我们的数据表明，在卵巢癌、乳腺癌和结直肠癌中，通过体细胞基因突变或启动子高甲基化导致km23沉默的情况很少见。
