Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival
Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival
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DOI：
10.1093/hmg/ddp107
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发表时间：
2009-05-15
影响因子：
3.5
通讯作者：
Gayther, Simon A.
中科院分区：
文献类型：
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作者：
Quaye, Lydia;Dafou, Dimitra;Gayther, Simon A.
肿瘤中常见的生殖系遗传变异和/或躯体改变可能与诊断为卵巢癌的妇女的存活率有关。基因关联的成功识别依赖于识别和测试候选基因的适当策略。我们使用微细胞介导的染色体转移方法和表达芯片分析来确定卵巢癌细胞系中与肿瘤抑制相关的基因。在1700例侵袭性卵巢癌病例中，对9个候选基因中的65个标记单核苷酸多态(TSNPs)进行了基因分型，以寻找与生存相关的因素。对于其中的两个基因，314个卵巢肿瘤中tSNPs的杂合性缺失(LOH)分析被用来确定体细胞基因缺失与生存之间的关系。我们发现caspase5基因中的一个tSNP和视网膜母细胞瘤结合蛋白基因中的两个tSNP[风险比(HR)=1.13(95%CI：1.00-1.27，P=0.042)]和两个tSNP[风险比(HR)=0.85(95%CI：0.75-0.95)，P=0.007和HR=0.83(95%CI：0.71-0.95)，P=0.009]与患者的生存显著相关。在多变量COX回归分析中调整了多个预后因素后，RBBP8的这两个相关性仍然显著(P=0.028和0.036)。然后，我们对314例卵巢肿瘤CASP5和RBBP8中的几个tSNPs进行了基因分型，以确定LOH的基因缺失。RbBP8基因缺失与预后显著相关[HR=2.19(95%CI：1.36~3.54)，P=0.001]。总之，一种新的卵巢癌细胞体外功能方法已经确定RBBP8是一个基因，其种系遗传变异和肿瘤中的体细胞变化与卵巢癌患者的生存相关。
Common germline genetic variation and/or somatic alterations in tumours may be associated with survival in women diagnosed with ovarian cancer. The successful identification of genetic associations relies on a suitable strategy for identifying and testing candidate genes. We used microcell-mediated chromosome transfer approach and expression microarray analysis to identify genes that were associated with neoplastic suppression in ovarian cancer cell lines. Sixty-five tagging single nucleotide polymorphisms (tSNPs) in nine candidate genes were genotyped in similar to 1700 invasive ovarian cancer cases to look for associations with survival. For two of these genes, loss of heterozygosity (LOH) analysis of tSNPs in 314 ovarian tumours was used to identify associations between somatic gene deletions and survival. We identified significant associations with survival for a tSNP in caspase 5 (CASP5) [hazard ratio (HR) = 1.13 (95% CI: 1.00-1.27), P = 0.042] and two tSNPs in the retinoblastoma binding protein (RBBP8) gene [HR = 0.85 (95% CI: 0.75-0.95), P = 0.007 and HR = 0.83 (95% CI: 0.71-0.95), P = 0.009]. After adjusting for multiple prognostic factors in a multivariate Cox regression analysis, both associations in RBBP8 remained significant (P = 0.028 and 0.036). We then genotyped 314 ovarian tumours for several tSNPs in CASP5 and RBBP8 to identify gene deletions by LOH. For RBBP8, 35% of tumours in 101 informative cases showed somatic allelic deletion; LOH of RBBP8 was associated with a significantly worse prognosis [HR = 2.19 (95% CI: 1.36-3.54), P = 0.001]. In summary, a novel in vitro functional approach in ovarian cancer cells has identified RBBP8 as a gene for which both germline genetic variation and somatic alterations in tumours are associated with survival in ovarian cancer patients.