SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer
SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer
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DOI：
10.1093/hmg/ddm375
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Dong, Jin-Tang
中科院分区：
文献类型：
--
作者：
Dong, Xue-Yuan;Rodriguez, Carmen;Dong, Jin-Tang
染色体6q14 - q22缺失在包括前列腺癌在内的多种人类癌症中较为常见，并且导入癌细胞的6号染色体可诱导细胞衰老，减缓细胞生长、致瘤性和转移，这表明在6q上存在一个或多个肿瘤抑制基因。为了确定6q肿瘤抑制基因，我们首先将常见缺失区域缩小到6q14 - 15的一个2.5Mb区间。在位于这个最小缺失区域且在正常前列腺中表达的11个基因中，只有snoRNA U50发生突变，表现出转录下调，并抑制前列腺癌细胞的集落形成。这种突变是一个2bp（TT）的纯合缺失，在30个前列腺癌细胞系/异种移植物中的2个以及89个局限性前列腺癌中的9个（119个中的11个，即9%的癌症）中被发现。89名前列腺癌患者中有2名（2%）在其生殖系DNA中也显示出相同突变，但104名无癌对照男性中无人出现该突变。在集落形成实验中，纯合缺失使U50功能丧失。对来自前瞻性队列中嵌套的病例对照研究的1371例前列腺癌病例和1371名匹配对照男性的分析表明，尽管在患者和对照中以相似频率检测到缺失的生殖系杂合基因型，但缺失的纯合性与具有临床意义的前列腺癌显著相关（优势比为2.9；95%置信区间为1.17 - 7.21）。这些发现确立了snoRNA U50作为前列腺癌中6q肿瘤抑制基因的合理候选基因，并且可能在其他类型癌症中也是如此。
Deletion of chromosome 6q14-q22 is common in multiple human cancers including prostate cancer, and chromosome 6 transferred into cancer cells induces senescence and reduces cell growth, tumorigenicity and metastasis, indicating the existence of one or more tumor-suppressor genes in 6q. To identify the 6q tumor-suppressor gene, we first narrowed the common region of deletion to a 2.5 Mb interval at 6q14-15. Of the 11 genes located in this minimal deletion region and expressed in normal prostates, only snoRNA U50 was mutated, demonstrated transcriptional downregulation and inhibited colony formation in prostate cancer cells. The mutation, a homozygous 2 bp (TT) deletion, was found in two of 30 prostate cancer cell lines/xenografts and nine of 89 localized prostate cancers (eleven of 119 or 9% cancers). Two of 89 (2%) patients with prostate cancer also showed the same mutation in their germline DNA, but none of 104 cancer-free control men did. The homozygous deletion abolished U50 function in a colony formation assay. Analysis of 1371 prostate cancer cases and 1371 matched control men from a case-control study nested in a prospective cohort showed that, although a germline heterozygous genotype of the deletion was detected in both patients and controls at similar frequencies, the homozygosity of the deletion was significantly associated with clinically significant prostate cancer (odds ratio 2.9; 95% confidence interval 1.17-7.21). These findings establish snoRNA U50 as a reasonable candidate for the 6q tumor-suppressor gene in prostate cancer and likely in other types of cancers.