The Lancet Oncology:非烟民患肺癌关键基因GPC5

2010-03-23 00:00 · betty

美国研究人员发现,非烟民罹患肺癌普遍与一个基因相关,如果这个基因发生变异,活性降低,则罹患肺癌风险可能增高。 这一发现有助于进一步研究肺癌靶向治疗和预测罹患肺癌高危人群。 找到关键 这种基因名为GPC5。梅奥诊所医学院研究人员发现,GPC5基因发生变异可能使非烟民罹患肺癌的风险增

美国研究人员发现,非烟民罹患肺癌普遍与一个基因相关,如果这个基因发生变异,活性降低,则罹患肺癌风险可能增高。

这一发现有助于进一步研究肺癌靶向治疗和预测罹患肺癌高危人群。

找到关键

这种基因名为GPC5。梅奥诊所医学院研究人员发现,GPC5基因发生变异可能使非烟民罹患肺癌的风险增加。

研究人员选取754名非吸烟者,提取他们的脱氧核糖核酸(DNA)样本,分析其中超过30万个DNA变体,研究影响非烟民罹患肺癌几率的基因变异。

综合考虑研究对象的年龄、性别、种族、慢性呼吸道疾病史、吸入二手烟量和家族肺癌患病史以后,研究人员发现,两个基因组发挥关键作用。

确认基因

研究人员从第一组DNA样本中找出44个最普遍的基因变异,再观察另外两组非吸烟者的这些基因变异。这两组研究对象中一半人已确诊为肺癌患者。

结果发现,同样两个基因组是关键所在,它们负责“打开”和“关闭”GPC5基因。

研究人员进一步研究发现,与健康人的肺部相比,肺腺癌患者的GPC5基因活性低50%。肺腺癌是一种最常见的肺癌。

研究人员据此认为,GPC5活性低可能导致非烟民罹患肺癌,有望通过进一步研究这一基因,研发肺癌靶向治疗新方法,并辨别罹患肺癌高危人群。

这是首次确认某个特定基因影响非烟民罹患肺癌风险。这项结果22日刊载于《柳叶刀肿瘤》杂志网络版。该杂志报道,全球肺癌患者中四分之一是非吸烟者。

有待深入

一些专家认为,需要进一步研究这种关联的原因。

美国华盛顿大学医学院拉马斯瓦米戈文丹博士在《柳叶刀肿瘤》杂志发表评论文章说,距离利用这项研究结果预测罹患肺癌高危人群还比较“遥远”。

“对于这些来自没有吸烟史人群的肿瘤样本的初步观察,需要进一步研究确认,”他说。

英国癌症研究会科学信息部主管卡特阿尼持有相同意见。英国广播公司(BBC)22日援引他的话报道,虽然英国90%的肺癌患者源于吸烟,但非烟民罹患这一疾病的数目仍然可观。

他说:“这些新研究结果可能帮助解释(非烟民罹患肺癌的)原因,但仍需要进行更多研究,确切解释这些基因变异如何与肺癌风险产生联系。”

推荐原文出处:

The Lancet Oncology doi:10.1016/S1470-2045(10)70042-5

Genetic variants and risk of lung cancer in never smokers: a genome-wide association study

Yafei Li PhD a *, Chau-Chyun Sheu MD f *, Yuanqing Ye PhD g *, Prof Mariza de Andrade PhD a *, Liang Wang PhD b *, Shen-Chih Chang PhD h *, Marie C Aubry MD b, Jeremiah A Aakre BS a, Prof Mark S Allen MD c, Feng Chen PhD f, Julie M Cunningham PhD b, Prof Claude Deschamps MD c, Ruoxiang Jiang BS a, Jie Lin PhD g, Randolph S Marks MD d, V Shane Pankratz PhD a, Li Su BS f, Yan Li MD a, Zhifu Sun MD a, Hui Tang PhD a, George Vasmatzis PhD b, Curtis C Harris MD i, Prof Margaret R Spitz MD g, Jin Jen PhD e, Renyi Wang MPH h, Prof Zuo-Feng Zhang MD h ?, Prof David C Christiani MD f j ?, Prof Xifeng Wu MD g ?, Dr, Prof Ping Yang PhD a

Background

Lung cancer in individuals who have never smoked tobacco products is an increasing medical and public-health issue. We aimed to unravel the genetic basis of lung cancer in never smokers.

Methods

We did a four-stage investigation. First, a genome-wide association study of single nucleotide polymorphisms (SNPs) was done with 754 never smokers (377 matched case-control pairs at Mayo Clinic, Rochester, MN, USA). Second, the top candidate SNPs from the first study were validated in two independent studies among 735 (MD Anderson Cancer Center, Houston, TX, USA) and 253 (Harvard University, Boston, MA, USA) never smokers. Third, further replication of the top SNP was done in 530 never smokers (UCLA, Los Angeles, CA, USA). Fourth, expression quantitative trait loci (eQTL) and gene-expression differences were analysed to further elucidate the causal relation between the validated SNPs and the risk of lung cancer in never smokers.

Findings

44 top candidate SNPs were identified that might alter the risk of lung cancer in never smokers. rs2352028 at chromosome 13q31.3 was subsequently replicated with an additive genetic model in the four independent studies, with a combined odds ratio of 146 (95% CI 126―170, p=594×10?6). A cis eQTL analysis showed there was a strong correlation between genotypes of the replicated SNPs and the transcription level of the gene GPC5 in normal lung tissues (p=196×10?4), with the high-risk allele linked with lower expression. Additionally, the transcription level of GPC5 in normal lung tissue was twice that detected in matched lung adenocarcinoma tissue (p=675×10?11).

Interpretation

Genetic variants at 13q31.3 alter the expression of GPC5, and are associated with susceptibility to lung cancer in never smokers. Downregulation of GPC5 might contribute to the development of lung cancer in never smokers.

Funding

US National Institutes of Health; Mayo Foundation.

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