Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome.
Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome.
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DOI：
10.7554/elife.83118
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发表时间：
2023-04-20
期刊：
影响因子：
7.7
通讯作者：
Mckay JD
中科院分区：
文献类型：
--
作者：
Cortez Cardoso Penha R;Smith-Byrne K;Atkins JR;Haycock PC;Kar S;Codd V;Samani NJ;Nelson C;Milojevic M;Gabriel AAG;Amos C;Brennan P;Hung RJ;Kachuri L;Mckay JD
全基因组关联研究(GWAS)已经确定了白细胞端粒长度(LTL)和肺癌易感性的遗传易感性变异。我们的研究旨在探索这些性状之间的共同遗传基础，并探讨它们对肺癌躯体环境的影响。我们对LTL(N=464,716)和肺癌(N=29,239例和56,450例对照)进行了遗传相关性、孟德尔随机化(MR)和共定位分析。基于RNA测序数据的主成分分析用于总结来自TCGA(N=343)的肺腺癌患者的基因表达谱。虽然LTL与肺癌风险之间没有全基因组的遗传相关性，但在MR分析中，LTL时间越长，无论吸烟与否，肺癌风险都会增加，特别是对于肺腺癌。在144个LTL遗传工具中，12个与肺腺癌风险共定位，并发现了新的易感基因座，包括MPHOSPH6、PRPF6和POLI。在肺腺癌肿瘤中，LTL的多基因风险评分与特定的基因表达谱(PC2)相关。PC2与较长的LTL相关的方面也与女性、从不吸烟和较早的肿瘤分期有关。PC2与细胞增殖评分和与基因组稳定性相关的基因组特征，包括拷贝数变化和端粒酶活性密切相关。这项研究确定了较长的基因预测LTL与肺癌之间的联系，并阐明了与肺腺癌LTL相关的潜在分子机制。国家癌症研究所(GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17-022)、INTEGRAL/NIH(5U19CA203654-03)、CRUK(C18281/A29019)和国家癌症研究所(ANR-10-INBS-09)。
Genome-wide association studies (GWASs) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Our study aims to explore the shared genetic basis between these traits and investigate their impact on somatic environment of lung tumours. We performed genetic correlation, Mendelian randomisation (MR), and colocalisation analyses using the largest available GWASs summary statistics of LTL (N=464,716) and lung cancer (N=29,239 cases and 56,450 controls). Principal components analysis based on RNA-sequencing data was used to summarise gene expression profile in lung adenocarcinoma cases from TCGA (N=343). Although there was no genome-wide genetic correlation between LTL and lung cancer risk, longer LTL conferred an increased risk of lung cancer regardless of smoking status in the MR analyses, particularly for lung adenocarcinoma. Of the 144 LTL genetic instruments, 12 colocalised with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6, PRPF6, and POLI. The polygenic risk score for LTL was associated with a specific gene expression profile (PC2) in lung adenocarcinoma tumours. The aspect of PC2 associated with longer LTL was also associated with being female, never smokers, and earlier tumour stages. PC2 was strongly associated with cell proliferation score and genomic features related to genome stability, including copy number changes and telomerase activity. This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas. Institut National du Cancer (GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17‐022), INTEGRAL/NIH (5U19CA203654-03), CRUK (C18281/A29019), and Agence Nationale pour la Recherche (ANR-10-INBS-09).