Kachuri Linda, Amos Christopher I, McKay James D, Johansson Mattias, Vineis Paolo, Bueno-de-Mesquita H Bas, Boutron-Ruault Marie-Christine, Johansson Mikael, Quirós J Ramón, Sieri Sabina, Travis Ruth C, Weiderpass Elisabete, Le Marchand Loic, Henderson Brian E, Wilkens Lynne, Goodman Gary E, Chen Chu, Doherty Jennifer A, Christiani David C, Wei Yongyue, Su Li, Tworoger Shelley, Zhang Xuehong, Kraft Peter, Zaridze David, Field John K, Marcus Michael W, Davies Michael P A, Hyde Russell, Caporaso Neil E, Landi Maria Teresa, Severi Gianluca, Giles Graham G, Liu Geoffrey, McLaughlin John R, Li Yafang, Xiao Xiangjun, Fehringer Gord, Zong Xuchen, Denroche Robert E, Zuzarte Philip C, McPherson John D, Brennan Paul, Hung Rayjean J
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada.
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada.
Carcinogenesis. 2016 Jan;37(1):96-105. doi: 10.1093/carcin/bgv165. Epub 2015 Nov 20.
Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000×) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73×10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64×10(-6)), rs112290073 (OR = 1.85, P = 1.27×10(-5)), rs138895564 (OR = 2.16, P = 2.06×10(-5); among young cases, OR = 3.77, P = 8.41×10(-4)). In addition, we found that rs139852726 (P = 1.44×10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84×10(-7)) and lung cancer (P = 2.37×10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.
5号染色体p15.33区域已被确定为肺癌易感位点，但其潜在的因果机制尚未完全阐明。此前对该位点的精细定位研究依赖于基因填充或仅研究了少数已知的常见变异。本研究通过研究大量新的罕见变异及其通过端粒长度的潜在机制，相比之前的研究有了显著进展。通过对576名个体进行靶向深度测序（平均覆盖深度大于4000×）来确定用于精细定位研究的变异。随后，在5164例欧洲血统的病例和5716例对照中对4652个单核苷酸多态性（SNP）进行基因分型，其中包括1108个新的SNP。在调整已知风险位点rs2736100和rs401681后，我们在LPCAT1基因中鉴定出一个新的独立肺癌易感变异：rs139852726（比值比=0.46，P=4.73×10^(-9)），以及在TERT基因中鉴定出三个新的腺癌风险变异：rs61748181（比值比=0.53，P=2.64×10^(-6)）、rs112290073（比值比=1.85，P=1.27×10^(-5)）、rs138895564（比值比=2.16，P=2.06×10^(-5)；在年轻病例中，比值比=3.77，P=8.41×10^(-4)）。此外，我们发现rs139852726（P=1.44×10^(-3)）在922名健康个体的样本中与端粒长度相关。基于基因的SKAT - O分析表明TERT是5p15.33区域中与腺癌（P=7.84×10^(-7)）和肺癌（P=2.37×10^(-5)）风险最相关的基因。在这项最大规模的精细定位研究中，我们研究了5p15.33区域内大量罕见和新的变异，鉴定出了具有显著影响的新的肺癌和腺癌易感位点，并为端粒长度作为潜在的潜在机制的作用提供了支持。
