Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland.
Department of Genetics, Genomics and Informatics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee.
Cancer Res. 2021 Jun 15;81(12):3162-3173. doi: 10.1158/0008-5472.CAN-20-3196. Epub 2021 Apr 14.
Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: at 6q25.3, at 6q26, and (6q24.1) and (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work. SIGNIFICANCE: This study identifies four genes associated with lung cancer risk, which could help guide future lung cancer prevention and treatment approaches.
虽然肺癌已知是由环境因素引起的，但也有遗传因素，肺癌的遗传病因仍研究不足。我们之前使用具有肺癌病史的家族中的微卫星数据在 6q23-25 上确定了一个肺癌风险位点。为了进一步阐明该信号，我们对我们的 9 个最强连锁家族进行了靶向测序。测序数据的两点连锁分析表明该信号具有异质性，不同家族可能具有不同的风险变体。一些家族共享了三个特定的单倍型：家族 42 和 44 中的 6q25.3-26、家族 47 和 59 中的 6q25.2-25.3 以及家族 30、33 和 35 中的 6q24.2-25.1。基于区域的对数优势评分和表达数据确定了每个单倍型重叠的可能候选基因：6q25.3 上的 ，6q26 上的 ，6q24.1 上的 （6q24.2）和 （6q24.2）。进一步的注释用于确定这些基因中潜在的风险变体。这四个基因都是肺癌风险的候选基因，它们与肺癌或其他癌症都有联系。然而，这是这些基因中的任何一个首次被牵连到种系风险中。这些基因的功能分析计划在未来的工作中进行。意义：本研究确定了与肺癌风险相关的四个基因，这可能有助于指导未来的肺癌预防和治疗方法。
