Carapezza Giovanni, Minardi Simone Paolo, Noci Sara, Pintarelli Giulia, Zanutto Susanna, Incarbone Matteo, Tosi Davide, Dragani Tommaso Antonio, Colombo Francesca, Pierotti Marco Alessandro, Gariboldi Manuela
Cogentech S.R.L.Benefit C. With Only Stakeholder Fondazione IFOM ETS, Milano, Italy.
Fondazione IRCCS Istituto Nazionale Dei Tumori, Milano, Italy.
Genes Chromosomes Cancer. 2025 Mar;64(3):e70040. doi: 10.1002/gcc.70040.
Approximately 10%-15% of all lung cancers arise in non-smokers. Although there are no established aetiological factors, non-smokers with a family history of cancer have an increased risk of lung cancer, implying host genetic factors in lung cancer susceptibility. We sought to identify, in a cohort of 75 patients recruited before lung lobectomy, germline alterations with a strong association with lung cancer. Whole-exome sequencing was performed on genomic DNA from peripheral blood. Six resources were used to select pathogenic germline variants with strong clinical significance. In total, 33 pathogenic or likely pathogenic variants in 31 genes were identified. Of these, 13 were located in cancer-predisposing genes (nine were lung cancer drivers), most of which were involved in DNA repair mechanisms and diseases of metabolism. Among DNA repair-related genes, BRCA1 and BRCA2, and ATM have also been identified in other studies on non-smokers. Our results strongly support the hypothesis that a number of non-smoker lung cancer patients carry germline variants in cancer-predisposing genes, suggesting that lung cancer patients, particularly non-smokers, should be considered for germline molecular testing.
所有肺癌病例中约有10%-15%发生在不吸烟者身上。尽管尚无确定的病因学因素，但有癌症家族史的不吸烟者患肺癌的风险增加，这意味着宿主遗传因素在肺癌易感性中起作用。我们试图在75名肺叶切除术前招募的患者队列中，确定与肺癌有强关联的种系改变。对来自外周血的基因组DNA进行了全外显子测序。使用了六种资源来选择具有强临床意义的致病性种系变异。总共鉴定出31个基因中的33个致病性或可能致病性变异。其中，13个位于癌症易感基因中（9个是肺癌驱动基因），其中大多数参与DNA修复机制和代谢疾病。在与DNA修复相关的基因中，BRCA1和BRCA2以及ATM在其他关于不吸烟者的研究中也已被鉴定出来。我们的结果有力地支持了这样一种假设，即许多不吸烟肺癌患者携带癌症易感基因中的种系变异，这表明肺癌患者，尤其是不吸烟者，应考虑进行种系分子检测。
