PURPOSE Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. PATIENTS AND METHODS Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluated for lung abnormalities. RESULTS YAP1 R331W missense mutation from the original family was identified and validated in the external controls and the cohort with lung adenocarcinoma. The YAP1 mutant-allele carrier frequency was 1.1% in patients with lung adenocarcinoma compared with 0.18% in controls (P = .0095), yielding an odds ratio (adjusted for age, sex, and smoking status) of 5.9. Among the relatives, YAP1-mutant carriers have overwhelmingly higher frequencies of developing lung adenocarcinoma or ground-glass opacity lung lesions than those who do not carry the mutation (10:0 v 1:7; P < .001). YAP1 mutation was shown to increase the colony formation ability and invasion potential of lung cancer cells. CONCLUSION These results implicated YAP1 R331W as an allele predisposed for lung adenocarcinoma with high familial penetrance. Low-dose computed tomography scans may be recommended to this subpopulation, which is at high risk for lung cancer, for personalized prevention and health management.

中文翻译：

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致癌基因 YAP1 的 R331W 错义突变是具有医学可操作性的肺腺癌的种系风险等位基因

目的 腺癌是从不吸烟患者中最主要的肺癌类型。来自全基因组关联研究的风险等位基因具有较小的优势比和不明确的生物学作用。在这里，我们采用了一种具有适当医学可操作性的方法来识别具有低人口频率但高致病潜力的等位基因。患者和方法 对一个肺腺癌密度异常高的家庭进行了全基因组测序，该家庭具有来自受影响母亲、四个受影响的女儿和一个未受影响的儿子的可用 DNA。通过基质辅助激光解吸电离飞行时间质谱法证实了候选风险等位基因。验证是在 1,135 名无癌症参与者和 1,312 名肺腺癌患者的外部队列中进行的。通过对原始先证者的亲属和确定的风险等位基因携带者的亲属进行基因分型来进行家庭随访。胸部低剂量计算机断层扫描评估肺部异常。结果 来自原始家族的 YAP1 R331W 错义突变在外部对照和肺腺癌队列中得到鉴定和验证。肺腺癌患者的 YAP1 突变等位基因携带频率为 1.1%，而对照组为 0.18% (P = .0095)，优势比（根据年龄、性别和吸烟状况进行调整）为 5.9。在亲属中，YAP1 突变携带者发生肺腺癌或磨玻璃样混浊肺病变的频率远远高于未携带该突变的携带者 (10:0 v 1:7; P < .001)。YAP1 突变显示增加肺癌细胞的集落形成能力和侵袭潜力。结论 这些结果表明 YAP1 R331W 是易患肺腺癌的等位基因，具有高家族外显率。低剂量计算机断层扫描可能会被推荐给这个肺癌高风险亚群，以进行个性化的预防和健康管理。