Krantz Seth B, Zeeshan Kanwal, Kuchta Kristine M, Hensing Thomas A, Mangold Kathy A, Zheng S Lilly, Xu Jianfeng
Department of Surgery, NorthShore University HealthSystem, Evanston, Ill.
Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Ill.
JTCVS Open. 2022 Sep 21;12:399-409. doi: 10.1016/j.xjon.2022.09.001. eCollection 2022 Dec.
To determine the frequency of pathogenic mutations in high-penetrance genes (HPGs) in patients with non-small cell lung cancer (NSCLC) and identify whether such mutations are associated with clinicopathologic outcomes.
Patients with NSCLC who had consented to participate in a linked clinical database and biorepository underwent germline DNA sequencing using a next-generation sequencing panel that included cancer-associated HPGs and cancer risk-associated single nucleotide polymorphisms (SNPs). These data were linked to the clinical database to assess for associations between germline variants and clinical phenotype using Fisher's exact test and multivariable logistic and Cox regression.
We analyzed 151 patients, among whom 33% carried any pathogenic HPG mutation and 23% had a genetic risk score (GRS) >1.5. Among the patients without any pathogenic mutation, 31% were at cancer stage II or higher, compared with 55% of those with 2 types of HPG mutations ( = .0293); 40% of patients with both types of HPG mutations had cancer recurrence, compared with 21% of patients without both types ( = .0644). In multivariable analysis, the presence of 2 types of HPG mutations was associated with higher cancer stage (odds ratio [OR], 3.32; = .0228), increased recurrence of primary tumor (OR, 2.93; = .0527), shorter time to recurrence (hazard ratio [HR], 3.03; = .0119), and decreased cancer-specific (HR, 3.53; = .0039) and overall survival (HR, 2.44; = .0114).
The presence of mutations in HPGs is associated with higher cancer stage, increased risk of recurrence, and worse cancer-specific and overall survival in patients with NSCLC. Further large studies are needed to better delineate the role of HPGs in cancer recurrence and the potential benefit of adjuvant treatment in patients harboring such mutations.
确定非小细胞肺癌（NSCLC）患者高穿透性基因（HPG）中致病突变的频率，并确定此类突变是否与临床病理结果相关。
同意参与关联临床数据库和生物样本库的NSCLC患者，使用包含癌症相关HPG和癌症风险相关单核苷酸多态性（SNP）的二代测序面板进行种系DNA测序。这些数据与临床数据库相关联，以使用Fisher精确检验以及多变量逻辑回归和Cox回归评估种系变异与临床表型之间的关联。
我们分析了151例患者，其中33%携带任何致病HPG突变，23%的遗传风险评分（GRS）>1.5。在没有任何致病突变的患者中，31%处于癌症II期或更高阶段，而有2种HPG突变的患者中这一比例为55%（P = 0.0293）；有2种HPG突变的患者中有40%发生癌症复发，而没有这两种突变的患者中这一比例为21%（P = 0.0644）。在多变量分析中，存在2种HPG突变与更高的癌症阶段相关（比值比[OR]，3.32；P = 0.0228），原发性肿瘤复发增加（OR，2.93；P = 0.0527），复发时间缩短（风险比[HR]，3.03；P = 0.0119），以及癌症特异性生存率降低（HR，3.53；P = 0.0039）和总生存率降低（HR，2.44；P = 0.0114）。
HPG中存在突变与NSCLC患者更高的癌症阶段、复发风险增加以及更差的癌症特异性生存率和总生存率相关。需要进一步的大型研究来更好地描绘HPG在癌症复发中的作用以及对携带此类突变患者进行辅助治疗的潜在益处。
