Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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 (P = .0293); 40% of patients with both types of HPG mutations had cancer recurrence, compared with 21% of patients without both types (P = .0644). In multivariable analysis, the presence of 2 types of HPG mutations was associated with higher cancer stage (odds ratio [OR], 3.32; P = .0228), increased recurrence of primary tumor (OR, 2.93; P = .0527), shorter time to recurrence (hazard ratio [HR], 3.03; P = .0119), and decreased cancer-specific (HR, 3.53; P = .0039) and overall survival (HR, 2.44; P = .0114). CONCLUSIONS: 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.