A High Percentage of NSCLC With Germline CHEK2 Mutation Harbors Actionable Driver Alterations: Survey of a Cancer Genomic Database and Review of Literature

Abstract

IntroductionGermline CHEK2 mutations are rare and have not been associated with increased risk of NSCLC. MethodsWe identified two sequential primary NSCLCs harboring distinct actionable driver alterations (EGFR E746 _S752 delinsV and CD74-ROS1) in a patient with NSCLC with a novel germline CHEK2 mutation S5fs∗54 (c.14_20delCGGATGT). We queried a genomic database of NSCLC samples profiled by plasma next-generation sequencing (Foundation Medicine Inc.) and performed a literature search of germline CHEK2 mutations in NSCLC. ResultsOf 6101 patients with unique NSCLC profiled by plasma next-generation sequencing, 53 cases (0.87%) of germline CHEK2 mutation were identified (male-to-female ratio, 49%:51%; median age = 75 y). The median allele frequency of CHEK2 was 49% (interquartile range: 49%–51%). Ten unique CHEK2 germline mutations were identified. Literature review identified 15 additional cases of germline CHEK2 mutations in NSCLC. Overall, a total of 70 CHEK2 germline mutations (21 unique CHEK2 alterations) were identified. Among these 70 CHEK2 germline mutations, 54.3% were amino acid substitutions (point mutation), 40.0% were frameshift mutations, and 5.7% were splice site mutations. Of these 70 total cases assessed, 29 (41.4%) potentially actionable driver alterations were identified with KRAS G12C mutation (27.6%) being the most common and KRAS G12A/C/D/R/S/V mutations together constituting 51.7% of these driver mutations. ConclusionsGermline CHEK2 mutations are rare in NSCLC. A large proportion of these cases harbor actionable driver alterations. The relationship between germline CHEK2 mutations and actionable driver alterations in NSCLC may be worth further investigation.