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

INTRODUCTION

Germline mutations are rare and have not been associated with increased risk of NSCLC.

METHODS

We identified two sequential primary NSCLCs harboring distinct actionable driver alterations (EGFR E746 _S752 delinsV and ) in a patient with NSCLC with a novel germline 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 mutations in NSCLC.

RESULTS

Of 6101 patients with unique NSCLC profiled by plasma next-generation sequencing, 53 cases (0.87%) of germline mutation were identified (male-to-female ratio, 49%:51%; median age = 75 y). The median allele frequency of was 49% (interquartile range: 49%-51%). Ten unique germline mutations were identified. Literature review identified 15 additional cases of germline mutations in NSCLC. Overall, a total of 70 germline mutations (21 unique alterations) were identified. Among these 70 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 G12C mutation (27.6%) being the most common and G12A/C/D/R/S/V mutations together constituting 51.7% of these driver mutations.

CONCLUSIONS

Germline mutations are rare in NSCLC. A large proportion of these cases harbor actionable driver alterations. The relationship between germline mutations and actionable driver alterations in NSCLC may be worth further investigation.