Brief report: Clinical and Functional Characterization of Rare Germline and Somatic EGFR Variants in Three Patients with Non-Small Cell Lung Cancer.
TL;DR
Findings highlight the clinical relevance of germline EGFR variants in NSCLC and support the value of in-silico and in-vitro analyses for variant interpretation and response prediction.
Abstract
To date hereditary risk factors for non-small cell lung cancer (NSCLC) are poorly understood. While most cases are considered sporadic, rare monogenic germline alterations in EGFR and TP53 have been reported to be associated with increased risk of NSCLC. While identification and accurate functional characterization of such variants are essential for improving risk assessment and personalized therapeutic strategies, they remain limited. Germline whole genome sequencing (WGS) was performed to identify potential hereditary causes of NSCLC within Task Force 5 of the German National Network for Genomic Medicine. Detected EGFR variants were further investigated using in silico structural modeling and in vitro functional characterization in Ba/F3 cell models to investigate their oncogenic potential and sensitivity to tyrosine kinase inhibitors (TKIs). We identified two different EGFR germline variants (NM_005228.5:c.2155G>A, p.(Gly719Ser); NM_005228.5: c.2327G>A, p.(Arg776His)) in three patients with NSCLC, each harboring a different somatic compound variants (p.(Gly719Ser)+p.(Ser768Ile), p.(Gly719Ala)+p.(Arg776His), p.(Arg776His)+p.(Leu861Gln) (liver metastasis) and p.(Arg776His)+p.(Gly719Ser)). In silico analyses predict that p.(Gly719Ser) and p.(Gly719Ala) stabilize the active EGFR kinase conformation, whereas p.(Ser768Ile), p.(Arg776His) and p.(Leu861Gln) destabilize the inactive conformation. Consistent with these predictions, cis co-expression of the compound variants in the Ba/F3 assay demonstrated oncogenic activity and sensitivity to afatinib. Clinically two individuals achieved a partial response to afatinib treatment. These findings highlight the clinical relevance of germline EGFR variants in NSCLC and support the value of in-silico and in-vitro analyses for variant interpretation and response prediction. Broadening germline testing and functional variant characterization may enhance risk prediction and targeted therapy for individuals with NSCLC.