Developmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Multiple primary lung tumors in smokers are often linked to carcinogen exposure (field cancerization).
• The origin of multiple EGFR-mutant lung tumors in non-smokers without known exposures is unclear.

Purpose of the Study:

• To investigate the underlying mechanisms for multiple, distinct EGFR-mutant non-small cell lung cancer (NSCLC) tumors at presentation in patients without known environmental exposures.
• To identify genetic predispositions contributing to the development of multiple primary EGFR-mutant lung tumors.

Main Methods:

• Whole-exome sequencing (WES) and hypermutable poly(guanine) (poly(G)) repeat genotyping were used for lineage tracing.
• Phylogenetic analysis was performed on multiple tumors from ten patients with early-stage, resectable NSCLC.
• In vitro modeling was used to assess the functional impact of identified germline EGFR variants.

Main Results:

• Four patients showed evidence of developmental mosaicism, suggesting a common non-germline cell of origin for their multiple tumors.
• Two patients had germline EGFR variants that enhanced signaling activity in vitro.
• Developmental mosaicism and germline EGFR variants were identified as distinct mechanisms predisposing to multiple EGFR-mutant tumors.

Conclusions:

• Developmental mosaicism represents a novel mechanism for genetic predisposition to multiple primary EGFR-mutant lung cancers.
• Germline EGFR variants also contribute to the development of multiple EGFR-mutant tumors.
• These findings have significant implications for understanding the etiology and guiding the clinical management of EGFR-mutant NSCLC.