Germline EGFR Mutations and Familial Lung Cancer.

Area of Science:

• Genetics
• Oncology
• Pulmonology

Background:

• Inherited factors influencing lung cancer risk are not well understood.
• Germline pathogenic variants (PVs) in genes like EGFR can predispose individuals to lung cancer.
• Characterizing these variants is crucial for identifying at-risk families.

Purpose of the Study:

• To investigate the clinical characteristics of families with germline EGFR PVs.
• To understand the inheritance patterns and penetrance of EGFR PVs.
• To identify potential founder effects and geographic enrichment of specific EGFR variants.

Main Methods:

• Prospective enrollment of lung cancer patients and relatives in the Investigating Hereditary Risk from T790M study (NCT01754025).
• Germline testing for EGFR PVs, including EGFR T790M.
• Clinical phenotyping, somatic mutation analysis, and genome-wide haplotyping.

Main Results:

• 141 participants from 59 kindreds were enrolled; 116 were tested for EGFR T790M.
• 55% of carriers (50/91) were diagnosed with lung cancer, with 52% diagnosed by age 60.
• A shared 4.1-Mb haplotype among 89% of carriers suggested a recent founder variant in the Southeastern US.
• 95% of lung cancers in carriers had an EGFR driver comutation.
• Lung nodules were detected in 9/36 germline carriers without cancer, including a young individual.

Conclusions:

• This is the first prospective study of familial EGFR-mutant lung cancer.
• A recent founder germline EGFR T790M variant is enriched in the Southeastern US.
• High prevalence of EGFR-driven lung adenocarcinomas and nodules supports CT screening for high-risk individuals and families.