HEREDITARY LUNG CANCER

Hereditary Lung Cancer Risk — germline EGFR T790M causes familial lung cancer treatable with targeted therapy, and never-smoker lung cancer is increasingly recognized as having distinct genetic drivers.

Whole genome sequencing evaluates germline lung cancer risk genes — EGFR (T790M germline), TP53, BRCA2, CHEK2, HER2 (ERBB2), and additional susceptibility variants — distinguishing hereditary from environmental lung cancer risk.

EGFR
TP53
BRCA2
CHEK2
CHRNA3
TERT

About this condition

Lung Cancer — Hereditary Risk

Approximately 10-15% of lung cancers occur in never-smokers, and these cancers have distinct molecular profiles. Germline EGFR T790M is one of the most well-characterized hereditary lung cancer variants — families with this germline variant develop lung adenocarcinoma, often bilateral and multifocal, responsive to osimertinib (a third-generation EGFR TKI). TP53 germline variants (Li-Fraumeni syndrome) confer elevated lung cancer risk. BRCA2 carriers have approximately 1.8x increased lung cancer risk. CHEK2 and EGFR rare germline variants are additional risk factors.

The distinction between germline and somatic EGFR testing is critical. Somatic EGFR testing (on tumor tissue) guides targeted therapy selection for existing lung cancer. Germline EGFR testing identifies individuals predisposed to developing lung cancer — enabling screening and early detection. Families with germline EGFR T790M can benefit from low-dose CT screening beginning earlier than standard guidelines. This germline-somatic distinction is frequently misunderstood, even by oncologists.

Lung cancer heritability is approximately 18% based on twin studies. Beyond high-penetrance genes, GWAS have identified multiple common susceptibility variants at CHRNA3/CHRNA5 (nicotinic acetylcholine receptor — also mediates nicotine dependence), TERT (telomerase), TP63, and HLA region loci. Polygenic risk scores combining these variants can identify individuals at elevated risk who benefit from earlier or more intensive low-dose CT screening — particularly relevant for those with occupational exposures or family history.

Germline EGFR T790M causes familial lung cancer treatable with osimertinib — a targeted therapy. This is DIFFERENT from somatic EGFR testing. Families with multiple lung cancer cases (especially never-smokers) should have germline EGFR evaluation.

Gene locus: EGFR (7p11.2), TP53 (17p13.1), BRCA2 (13q13.1), CHEK2 (22q12.1), CHRNA3/5 (15q25.1), TERT (5p15.33)

Germline and somatic EGFR testing serve different purposes. Germline testing identifies families predisposed to lung cancer — enabling screening and prevention. WGS captures germline EGFR plus all additional hereditary lung cancer genes.

Germline EGFR T790M families develop bilateral lung adenocarcinoma responsive to osimertinib — molecular diagnosis enables screening and targeted treatment

Families carrying germline EGFR T790M develop non-small cell lung cancer — often bilateral and multifocal — that responds to third-generation EGFR tyrosine kinase inhibitors (osimertinib). Identification of the germline variant enables low-dose CT screening for all carrier family members, with early detection at stages where surgical cure is possible. Without germline testing, at-risk family members remain unscreened until symptomatic — when lung cancer is often advanced.

Never-smoker lung cancer is 10-15% of all lung cancers — genetic evaluation is particularly important when smoking is not the driver

When lung cancer occurs in a never-smoker, the likelihood of a genetic contribution is substantially higher. Germline EGFR variants, TP53 (Li-Fraumeni), and BRCA2 should be evaluated. Additionally, never-smoker lung cancers are more likely to have targetable somatic drivers (EGFR, ALK, ROS1, RET fusions) — and germline predisposition testing complements somatic profiling. WGS provides the germline genetic evaluation that identifies familial risk factors distinct from the somatic tumor profiling.

Hereditary Lung Cancer Risk — germline EGFR T790M causes familial lung cancer treatable with targeted therapy, and never-smoker lung cancer is increasingly recognized as having distinct genetic drivers.

Lung Cancer — Hereditary Risk

Germline and somatic EGFR testing serve different purposes. Germline testing identifies families predisposed to lung cancer — enabling screening and prevention. WGS captures germline EGFR plus all additional hereditary lung cancer genes.

Germline EGFR T790M families develop bilateral lung adenocarcinoma responsive to osimertinib — molecular diagnosis enables screening and targeted treatment

Never-smoker lung cancer is 10-15% of all lung cancers — genetic evaluation is particularly important when smoking is not the driver

Others in Hereditary Cancer

One test. A lifetime of answers.