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Condition report · Cancer

Hereditary Lung Cancer

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.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

Inherited susceptibility to lung cancer in genes such as EGFR predispose patients to a lifelong increased risk of lung cancer.

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. The same applies to KRAS G12C, the most common KRAS change in lung adenocarcinoma: it is acquired in the tumor, not inherited, and is found by tumor testing, where it can make a person eligible for targeted drugs such as sotorasib or adagrasib. Germline sequencing of blood or saliva, including this report, does not look for it. 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.

The condition we analyse

A malignant neoplasm involving the lung.

Genes analysed

Also known as

adenocarcinoma of lung, response to tyrosine kinase inhibitor in, autosomal dominant, somatic mutation; adenocarcinoma of lung, somatic; cancer of lung; lung cancer, protection against, autosomal dominant, somatic mutation; lung cancer, resistance to, autosomal dominant, somatic mutation; lung cancer, somatic; lung cancer, susceptibility to, autosomal dominant, somatic mutation; malignant lung neoplasm; malignant lung tumor; malignant lung tumour; malignant neoplasm of lung; malignant neoplasm of the lung; malignant tumor of lung; malignant tumor of the lung; malignant tumour of lung; malignant tumour of the lung; nonsmall cell lung cancer, response to tyrosine kinase inhibitor in, autosomal dominant, somatic mutation; nonsmall cell lung cancer, somatic; nonsmall cell lung cancer, susceptibility to, autosomal dominant, somatic mutation

Includes 63 related subtypes ↓
  • acinar lung adenocarcinoma
  • adenosquamous lung carcinoma
  • asbestos-related lung carcinoma
  • basaloid large cell lung carcinoma
  • bronchogenic carcinoma
  • bronchus carcinoma in situ
  • bronchus mucoepidermoid carcinoma
  • classic pulmonary blastoma
  • combined lung carcinoma
  • combined small cell lung carcinoma
  • epithelial predominant pulmonary blastoma
  • fetal lung interstitial tumor
  • Graham-Boyle-Troxell syndrome
  • large cell carcinoma with rhabdoid phenotype
  • large cell lung carcinoma, clear cell variant
  • lung adenocarcinoma
  • lung adenocarcinoma in situ
  • lung adenoid cystic carcinoma
  • lung carcinoma
  • lung carcinoma in situ
  • lung colloid adenocarcinoma
  • lung combined large cell neuroendocrine carcinoma
  • lung combined type small cell adenocarcinoma
  • lung epithelial-myoepithelial carcinoma
  • lung giant cell carcinoma
  • lung hilum cancer
  • lung hilum carcinoma
  • lung inflammatory myofibroblastic tumor
  • lung large cell carcinoma
  • lung leiomyosarcoma
  • lung lymphoma
  • lung meningioma
  • lung non-Hodgkin lymphoma
  • lung occult adenocarcinoma
  • lung occult large cell carcinoma
  • lung occult squamous cell carcinoma
  • lung pleomorphic carcinoma
  • lung sarcoma
  • lung sarcomatoid carcinoma
  • lung signet ring cell carcinoma
  • lung superior sulcus carcinoma
  • lymphoepithelioma-like lung carcinoma
  • malignant superior sulcus neoplasm
  • minimally invasive lung adenocarcinoma
  • mixed mucinous and nonmucinous bronchioloalveolar adenocarcinoma
  • mucinous bronchioloalveolar adenocarcinoma
  • non-small cell lung carcinoma
  • non-small cell squamous lung carcinoma
  • nonmucinous bronchioloalveolar adenocarcinoma
  • occult small cell lung carcinoma
  • papillary lung adenocarcinoma
  • pleuropulmonary blastoma
  • pleuropulmonary blastoma type 1
  • pleuropulmonary blastoma type 2
  • pleuropulmonary blastoma type 3
  • primary pulmonary diffuse large B-cell lymphoma
  • pulmonary blastoma
  • pulmonary large cell neuroendocrine carcinoma
  • pulmonary mucoepidermoid carcinoma
  • small cell lung carcinoma
  • solid adenocarcinoma with mucin production
  • squamous cell lung carcinoma
  • well-differentiated fetal adenocarcinoma of the lung
MONDO:0008903OMIM 211980MedGen 66885

Why whole genome sequencing

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.

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