Genetic predisposition for lung cancer

Lung cancer is the leading cause of cancer-related deaths worldwide in both men and women1. In 
several cancers hereditary factors are known to play a key role in the development of cancer. The best studied example is probably the BRCA gene in breast and ovarian cancer2. However also in other cancers, genes likely play a relevant role. Individuals with first-degree relatives with lung cancer have an increased risk of lung cancer even after adjustment for smoke exposure and other confounders3. 
The median age of patients with lung cancer is a proximally 64 years but it can also occur at a much younger age4. When lung cancer occurs at a younger age, so called pathogenic germline variants (PGV) are more often present. In a prospective multisite cohort study of 2984 patients with different cancers, the incidence of PGV for lung cancer was 14.7%5. Genome wide association studies (GWAS) have reported 45 lung cancer susceptibility loci with varying strength of evidence and highlighted suspected causal genes at each locus6.  GWAS identified susceptibility pathways for the role of chromosome 15q25.1 locus as a leading susceptibility region for lung cancer7. This variant allele is also associated with COPD and smoking intensity8.  There are even associations with susceptibility regions and histological subtypes of lung cancer. The 5p15 locus is associated with adenocarcinoma9 and locus 6p21 with squamous cell carcinoma10. Rare germline mutations in TP53, RB1 and EGFR have been shown to confer inherited predisposition to lung cancer11-13. In addition, functional germline polymorphisms in EGFR have been associated with exon 19 deletions in EGFR mutated non-small cell lung cancer previously14. GWAS has identified 23 loci associated with lung cancer survival, however none of these loci was reported in more than one study6.
Combining GWAS data with gene expression (mRNA) data may strengthen these associations and help to come to a better understanding of lung cancer in terms of screening, prevention and treatment.