Genetic Susceptibility to Lung Cancer

Lung cancer is the most common cause of cancer death in the United States, with an estimated 158,080 deaths in 2016 (accounting for 27% of all cancer deaths), and the second most frequent cancer diagnosed, behind breast cancer in women and prostate cancer in men, with an estimated 224,390 new diagnoses in 2016. Both lung cancer incidence and mortality rates have decreased with the reduction in tobacco smoking; however, lung cancer continues to be the cause of substantial morbidity and mortality. Survival remains poor, with a 5-year survival rate of about 17%. The 5-year survival rate has changed little over time because lung cancers are still most often diagnosed at advanced stages when treatment is less effective. Only recently has there been evidence that screening for lung cancer using low-dose computed tomography is an effective means of reducing mortality. In 2013, the US Preventive Services Task Force issued a recommendation for lung cancer screening for high-risk individuals. Advances in the treatment of lung cancer have also been slow. Since the early 2000s, treatment targeted to molecular signatures in lung tumors, such as epidermal growth factor receptor ( EGFR ) inhibitors, has resulted in improved survival in particular subgroups of patients. Unfortunately, the development of drug-resistant mutations is a problem that affects overall survival for patients with lung cancer, and continued drug development is crucial. To better understand the profile of a high-risk individual and to aid in the development of chemopreventive agents and targeted treatments, it is essential to understand the genetics underlying lung cancer development.

Cancer of the lung has frequently been cited and is a well-established example of a malignancy that is solely determined by the environment, with risks associated with cigarette smoking and certain occupations, such as mining, asbestos exposure, shipbuilding, and petroleum refining. About 85% to 90% of lung cancer risk is attributable to cigarette smoking. However, lung cancer develops in only 15% of smokers, suggesting a differential susceptibility to the effects of tobacco carcinogens. It is possible that variation in genetic profiles contributes to this differential susceptibility. In addition, 10% to 15% of lung cancers occur in never-smokers. Little is understood about risk in never-smokers, although exposure to secondhand cigarette smoke certainly contributes to the risk of lung cancer. Environmental tobacco smoke exposure has been associated with a 20% to 30% increased risk for the development of lung cancer among never-smokers. In a meta-analysis of 22 studies, the authors reported that exposure to tobacco smoke in the workplace increased the risk of lung cancer by 24% and this increased risk was highly correlated with duration of exposure.

There is overwhelming evidence of the carcinogenic effects of cigarette smoking and other environmental exposures and the occurrence of multiple somatic mutations in lung tumors. Known mutations and loss of heterozygosity in oncogenes and tumor suppressor genes involved in lung carcinogenesis accumulate in individual somatic cells during lung tumor initiation and progression. In 2013, the systematic genetic analysis of alterations in lung tumors was described in several published reports. The Cancer Genome Atlas noted that the results of sequencing 178 squamous cell carcinomas demonstrated the complexity of lung tumors, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 copy number alterations per tumor. These observations highlight the genetic complexity of lung cancers compared with most other cancers. Recurrent mutations were identified in 11 genes. A total of 64% of cases carried a somatic alteration in a gene for which a targeted treatment could be proposed based on currently existing therapies (although many of these therapies are not currently indicated for lung cancer). Similarly, sequencing of 183 lung adenocarcinoma tumor/normal DNA pairs showed a mean exonic somatic mutation rate of 12 events per megabase. Higher mutation rates were seen among smokers than among never-smokers, and the mutation signature varied with smoking. Several previously identified mutations were reported, including those in tumor protein p53 ( TP53 ), Kirsten rat sarcoma ( KRAS ), EGFR , serine/threonine kinase 11 ( STK11 ), and v-raf murine sarcoma viral oncogene homologB ( BRAF ). In addition, novel candidates were identified. In total, 25 genes were significantly mutated and often associated with smoking history, age, stage, and progression-free survival. Smaller numbers of small cell lung tumors have been sequenced. In another study of 53 tumor samples/normal tissue pairs, investigators identified 22 significantly mutated genes, including members of the sex determining region Y (SRY)-box ( SOX ) family of genes. Susceptibility to selected mutations also varies according to host-specific factors. For example, mutations in EGFR are much more common in women, Asians, and never-smokers and individuals presenting with adenocarcinomas, while mutations affecting KRAS are more common in men, individuals of European descent, smokers, and those with squamous histology. Susceptibility to somatic mutations may be due to individual differences in risk associated with the inhalation of known carcinogens; i.e., individuals differ in their susceptibility to these environmental insults. The potential role that inherited germline genetic variation plays in influencing lung cancer susceptibility is the topic of this chapter.

Evidence indicates that allelic variation at genetic loci affects inherited susceptibility to lung cancer. Epidemiologic evidence demonstrates familial aggregation of lung cancer after adjusting for familial clustering of cigarette smoking and other risk factors, and differential susceptibility to lung cancer is inherited in some families. Studies of inherited susceptibility to lung cancer, including major susceptibility loci and loci with less pronounced effects, are described in this chapter. Also discussed is how these genetic risks relate to well-known environmental factors, particularly cigarette smoking.