Mechanism
Pathogenesis
Large scale studies such as The Cancer Genome Atlas (TCGA) have systematically characterized recurrent somatic alterations likely driving lung adenocarcinoma initiation and development. Gene mutations and copy number alterations
Since smoking is a strong mutagenic factor, lung adenocarcinoma is one of the tumor types with the highest number of mutations. Common somatic mutations in lung adenocarcinoma affect many oncogenes and tumor suppressor genes, including TP53 (mutated in 46% of cases), EGFR (27%), KRAS (32%), KEAP1, STK11 and NF1. EGFR and KRAS mutations tend to appear in a mutually exclusive fashion. KRAS mutations are associated with smoking habits, whereas EGFR mutations occur more frequently in females, people of Asian ethnicity and never-smokers.Copy number amplifications in oncogenes such as TERT, MDM2, EGFR, MET, and MYC have been reported, as well as deletions of tumor suppressor genes such as CDKN2A.Frequent alterations occur in genes belonging to the receptor tyrosine kinase pathway, of which EGFR is the most prominent example. This pathway is involved in cell proliferation and survival and it is often deregulated in cancer. As a consequence, targeted therapies have been developed to inhibit mutant pathway components. Chromosomal rearrangements
Three membrane associated tyrosine kinase receptors are recurrently involved in fusions or rearrangements in adenocarcinomas: ALK, ROS1, and RET, and more than eighty other translocations have also been reported in adenocarcinomas of the lung.In ALK rearrangements, the most common partner gene is EML4. EML4-ALK fusions tend to occur in tumors that do not carry EGFR or KRAS mutations and have also a lower frequency of TP53 mutations.
having an elevated number of mutations).Therapeutic approaches combining multiple immune checkpoint inhibitors or one immune checkpoint inhibitors and a cytotoxic agent are undergoing clinical trials as of 2018. Howerver, the KEYNOTE-598 phase III trial has reported in 2021 that adding ipilimumab to pembrolizumab for NSCLC patients with PD-L1 tumor proportion score ≥50% does not confer any efficacy benefit, but may introduce greater toxicity. The potential role of anti-PD-1 agents as neoadjuvant therapy in resectable NSCLCs is also being investigated. Epidemiology
As for other lung cancer subtypes, lung adenocarcinoma incidence is strongly associated with smoking. Incidence of pulmonary adenocarcinoma has been increasing in many developed Western nations in the past few decades, with a share reaching 43.3% of all lung cancers in the US as of 2012, thus replacing squamous cell lung carcinoma as the most common type of lung cancer. This can be largely attributed to the decreasing smoking rates, which favors the adenocarcinoma histology. Indeed, although smoking is still its strongest risk factor, lung adenocarcinoma is by far the most common among lifelong non-smokers (<100 cigarettes in a lifetime). == References ==