There are four types of lung cancer: Large cell carcinoma, squamous cell carcinoma, small cell lung cancer, and adenocarcinoma of the lung. The ratio of incidence of the different types varies with cause of cancer. Adenocarcinoma, which means the cancer started in the glandular tissue inside the lung, is more prevalent among light smokers, former smokers, and never smokers than it is among heavy smokers. Small cell lung cancer and squamous cell carcinoma are more common in heavy smokers than in the general lung cancer patient population. An analysis of published reports related to the histology of lung cancer which included smoking data, showed that adenocarcinoma was more prevalent amongst non smokers in comparison to squamous cell carcinoma (62 against 18 percent; based on 5144 cases). In comparison, adenocarcinoma cases were less prevalent amongst smokers (19 against 53 percent; based on 21,853 cases). The most recent lung cancer cases involving never smokers continue to identify adenocarcinoma as the most prevalent histology.
In comparison to other forms of adenocarcinoma, the BAC subset of adenocarcinoma has been associated even more strongly with never smokers. In a recent analysis, never smokers accounted for around 23 percent of BAC.
Recent technological advances have increased the understanding about the molecular biology of lung cancer, enabling the identification of significant variations that exist between never smokers and smokers with lung cancer.
One of the most noticeable variations between the incidence of lung cancer amongst never smokers and current and former smokers has been seen in the expression and mutations of the epidermal growth factor receptor (EGFR). Mutations occurring in the EGFR gene are more prevalent in lung tumors of never smokers in comparison to smokers. In a detailed analysis involving more than 400 patients with the most prevalent activating mutations present in the EGFR gene (mostly deletions in exon 19 and the L858R mutation on exon 21), it was noticed that some variations in the incidence of mutations were gender based, yet never smokers showed a significantly higher incidence of exon 19 and 21 mutations in comparison to regular smokers, in both men and women. Moreover, a separate immunohistochemical profile of the EGFR pathway has also been confirmed in never versus regular smokers, even when EGFR mutations are not present.
In comparison, it has been assumed that KRAS mutations are more prevalent amongst lung cancer patients who are regular smokers. However, in a more recent analysis involving 482 lung adenocarcinoma cases, it was noticed that the rate of KRAS mutations in codons 12 and 13 was not significantly different amongst never smokers (15 percent) in comparison to former smokers (22 percent) and regular smokers (25 percent). However, the type of mutations was majorly different characterized by more transition mutations (G to A) in comparison to transversion mutations (G to T or G to C) occurring in tumors of patients who have a history of smoking.
Major variations have also been noticed in the mutations and expression patterns of other types of genes while comparing never smokers to smokers. Some examples include p53, belonging to the NER family of proteins, together with ERCC1, which is associated with DNA repair, p38 (downstream of mitogen-activated protein kinase [MAPK]), nitrotyrosine (a marker of nitric oxide protein damage), other chromosomal abnormalities and methylation of p16. In lung cancer patients who are never smokers, the microRNA-21 (miR-21) seems to be increased, especially in individuals with EGFR mutations and can play an important role in lung carcinogenesis.
A fusion gene that has portions of both the echinoderm microtubule-associated protein-like 4 (EML4) gene as well as the anaplastic lymphoma kinase (ALK) gene in NSCLC is present in 3 to 7 percent of NSCLC and seems to be mutually exclusive in relation to EGFR and KRAS mutations. This is more common amongst never smokers who are diagnosed with lung cancer. Trials involving ALK receptor tyrosine kinase inhibitors are currently underway amongst patients with the EML4-ALK fusion protein.
In order to identify other important biomarkers in lung cancer amongst never smokers, a multi-institutional effort is currently underway, funded and sponsored by the National Cancer Institute's Early Detection Research Network and the Canary Foundation. The project was initiated in May 2009.