By Adi F. Gazdar, MD
While all of the major histological forms of lung cancer are strongly associated with smoking, an important subset (about 20% worldwide, 10–15% in the US) arise in lifetime never-smokers. Lung cancer in never-smokers (LCNS) targets the female gender, East Asian ethnicity, and adenocarcinoma histology. 1 While environmental smoke exposure (ESE), or secondhand smoke, is usually considered the major cause of LCNS, ESE is a weak carcinogen, and the other known risk factors are modest in effect or frequency. Thus, we do not understand the major cause or causes of LCNS.
A comparison of the genetic changes in lung cancers arising in ever and neversmokers may shed some light on the causes of LCNS. We know that there are major differences in the patterns of mutations involving specific genes, but as these are covered in other newsletters, they will not be discussed further here.
The major differences in tumoracquired changes (other than the specific targeted genes) consist of two major types: the overall number of mutations and specific types of mutational change.2 Tobacco exposure is a powerful carcinogen, and exposure over the decades between smoking initiation and tumor appearance results in numerous “driver” and “passenger” mutations in coding and non-coding regions of the genome. Thus, the three major forms of lung cancer are among the five tumor types with the largest number of mutations.3 These mutations are present throughout the respiratory epithelium. However, never-smokers have many fewer mutations (perhaps tenfold to one hundredfold less), and have a more limited distribution in non-malignant epithelium.
The other form of change involves the specific pattern of base pair substitutions involved in the resultant mutations. Of the four base pairs, six major forms of changes may occur, and are known as either transversions or transitions. Tobacco exposure results in a specific base pair change known as G>T:C>A transversions. By contrast, the commonest form of base pair substitution in never-smoker tumors is known as G>A:C>T transitions. Recently we have learned that the base pairs immediately preceding and following the substitution may also play a role a role in the pathogenesis of specific tumors.3 These findings greatly increase the number and complexity of the base pair changes, and we are still trying to understand their roles in lung cancers.
In addition to tumor-acquired genetic changes, genetic variations may predispose to cancer. The human genome, consisting of about 3 billion nucleotides, contains about 10 million genetic variations known as single nucleotide polymorphisms (SNPs). Genomewide association studies (GWAS) scan the entire genome to identify genetic variants associated with lung and other cancers. Earlier studies had identified SNPs associated with an increased tendency to smoke and others associated with all forms of lung cancer. More recent work has focused on identifying SNPs associated with lung cancer in Asian women never-smokers.4 Pathway analyses involving the affected genes are being performed to try and elucidate the different roads to cancer in smokers and never-smokers.
Unlike individual SNPs, inherited gene mutations (such as BRCA gene mutations in breast cancer) may have high penetrance, resulting in greatly increased cancer risks. Modest numbers of high-risk families have been identified with lung cancer and potential or actual genes identified. One mutation in the EGFR gene, T790M, while rare in the general population, is present in up to 1% of lung cancers. Of interest, subjects who inherit this mutation are most at risk for lung cancer if they are women and never-smokers.5
From these findings we can draw the following conclusions:
1) Lung cancers arising in smokers and never-smokers are different tumors at the genetic level.
2) These two distinct types of tumors share some etiologic factors, but the major cause or causes of lung cancers in never-smokers remain unknown.
3) Molecular studies, combined with clinical observations and epidemiological findings may shed further light on the origins and causes of lung cancers arising in never-smokers.