The Genetics of Lung Cancer
Everyone is aware of the link between cigarette smoking and lung cancer. However, recent research is showing strong genetic contributors to the development of these cancers. Even among smokers, genetics appear to play some role. Not every smoker develops lung cancer and not everyone who develops lung cancer smokes.
In the US, lung cancer is the second leading cause of cancer in both men and women and the leading cause of cancer death. In 2015, it was estimated that approximately 158,000 would die from lung cancer, representing about 27% of all deaths from cancer. The age-adjusted death rate is higher in men than women: 56.1/100,000 vs 36.4/100,000 persons. There are now over 400,000 people living in the US who have been diagnosed with lung cancer. Over 200,000 cases per year of new lung cancer cases are expected, representing 13% of all cancer diagnoses. Around the world, lung cancer is the most common cancer with approximately 1.8 million new cases and 1.2 million deaths annually. The NIH estimates that lung cancer care costs over $125 billion per year with lost productivity due to early death estimated to be another approximate $135 billion.
Molecular genetic studies demonstrate many genetic loci that plays a role in sporadic lung cancers. These are found both in growth-promoting oncogenes as well as growth-suppressing tumor suppressor genes. In adenocarcinoma of the lung, oncogene KRAS has been found to be mutated in approximately 30% of all cases. Additionally, in NSCLC (non-small cell lung cancer), CyclinD1 and EGFR15 have been shown to be over-expressed and amplified in 2.5-10% and 6% respectively. C-erbB2 or BCL2 oncogenes are over-expressed in approximately 25% of cases. Novel mutations, such as BRAF, are over-expressed in about 2% of cases of lung adenocarcinoma. A subset of NSCLC over-expresses a transforming EML4-ALK fusion gene. The familial relative risk ratio of lung cancer patients has been calculated to be RR approximately 2.00, similar to breast and prostate cancer. This cannot be explained by shared environmental risk factors as a meta-analysis revealed a 1.5 increased risk of lung cancer in non-smokers if they had an affected first degree relative. An additional linkage analysis of 52 high risk pedigrees shows lung cancer susceptibility at chromosome 6q23-25. Significant evidence has been discovered that genetic polymorphisms in certain genes correlate to lung cancer risk. Another study conducted genome wide association studies (GWAS) and found 3 genetic loci for lung cancer risk: 15q25, 5p1s, and 6p21.
Over the past decade, many studies have been conducted to establish the genetic contributors to lung cancer. In one study, three groups of researchers compared the entire genome between healthy subjects and those afflicted with lung cancer. They identified a region of genetic variation on chromosome 15 that appears to affect the probability of developing lung cancer. These researchers discovered that approximately 50% of the population carries a single copy of this gene variant. A single copy of this gene variant can raise the risk of developing lung cancer 30%. Additionally, it has been estimated that 10% of the population carries two copies of this mutation, which in turn raises cancer risk approximately 80%. This genetic risk is observed in smokers and non-smokers alike. A smoker has a 15% lifetime risk of developing lung cancer. It goes up to 23% if they possess the genetic variant on chromosome 15. In one of the three studies conducted at the University of Texas MD Anderson Cancer Center with approximately 6,000 cancer patients, the risk of cancer was found to be increased with this genetic mutation despite smoking history. Some of the researchers, however, felt the risk was increased because it made those carrying the genetic mutation susceptible to nicotine addiction. It has been discovered that the genes for the brain’s nicotine receptors are found on the same region on chromosome 15. One researcher found that the more copies of the genetic mutation, the more cigarettes a person was likely to smoke.
Smoking has been previously shown to have an increased incidence of DNA lesions. This includes those sustained from oxidative damages. One study investigated the link between lung cancer and the activity of the DNA-repair enzyme 8-oxoguanine DNA N-glycosylate (OGG). This enzyme is responsible for repairing DNA oxidative lesions. This study included lung cancer patients from Sheba Medical Center with histopathologically confirmed operable NSCLC. These researchers developed an assay to measure OGG activity in peripheral blood mononuclear cells. The data analyzed from this study demonstrated that reduced OGG activity is associated with NSCLC and further that reduced activity is a risk factor for lung cancer. The association between reduced OGG activity and lung cancer was found to be statistically significant after adjusting for confounding variables. This study clearly demonstrates the interplay between environmental and intrinsic genetic factors. Smoking causes increased DNA oxidative damage while reduced OGG by genetic factors decreases the ability to repair this oxidative damage. In smokers with decreased OGG activity, mutations occur faster than in smokers with normal OGG activity. Additionally, non-smokers with a lower OGG activity have an increased relative risk of lung cancer.
Another study examined the role of MicroRNA (miRNA) in lung carcinogenesis. miRNA genes are often located at fragile sites (FRAs) and are increasingly shown to have a role in human tumorigenesis. Additionally, they are also located at minimal regions of loss of heterozygosity, minimal regions of amplification, or common breakpoint regions. The precise mechanism of miRNA expression is unknown but several genetic and epigenetic alterations have been observed. In certain cancers, overexpression, under-expression and alterations of precursor cells have been detected. In the current study, miRNA expression profiles were investigated in human lung cancer as well as miRNA regulation by epigenetic mechanisms. miRNAS were identified that were expressed differently based on histological classifications of lung cancers. This study compared lung cancer tissue versus noncancerous lung tissue. They found 43 miRNAs that has statistical differences between the groups. Several of these differences were associated with FRAs, three of them actually inside FRAs (hsa-mir-21 at FRA17B, hsa-mir-27b at FRA9D, and hsa-mir-32 at FRA9E). Another region detected in lung cancer was found to be 9q34.3. In adenocarcinomas and squamous cell carcinomas, a reduced expression of let-7a-2 and let-7f-1 was found at a statistically significant level. There were six miRNAs (hsa-mir-21, hsa-mir-191, hsa-mir-155, hsa-mir-210, hsa-mir-126*, and hsa-mir-224) found in both histological types of NSCLC. This study also explored the correlation between miRNA expression profiles and patient survival. They found eight miRNAs linked to survival in adenocarcinoma. Additionally, high expression of either hsa-mir-155, hsa-mir-17-3p, hsa-mir-106a, hsa-mir-93, or hsa-mir-21 combined with low expression of either hsa-let-7a-2, hsa-let-7b or hsa-mir-145 predicted significantly worse prognosis.
An interesting study shows a genetic link between COPD and lung cancer. While it has been well know over the past 30 years that smokers who persistently show a decreased FEV1 are more at risk of lung cancer, this study suggests that this is because there is a genetic link between the two and they are not distinct diseases. Based on twin studies, the heritability of lung cancer and reduced FEV1 is approximately 15-25% and 40-70%, respectfully. Meta-analytic studies identified genetic variants that appear in both COPD and lung cancer and seem to be significant: GSTM1, 4q22, 4q31, 6p21, and 15q25. At a subcellular level, many of the signaling pathways seem to be shared in both COPD and lung cancer. These include the signaling pathways P13K, NF-KB and STAT3 signaling molecules.
The studies being done regarding the genetics of lung cancer is vast and the above discussion represents only a sampling of the research at present. Current and future studies will surely find more detailed knowledge of the role genes play in the development of lung cancer. But, despite the newly discovered genetic knowledge, smoking still represents a very significant contributing factor to lung cancer and is currently the most modifiable. No discussion of lung cancer can neglect the topic of smoking cessation. Novel strategies need to be developed in that area as well and unless that is done, we will never win the war against lung cancer.
Linda Girgis MD, FAAFP is a family physician practicing in South River, New Jersey. She was voted one of the top 5 healthcare bloggers in 2016. Follow her on twitter@DrLindaMD.