The causal relationship between smoking and lung cancer is one of the strongest and most well established in all the health sciences. Asbestos defense attorneys have therefore been eager to determine if there is a causal relationship between smoking and mesothelioma. If such a relationship were identified, in certain cases with the right case-specific facts, smoking could therefore be used as an alternative cause in mesothelioma litigation. Broadly speaking, however, no association has been identified. In fact, much of the epidemiology evaluating this the relationship between smoking and mesothelioma has suggested that no association (causal or otherwise) exists.
Such was the state of affairs before the genetics of cancer (generally) and mesothelioma (specifically) has become better understood. In a recent blog post, we discussed how a significant number of cancer patients, including those with mesothelioma, are carriers of germline mutations that drive those cancers. This means that the genetic makeup of some individuals makes them predisposed to developing cancer, independent of environmental factors and is referred to as genetic predisposition. Conversely, it is also well understood that an individual can be susceptible to environmentally induced cancer by virtue of his or her genetic makeup. This is referred to as genetic susceptibility. We have previously written about the courtroom distinction between genetic susceptibility and genetic predisposition.
So, could genetic susceptibility be the link between smoking and mesothelioma?
In other words, is it possible that the existing epidemiological literature has failed to find a link between smoking and mesothelioma because the general population is genetically diverse? But if epidemiological studies focused on individuals with a specific genetic susceptibility (in the form of specific genetic mutations), might these studies identify a causal association between smoking and mesothelioma that was not previously uncovered with broader, population-based epidemiological studies?
Indeed, it is well known that only 10-20% of heavily asbestos-exposed individuals present with mesothelioma and approximately 10 – 20% of mesothelioma patients have no demonstrable exposure to asbestos. For these reasons, it is well accepted that factors other than asbestos can cause mesothelioma in certain individuals. The discovery of genetic alterations in smokers who present with mesothelioma highlights the need to screen for mutations in high-risk individuals. Below we consider the role that genetic susceptibility may play in driving smokers to mesothelioma.
CDKN2A Deletions Drive Mesothelioma
A person’s susceptibility to developing mesothelioma can result from errors in their genetic code known as mutations or variants. One important type of genetic mutation is referred to as a deletion, or a genetic mutation in which a part of a chromosome or a sequence of DNA is lost during DNA replication. Deletion of one gene in particular, CDKN2A/p16, a tumor suppressor, is one of the most common genetic alterations in malignant mesotheliomas, occurring in up to 74% of pleural mesotheliomas and 35% of peritoneal mesotheliomas. CDKN2A deletions increase the chance of developing mesothelioma and therefore should be taken into consideration to better estimate individual risk in those individuals who have been alleged to be exposed to asbestos.
Smoking and Mesothelioma
Germline CDKN2A mutations (i.e., mutations that are inherited from a person’s mother or father) may confer an increased sensitivity to carcinogens in tobacco smoke. We know this because, among carriers that have ever smoked, the risk for several types of cancers are significantly elevated when compared with non-smokers. Thus, it is possible that carriers of the CDKN2A mutation may be susceptible to developing mesothelioma through smoking, independent of asbestos exposure. These individuals can be identified through genomic sequencing and such a finding would help prove alternative cause in an asbestos case.
In addition, although the exact mechanism is unknown, it is believed that smoking indirectly inactivates CDK2NA/p16 through epigenetic factors (i.e., environmental factors), thereby increasing the risk of mesothelioma. Research has shown that exposure to tobacco-associated carcinogens increased the likelihood of p16 inactivation, which significantly correlated with pack-years smoked and duration of smoking. Notably, in this study asbestos exposure was not associated with methylation of p16.
Traditionally, plaintiff experts dismiss the role of cigarette smoking in the causal pathway to mesothelioma. As support, they assert that epidemiological studies fail to demonstrate an association between smoking and mesothelioma. However, genomic techniques have the potential to shed light on specific inherited factors that might support the assertion that specific individuals are genetically susceptible to smoking-induced mesothelioma. Such an argument could be used to challenge the view that asbestos was the cause of mesothelioma, especially where asbestos exposure is highly questionable.
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