New Paper Explores Heritable Genetic Factors Related To Mesothelioma

A new paper by Kharazmi and colleagues present important data regarding the heritable nature of mesothelioma using epidemiological techniques to analyze the population-based Swedish Cancer Registry. The results, reported in the European Journal of Cancer, are important because the findings confirm that both genes and exposures are relevant, and on their face, appear helpful to both plaintiffs and defendants. Overall, the paper supports the view that genetics and mesothelioma are strongly linked in some instances, with 30-60-fold Hazard Ratio numbers for persons from families with a family history of mesothelioma.

Investigation Focused On Occupation and Family History of Mesothelioma

These investigators attempted to determine how much of an individual’s risk of mesothelioma can be attributed to occupation, inherited genetic mutations, or both. To that end, they utilized the Swedish Family-Cancer Database (FCD) to explore the effect of occupation on familial risk of mesothelioma. The FCD contains detailed data on 16.1 million individuals in Sweden, including disease histories obtained from registries and organized using national registration numbers assigned to people from 1958-2015. Of these, the investigators were able to study approximately 6 million individuals for whom both cancer and occupational data were available. The investigators then stratified individuals into a series of groups, including (1) whether they worked in an asbestos-related occupation; and (2) whether they had a family history of mesothelioma.

Occupation Drives Some Mesothelioma Risk

Not surprisingly, individuals who worked in asbestos-related occupations were significantly more likely to present with mesothelioma. The influence of occupation was demonstrated by elevated Hazard Ratios (HRs) in the range of 3 -5-fold for individuals with no family history of mesothelioma.

Family History of Mesothelioma (Genetics) Also Drives Mesothelioma Risk

The study results also suggest that a family history of mesothelioma is a significant factor for mesothelioma risk. The Hazard Ratios for individuals who had both an asbestos-related occupation and a family history of mesothelioma were 10-fold more likely to present with mesothelioma (HRs of 25 – 65). The investigators interpret this finding as indicating that the high HRs indicate that the risk of pleural mesothelioma involves a “strong interaction” between a family history of mesothelioma (one or more) and asbestos-related occupation..

Family History of Mesothelioma But No Asbestos-Related Occupation

Interestingly, the investigators also reported elevated mesothelioma HRs for individuals with a family history of mesothelioma but no asbestos-related occupation (HRs of 1.6 – 3.3). However, these HRs were not statistically significant due to the low number of mesotheliomas in this group (6 individuals total).

A Mixed Bag for Causation Analysis

Overall, these findings highlight the fact that there are limits to the conclusions that can be reached from population-based epidemiology studies. The results indicate a cohort of persons for whom it would useful to perform genetic sequencing to determine precisely which genetic factors these non-asbestos-exposed individuals did or did not carry (including epigenetic markers). The results are a mixed bag for plaintiffs and defendants. They offer yet another example of why lawyers and other professional advisors (e.g. actuaries) can do more for their clients if the professionals develop at least a working knowledge of genetic factors.

Plaintiff’s counsel and their experts are likely to point to this study as evidence of genetic susceptibility, and to support arguments that asbestos is extra hazardous in individuals with a certain genetic makeup. Indeed, we are seeing examples of plaintiff counsel arguing that some people are more susceptible to mesothelioma than are others. One result could be that some plaintiff’s counsel may decide it is desirable to embrace genetic testing as part of their thinking about whether to take on and invest in subsets of cancer cases, and then argue relative risks based on genetic factors. Another result is that defense lawyers and other advisors need a working knowledge of genetic factors in order to better estimate future claims and prepare for arguments from plaintiffs.

On the defense side, the results of the paper further suggest our continuing theme that defendants need to investigate for a family history of mesotheliomas and other cancers. It also will be useful for defense counsel and experts to be prepared to address the findings from this study and point out both the shortcomings and possible messages. One shortcoming is that no genetic testing was performed on any of the individuals in the study (from a blood draw or from tumor tissue).  On the other hand, defense interests may cite the study because the results suggest that purely “genetic” factors lead to the development of some number of mesotheliomas. In fact, it stands to reason for defendants to argue that the small number of mesothelioma cases with no evidence of asbestos-related occupations arose in persons carrying genetic mutations that drove the induction of their cancer, even in the absence of asbestos exposure.

In sum, this study highlights the importance of using both epidemiology and genomics to investigate mesotheliomas, especially when no obvious asbestos exposure can be identified. In fact, if the right genetic sequencing is performed (e.g. whole genome), specific gene variants can be looked for and ruled out. In contrast, single gene testing would produce less robust answers to the specific causation question: why did this cancer develop in this person?

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