Study Identifies New Genetic Mutation Linked to Mesothelioma—LRRK2

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In a study published on May 18, 2021 in Human Molecular Genetics, researchers at Fox Chase Cancer Center in Philadelphia, along with a team of international researchers, identified another genetic mutation, in addition to BAP1, that may predispose individuals to malignant mesothelioma.

The authors of the study, which was overseen by Joseph R. Testa, PhD, FACMG of the Cancer Signaling and Epigenetics Program at Fox Chase, first recognized that at this point, “[t]here is irrefutable evidence that germline BAP1 mutations contribute to malignant mesothelioma susceptibility.” This is commonly referred to as BAP1 tumor predisposition syndrome (BAP1-TPDS). As previously reported by Asbestos Case Tracker here and here, over the past several years, we have seen defense strategies based on the BAP1 mutation continue to develop in practice. However, given that the BAP1 mutation has not been found in all mesothelioma cases with a family history of cancer, the authors of the study sought to identify other germline mutations that may predispose individuals to malignant mesothelioma and other cancers. For example, the authors focus partly on one study of an Italian family with eight confirmed cases of malignant mesothelioma between 1987 and 2016—six women and two men—but displayed no evidence of a BAP1 mutation.

The study was small, involving only twelve mesothelioma patients selected from a group of 141 who had a family history of cancer but did not express a BAP1 mutation. The original cohort was comprised of 150 malignant mesothelioma cases with a history of asbestos exposure and past personal or family history of cancer. Of those, nine patients that presented with germline mutations affecting the coding sequence of the BAP1 gene were eliminated. Then, whole genome sequencing (WGS) was performed on germline DNA from twelve of the remaining cases without BAP1 mutations. These twelve were “selected from families having a high overall incidence of cancer generally, not necessarily a personal or family history strongly indicative of BAP1-TPDS.” The authors also performed WGS on two malignant mesothelioma cases from the Italian family noted above that lacked the BAP1 mutation.

While the authors found three genes that were most frequently altered in malignant mesothelioma patients, one gene, LRRK2, was particularly noteworthy. LRRK2, which is leucine rich repeat kinase gene 2, “encodes a kinase that is involved in oxidative stress, inflammation, and autophagy,” and LRRK2 mutations have been previously linked to Parkinson’s disease. In macrodissecting a malignant mesothelioma tumor sample from the Italian family discussed above, the researchers found evidence suggesting that the mutant gene acted as a driver for malignant mesothelioma. As such, the researchers posed “[a]s is the case for BAP1, germline mutation of LRRK2 may make individuals highly susceptible to the carcinogenic effects of asbestos.” Additionally, further analysis suggested that the “loss of LRRK2 expression is a newly recognized common tumor suppressor alteration in malignant mesothelioma.” That is, Dr. Testa explained, “expression of the LRRK2 gene was lost in 60% of the approximately 30 primary mesothelioma tumors and mesothelioma cell lines that we subsequently examined,” which “suggests that in addition to being a cancer predisposition gene, loss of expression of this newly recognized tumor suppressor gene is a frequent finding in mesothelioma and may serve as a biomarker for identifying those patients most likely to benefit from specific therapies that target pathways affected by LRRK2 loss.”