Genetic Risk Factors for Mesothelioma

Malignant pleural mesothelioma (MPM) is a rare type of cancer found in the lining of the lungs. 9 out of 10 cases of MPM are caused by exposure to asbestos. Now banned in most countries, asbestos is a fibrous material that was widely used in the building industry. Inhaling asbestos fibres can damage the lining of the lungs and, over time, lead to cancer. 2 studies have presented data on genetic risk factors associated with MPM. Understanding the risk factors for this cancer may help direct screening and treatment guidelines.

You might be wondering why the BHD Foundation are blogging about MPM. These studies caught our attention due to the mention of folliculin (FLCN). Mutations in FLCN cause Birt-Hogg-Dubé Syndrome (BHD).

The first paper studied the association of kidney cancer with MPM. They looked at the records of 8295 people with kidney cancer. 6 people had kidney cancer and MPM. 2 of these were found to have genetic mutations. One mutation was in a gene called BAP1. This has a known link to MPM. The other individual had a mutation in FLCN. One limitation of this study was that it was primarily designed to look for mutations in BAP1 and not FLCN. So it is possible that other individuals had mutations in FLCN but were not identified.

 The authors of the second paper performed genetic sequencing on 113 patients with MPM. Mutations in 9 different genes, including FLCN, were found. Many of these genes are involved in a pathway in our cells called the DNA damage response. The DNA damage response is one of the ways our cells can repair our DNA if it gets damaged. DNA can be damaged by external sources such as smoking, UV exposure and asbestos. When our DNA is damaged, there is an increased risk of cancer. If there is a mutation in one of these DNA damage repair genes, the pathway doesn’t work, and our DNA cannot be repaired. It has been shown previously that FLCN also plays a role in the DNA damage response.

Everyone has 2 copies of FLCN and only one of them needs to be mutated to have BHD. The authors also observed loss of heterozygosity for FLCN. This means that a mutation in the second copy of FLCN was also found. In BHD, mutation in the second copy of FLCN is thought to be required for the development of kidney cancer.

The authors also looked at asbestos exposure. Patients with MPM had been exposed to more asbestos throughout their life. A mutation in any one of the genes identified in this study was associated with MPM development and a lower exposure to asbestos. This highlights the important link between genetics and the environment in cancer.

Taken together, these studies have found 2 cases of individuals with BHD and MPM. Neither study reported the level of asbestos exposure in these individuals. Asbestos is likely still the primary driver of MPM and, to the best of our knowledge, these studies represent the only cases of BHD and MPM. This means that BHD is unlikely to increase the chance of developing MPM.

MPM is usually diagnosed at a later stage of the disease and as such  outcomes are poor. Increasing our knowledge of the risk factors of MPM can guide screening and diagnose MPM earlier. Understanding the genetic contribution to MPM can also help direct the treatment of the disease. Cancer treatment can vary depending on many factors including genetics. In the future, there may be drugs available that will be particularly effective in individuals with mutations in genes involved in the DNA damage response.

If you would like to know more about MPM please visit the Mesothelioma UK website.