New Study Sheds Light on Genetic Origins of Malignant Mesothelioma

Scientists in Australia have made a big step forward in understanding how a genetic mutation appears to drive the development of cancers such as malignant mesothelioma.

The gene in question is called p53. Also known as the “guardian of the genome” for its tumor-suppressing action, p53 has been found to be mutated in about half of all human cancers, including many cases of mesothelioma.

Although the primary external cause of mesothelioma is exposure to asbestos, the mutated p53 gene helps explain why some asbestos-exposed cells suddenly become cancerous and are able to grow and spread, unchecked.

It may also help scientists develop new, more effective mesothelioma treatments. Right now, the prognosis for mesothelioma is often very poor.

The p53 Gene and Mesothelioma Development

A mutation of the p53 gene, two copies of which are found in each cell, is common in many kinds of human cancer but, until now, scientists did not fully understand how these genetic changes impacted the function of the p53 protein.

In an article published by the Walter & Eliza Hall Institute of Medical Research, where the study was conducted, investigator Dr. Gemma Kelly explained the team’s discovery this way:

“Early during cancer development, one copy of the gene may undergo a sudden and permanent change through mutation, while the other copy of the gene remains normal. We found that the mutant p53 protein can bind to and ‘tackle’ the normal p53 protein, blocking it from performing protective roles such as DNA repair.”

Kelly says the change may make the cell more susceptible to further genetic changes that accelerate the development of tumors such as pleural mesothelioma.

While the mutant protein appears to stop normal p53 from performing it’s tumor protecting duties, it simultaneously allows p53 to perform other functions which actually promote tumor development.

“p53’s role in cancer is clearly more complicated than we had expected,” Dr Kelly says.

Implications for Mesothelioma Treatment

The new p53 research could have some important implications for people fighting malignant mesothelioma.

Gene therapy is one avenue that mesothelioma experts are investigating as a way to stop the spread of these aggressive tumors by targeting the mutated genes themselves.

But Dr. Kelly says gene therapy targeting mutated p53 may turn out to be ineffective if the mutation’s primary role is to direct the normal p53. That is because many established tumors have no normal p53 left.

Research conducted earlier this year in France confirmed the importance of p53’s role in the development of mesothelioma tumors, along with another gene called Cdkn2a.

For reasons that are still not understood, p53 mutations have been found to be more common in women mesothelioma patients than in men.

Sources:

“Mutant protein tackles DNA guardian to promote cancer development”, November 7, 2018, Walter & Eliza Hall Institute for Medical Research website, https://www.wehi.edu.au/news/mutant-protein-tackles-dna-guardian-promote-cancer-development

Aubrey, B, et al, “Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development”, October 26, 2018, Gene & Development, http://genesdev.cshlp.org/content/32/21-22/1420

Jean, D and Jaurand, MC, “Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis”, July 27, 2018, Internal Journal of Molecular Sciences