Characterising and exploiting common genetic alterations in mesothelioma for improved patient outcomes

Creaney J, Waddell N, Louw A, Lee YCG, Robinson BWS.


Lay synopsis: Mesothelioma is a deadly asbestos-induced cancer. Currently diagnosis of mesothelioma is difficult, and there are limited treatment options. Through characterisation and understanding of the genetic alterations that are common in mesothelioma we may be able to improve patient outcomes.

Scientific synopsis: High throughput sequencing studies in mesothelioma have shown that this is a tumour-type of genetic loss with few mutations in drug-targetable genes. Indeed the genes most frequently altered are the tumour suppressors CDKN2A, BAP1 and NF2. To date, sequencing studies have been performed using samples rich in tumour cells. Indeed, for the recent international sequencing consortia efforts specimens with less than 60% tumour cell content were specifically excluded. Thus the majority of potentially informative samples with heavy infiltrates of lymphocytes, fibroblast and macrophages were not included.

Until now the impact and interactions between tumour and non-tumour cells have been little explored in mesothelioma . In preliminary studies we have performed single cell sequencing on both mesothelioma tumour and pleural effusion samples to characterise the entire cellular milieu. In this research project additional samples will be analysed using advanced single cell technologies to address two of the major issues that limit our ability to select truly personalised cancer therapies – tumour heterogeneity and the dynamic changes in this heterogeneity during therapy.

In complementary studies, we will explore the biological consequence of alterations in the three genes; BAP1, CDKN2A and NF2. How these alterations affect mesothelioma cell biology is not fully known. These genes play important roles in normal cells to stop tumour formation, their role in mesothelioma development is thought to be significant. This study aims to evaluate if clinical benefit can be achieved based on knowledge of these common mesothelioma genetic alterations.

We have extensive experience in international genome sequencing projects and our team includes international leaders in MM research with one of the world’s largest and best studied cohorts of the disease.

NCARD Research Team

Jenette Creaney, Bruce Robinson

Students: Alistair Nash