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

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

Funding: iCARE Dust Diseases Care NSW (2020-2022)

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

Synopsis (scientific): To date, candidate and whole exome sequencing studies including that by The Cancer Genome Atlas (TCGA) Mesothelioma Working Group (Creaney and Robinson) have been performed on highly selected solid MM tumour samples from resections and have shown several genes are commonly affected, specifically the tumour suppressors CDKN2A, BAP1, and NF2. Results from our own independent whole genome sequencing study, which utilises tumour cells isolated from pleural effusions, confirms these key findings (NHMRC Project Grant #1089404). Both approaches focused on minimising the contribution of the non-tumour cellular milieu on the sequencing results. Surgical specimens with less than 60% tumour cells were specifically excluded from the TCGA study, 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 preliminary studies we have performed single cell sequencing on minimally manipulated MM patient 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 three genes which are commonly altered in MPM; BAP1, CDKN2A/p16 and NF2 will be studied. 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 MPM development is thought to be significant. This study aims to evaluate if clinical benefit can be achieved based on knowledge of these common MPM genetic alterations. Firstly, the diagnostic value of these new markers, compared to standard-of-care markers, will then be determined Correlation of tumour marker status with clinical data, specifically overall survival and treatment response will enable the prognostic and predictive significance of marker expression to be evaluated. In parallel, tumour cell growth and response to therapy will be evaluated using cell lines with different marker phenotypes. In light of recent interest in immunotherapy for MPM, the association of these genetic alterations on the immune-microenvironment will be examined.

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.