Detecting Clonal Structural Alterations from Multi-regional Profiling of Malignant Pleural Mesotheliomas
Malignant Pleural Mesothelioma (MPM) is a pleural tumour associated with asbestos exposure. There is a long latency period of 30-40 years between asbestos exposure and disease presentation, highlighting an unknown evolutionary trajectory. Throughout the latent years, different somatic genomic lesions are acquired by the growing tumour. In contrast to other malignancies, MPMs display modest single nucleotide mutational burden but a high frequency of structural alterations, in particular large-scale chromosomal losses.
In this thesis, I explore how multiregional sequencing data can shed light into inter- and intra-tumour heterogeneity of MPM, as well as the various cellular processes shaping the tumour evolution. I investigated the mutational diversity between different resected sites within individual tumours, as well as between MPMs in order to infer genomic alterations that occurred during early tumour evolution and potential clonal drivers of tumour development.
The existence of branched tumour evolution and widespread heterogeneity in MPMs was demonstrated: Copy number analysis revealed recurring truncal large-scale (aneuploidy level) and the focal losses of the tumour suppressor genes BAP1, PTPN13, FBXW7, CTCLT1, NF2, MYH9, EP300 and oncogenes NSD2, TEC and MTOR. Targeted sequencing of the recurring truncal losses of 1p36, 3p21 and 9p21 was used to attempt to identify deletion breakpoints. Gene fusion analysis revealed the extent of chromosomal rearrangements in MPM tumours, as well as the formation of potentially important fusions such as the potentially oncogenic CACNA1D-ERC2 fusion, in-frame PARD3BSTAB1 fusion, and intergenic fusions resulting in BAP1 and MTAP truncation. Finally, by analysis of gene fusion breakpoints, non-homologous end joining and alternative endjoining were revealed to be the likely structural mechanisms generating early extensive chromosomal rearrangements, in conjunction with truncal losses in homologous recombination and Hippo pathway genes.
These truncal genomic alterations are likely to exist throughout the tumour, and potentially drive cancer progression, as they include mesothelioma associated genes, oncogenes, and tumour suppressor genes. Thus, identifying them highlights potential Achilles’ heels for drug targeting and treatment.
Supervisor(s)Ed Hollox; Dean Fennell
Date of award2023-02-07
Author affiliationDepartment of Genetics and Genome Biology
Awarding institutionUniversity of Leicester