Whole-genome sequencing of human malignant mesothelioma tumours and cell lines

Abstract

Pleural mesothelioma is a cancer of serosal surfaces caused by environmental exposure to asbestos. Clinical outcome remains poor and while trials of new treatments are ongoing it remains an understudied cancer. Mesothelioma cell lines can readily be grown from primary tumour and from tumour cells shed into pleural effusion with the latter representing a particularly valuable source of DNA in clinical settings, procurable without the need for additional invasive procedures. However, it is not well understood how accurately patient-derived cultured tumour cells represent the molecular characteristics of their primary tumour. We used whole-genome sequencing of primary tumour and matched cultured cells to comprehensively characterize mutations and structural alterations. Most cases had complex rearranged genomes with evidence of chromoanagenesis and rearrangements reminiscent of chromoplexy. Many of the identified driver mutations were structural, indicating that mesothelioma is often caused by structural alterations and catastrophic genomic events, rather than point mutations. Because the majority of genomic changes detected in tumours were also displayed by the genomes of cultured tumour cells, we conclude that low-passage cultured tumour cells are generally suitable for molecular characterization of mesothelioma and may be particularly useful where tissue samples with high tumour cell content are not available. However, the subclonal compositions of the cell lines did not fully recapitulate the subclonal diversity of the primary tumours. Furthermore, longitudinal acquisition of major alterations in subclonal cell populations was observed after long-term passaging. These two factors define limitations of tumour-derived cell lines as genomic substrate for clinical purposes.

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

“…Yoshikawa et al discovered that chromothripsis (ie, chromosome shattering followed by random chromosomal rearrangement) (Fig. A) causes some of the genetic alterations in mesothelioma, a finding independently confirmed by Mansfield et al and most recently by Oey et al Moreover, Mansfield et al predicted that the vast array of genetic alterations in mesothelioma may lead to the production of neoantigens, which correlated with the clonal expansion of tumor‐infiltrating T lymphocytes (Fig. B and 5C) .…”

“…Because of the carcinogenic “field effect” caused by asbestos, mesotheliomas are often polyclonal . Recently, The Cancer Genome Atlas program published a study of 74 mesotheliomas that were investigated for genetic alterations using next‐generation sequencing (NGS), including whole‐exome sequencing (WES), messenger RNA expression, methylation analysis, microRNA expression, exomes, reverse‐phase protein array, and transcription factor analyses .…”

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

“…Recent studies have addressed this topic in malignant mesothelioma. With the intent to provide reliable cell line models of mesothelioma, Oey et al have characterized the genome of tumors and tumor-derived cell lines through whole genome sequencing (151). Here, the authors have identified recurrent events of high chromosomal instability like chromoanagenesis and chromotripsis.…”

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

“…Intra-tumor heterogeneity is still partially described in MPM, in part due to the use of omics approaches only in bulk tumor samples. MPM is likely a polyclonal tumor that comprises multiple subclones with variable cellular prevalence (41,42). To better define the polyclonal tumor origin and understand the tumor evolution of mesothelioma, further studies are required in a larger number of tumor samples.…”

“…These models remain interesting for screening and preliminary investigations. Primary tumor cells represent an intriguing alternative because they share similar molecular characteristic with the primary tumor, even though they show a reduction of subclonal diversity (15,42,67). However, the necessity to perform studies before 6-10 passages limits the number of experiments.…”