The largest genomic studies to date have demonstrated that mesothelioma is primarily defined by loss of function alterations in tumor suppressor genes.[1,2] Despite exposure to the carcinogen asbestos in most cases, mesothelioma has a lower tumor mutation burden than what has been reported for most solid tumors. Rather than single-nucleotide mutations, copy-number alterations seem to dominate the genomic landscape in this malignancy. The genes most commonly affected by mutations or copy-number alterations include NF2, BAP1, CDKN2A, and others (Figure 1A). Although these tumor suppressor genes are most frequently altered in mesothelioma, there are reports of possibly oncogenic EWSR1 fusions[5,6] and ALK fusions[7,8] in peritoneal mesothelioma. These fusions seem to affect younger patients without known asbestos exposure and arise independent of the more common mesothelioma alterations. A small number of clinical trials are underway with novel targeted therapies for NF2- and BAP1-altered mesothelioma patients.[9,10]
Chromothripsis and common alterations in mesothelioma. (A) When both copy-number alterations and mutations are considered, NF2, BAP1, and CDKN2A are the most frequently altered genes according to The Cancer Genome Atlas analysis (TCGA).2 Copy-number losses or deletions are more common than single-nucleotide mutations for most of these genes, likely because of underlying structural variants. This circular barplot was created with the R package circlize.3 The percentages of alterations are slightly higher than summarized in the TCGA report since we included both copy-number alterations and mutations regardless of whether the genes were fully inactivated. (B) Sometimes these structural variants are consistent with a pattern of chromothripsis, which likely results from the disordered reassembly of a shattered chromosome. This circos plot represents a pleural mesothelioma specimen from a prior publication.4 Copy number is presented as a normalized read depth (NRD) calculated in reference to the diploid level (yellow line, NRD = 2). Regions of the genome calculated to be within the normal diploid level are colored gray, regions of gain are colored blue, and regions of loss are colored red. Dashed lines are provided at increments of NRD = 1 with an upper boundary of NRD = 6. Breakpoint junctions are presented as magenta lines connecting two breakpoints. This circos diagram was made by James Smadbeck, PhD, at Mayo Clinic with a custom R package.
BAP1 is the most frequently mutated gene in mesothelioma and is also affected by copy-number alterations.[11,12]BAP1 alterations can be somatic or germline, and the BAP1 hereditary cancer syndrome predisposes patients to mesothelioma, uveal melanoma, and other malignancies. Because of discrepancies in the rates of detection of BAP1 alterations, high-density array CGH was used to identify alternating copy-number changes at chromosome 3p21 where BAP1 is located, suggesting that BAP1 is commonly affected by a process known as chromothripsis. Chromothripsis results from numerous double-strand breaks of a large segment of a chromosome or a whole chromosome that has been likened to the shattering of a chromosome (example in Figure 1B). The subsequent repair of these chromosomal breaks results in multiple novel rearrangements that are out of sequence from normal, and oscillating copy-number changes. It appears that the micronuclei that form around lagging chromosomes during cell division are not able to incorporate nuclear pore complexes and other noncore nuclear envelope proteins that protect chromosomes from fragmentation, and the loss of nuclear envelope integrity fosters chromosome fragmentation.
More direct evidence for chromothripsis in mesothelioma came from a study that used a form of sequencing that tiles larger fragments of the genome than standard approaches, and is optimized for the detection of structural variants. Among the 22 specimens that were profiled, 1,535 chromosomal rearrangements were detected and many of these rearrangements were in a pattern of chromothripsis that involved arms of chromosomes or full chromosomes. This analysis further suggested that these rearrangements have neoantigenic potential. In short, the genomic landscape of mesothelioma primarily involves tumor suppressor genes that are inactivated through structural variants, mutations, or both.
J Clin Oncol. 2022;40(6):681-692. © 2022 American Society of Clinical Oncology