Researchers examined the relationship between genomic complexity in multiple myeloma (MM) and its impacts on the transcriptome, in a new study reported in the journal Clinical Cancer Research. Copy-number alterations and chromosomal rearrangements were found to drive most effects on gene expression, while mutations were influential in the inactivation of tumor suppressor genes.
This study included data for 514 participants from the IA12 release of the prospective, observational CoMMpass trial (ClinicalTrials.gov Identifier: NCT01454297). In this study, the genomes and transcriptomes of newly diagnosed patients with MM were analyzed for relationships between genomic complexity or mutations and expression at the transcriptome level.
For analyses involving copy-number alterations, a gain was defined as having 3 copies of the chromosomal region of interest, and an amplification was defined as having 4 or more copies. In silico drug sensitivity screening was also performed on primary tumor samples and validated using the Cancer Dependency Map with the Celligner algorithm used to find cell lines appropriate for analysis in this study.
Gene mutations were less influential on transcriptomic variation than copy-number alterations were. Deregulated genes were most often associated with immunoglobulin translocations, hyperdiploidy, and gain chromosome 1q gain or amplification. Particular pathways demonstrated some impacts by other copy number alterations and gene mutations. Biallelic events carried the greatest effects on tumor suppressor genes. Certain hotspot mutations, such as in NRAS and KRAS genes, showed associations with differential gene expression across the transcriptome, particularly in the case of NRAS hotspot mutations.
Gain, and particularly amplification, of chromosome 1q21 was a predictor of PD-L1 downregulation, in addition to being a predictor of SLAMF7, GPRC5D, and MCL1 upregulation. Gain or amplification of chromosome 1q21 was also associated with transcriptional effects across the genome and upregulation of oncogene-driven proliferative pathways.
Analyses of BCL2 family gene expression showed significant positive relationships between BCL2 expression and CYLD gene deletion or translocation t(11;14), particularly when this translocation occurred with CYLD deletion. Expression of BCL2L1 appeared downregulated with translocation t(11;14) and upregulated with CYLD deletion. MCL1 expression was significantly associated with chromosome 1q gain/amplification. No significant relationships were seen between MCL1 expression and either translocation t(11;14) or CYLD deletion, or between chromosome 1q gain/amplification and either BCL2 or BCL21 expression.
Drug sensitivity screening suggested that refractoriness to BCL2 inhibition was linked to chromosome 1q gain or amplification. CYLD gene deletion and translocation t(11;14) were linked to a response to BCL2 inhibition. The researchers suggested the CYLD gene could potentially serve as a biomarker for sensitivity to BCL2 inhibition, however, they noted that this would require further study.
“Altogether, our study highlights the impact of detailed molecular profiling partnered with clinical annotations and how, when combined with large datasets of patients, this can be leveraged to study outcomes of targeted drugs in well-defined biological subgroups of MM patients,” the researchers concluded in their report.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Ziccheddu B, Da Vià MC, Lionetti M, et al. Functional impact of genomic complexity on the transcriptome of multiple myeloma. Clin Cancer Res. Published online September 15, 2021. doi:10.1158/1078-0432.CCR-20-4366