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Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic
Eileen M Boyle1, Patrick Blaney1,2, James H Stoeckle1
1Myeloma Research Program, Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
Purpose:
Chromosome 1 (chr1) copy-number abnormalities (CNA) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and are associated with a heterogeneous impact on outcomes, the drivers of which are largely unknown.
Experimental Design:
A multiomic approach comprising CRISPR, gene mapping of CNAs and SVs, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilization.
Results:
We identified two distinct groups of gain(1q): focal gains associated with limited gene-expression changes and a neutral prognosis, and whole-arm gains, which are associated with substantial gene-expression changes, complex genetics, and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT), and two of templated insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants.
Conclusions:
Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.
Insights
Chromosome 1 copy-number abnormalities (CNAs) in multiple myeloma have distinct impacts. Whole-arm 1q gains drive adverse outcomes by altering gene expression and pathways, offering potential therapeutic targets.
Area of Science:
- Genomics
- Cancer Biology
- Myeloma Research
Background:
- Chromosome 1 (chr1) copy-number abnormalities (CNAs) and structural variants (SVs) are common in newly diagnosed multiple myeloma (NDMM).
- These chr1 alterations have a varied impact on patient outcomes, but the underlying drivers are not well understood.
Purpose of the Study:
- To comprehensively analyze chr1 molecular variants in NDMM.
- To investigate the impact of these variants on gene expression and cellular pathways.
- To identify genetic drivers and prognostic markers associated with chr1 alterations.
Main Methods:
- A multiomic approach was employed, including CRISPR screening, gene mapping of CNAs and SVs, methylation analysis, gene expression profiling, and mutational analysis.
- CRISPR was used to identify functional dependencies on chr1.
- Gene set enrichment analysis was performed to understand pathway alterations.
Main Results:
- Two distinct groups of gain(1q) were identified: focal gains with limited gene expression changes and neutral prognosis, and whole-arm gains with significant gene expression changes, complex genetics, and adverse prognosis.
- Seven deletion regions, nine gain regions, three chromothripsis (CT) events, and two templated insertion (TI) events were identified on chr1.
- Hypomethylation of 1q genes and significant expression changes, including metabolic processes, apoptotic resistance, MAPK signaling, and transcription factor upregulation, were associated with whole-arm gains and adverse prognosis.
Conclusions:
- Genetic complexity on chr1 significantly influences the clinical phenotype of multiple myeloma.
- Whole-arm gains of 1q represent a critical prognostic group that deregulates multiple pathways.
- These deregulated pathways associated with whole-arm 1q gains may present therapeutic vulnerabilities for multiple myeloma patients.
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