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Search for rare protein altering variants influencing susceptibility to multiple myeloma
Matthew Scales1,2, Daniel Chubb1, Sara E Dobbins1
1Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.
Abstract:
The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1-5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6x10-6). Further analysis showed KIF18A displays a distinct pattern of expression across molecular subgroups of MM as well as being associated with patient survival. Our results inform future study design and provide a resource for contextualizing the impact of candidate MM susceptibility genes.
Insights
Researchers investigated rare genetic variants and multiple myeloma (MM) risk. While no common variants were found, a gene called KIF18A showed a significant association with MM development and patient survival.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The genetic factors contributing to inherited multiple myeloma (MM) risk are not well understood.
- Identifying genetic variants associated with MM is crucial for understanding disease etiology and developing targeted therapies.
Purpose of the Study:
- To investigate the association between rare, protein-altering genetic variants and the risk of developing multiple myeloma (MM).
- To identify specific genes that may confer susceptibility to MM through rare variant analysis.
Main Methods:
- Exome sequencing data from 513 MM cases and 1,569 healthy controls were analyzed.
- Single variant and gene burden tests were performed to identify statistically significant associations.
- KIF18A gene expression patterns and its association with patient survival were further investigated.
Main Results:
- No recurrent low-frequency coding alleles (1-5%) were found to be statistically associated with MM risk.
- A significant association was identified between variation in the KIF18A gene and MM risk (P = 3.6x10^-6).
- KIF18A exhibited differential expression across MM molecular subgroups and was linked to patient survival outcomes.
Conclusions:
- Rare coding variants with moderate effects do not appear to be a major driver of inherited MM risk.
- The KIF18A gene is a promising candidate for further investigation in multiple myeloma pathogenesis.
- Findings provide a foundation for future genetic studies and the interpretation of candidate MM susceptibility genes.