Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy
Open accessAbstract
We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions.
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Limiting the analysis to genes known to be recurrently mutated in MM reduced the chance of highlighting a false positive.
“limiting the analysis to genes known to be recurrently mutated in MM reduced the chance of highlighting a false positive55”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [55]
Multiple myeloma is frequently multiclonal.
“this cancer is known to be frequently multiclonal55,56”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [55]
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- Authors
- Lohr, J. G., Stojanov, P., Carter, S. L., Cruz-Gordillo, P., Lawrence, M. S., Auclair, D., Sougnez, C., Knoechel, B., Gould, J., Saksena, G., Cibulskis, K., McKenna, A., Chapman, M. A., Straussman, R., Levy, J., Perkins, L. M., Keats, J. J., Schumacher, S. E., Rosenberg, M., Getz, G., Golub, T. R., Anderson, K. C., Richardson, P., Krishnan, A., Lonial, S., Kaufman, J., Siegel, D. S., Vesole, D. H., Roy, V., Rivera, C. E., Rajkumar, S. V., Kumar, S., Fonseca, R., Ahmann, G. J., Bergsagel, P. L., Stewart, A. K., Hofmeister, C. C., Efebera, Y. A., Jagannath, S., Chari, A., Trudel, S., Reece, D., Wolf, J., Martin, T., Zimmerman, T., Rosenbaum, C., Jakubowiak, A. J., Lebovic, D., Vij, R., & Stockerl-Goldstein, K.
- Affiliations
- Broad Institute (US)
- Addenbrooke's Hospital (GB)
- Multiple Myeloma Research Foundation (US)
- Translational Genomics Research Institute (US)
- Corresponding author
- Golub, Todd R.
- ORCID
- Lohr, Jens G.
- Carter, Scott L.
- Lawrence, Michael S.
- Auclair, Daniel
- Knoechel, Birgit
- Gould, Joshua
- Saksena, Gordon
- Cibulskis, Kristian
- McKenna, Aaron
- Straussman, Ravid
- Perkins, Louise M.
- Keats, Jonathan J.
- Schumacher, Steven E.
- Rosenberg, Mara
- Getz, Gad
- Golub, Todd R.
- Anderson, Kenneth C.
- Richardson, Paul
- Krishnan, Amrita
- Lonial, Sagar
- Kaufman, Jonathan
- Siegel, David S.
- Roy, Vivek
- Rajkumar, S. Vincent
- Kumar, Shaji
- Bergsagel, P. Leif
- Hofmeister, Craig C.
- Efebera, Yvonne A.
- Jagannath, Sundar
- Trudel, Suzanne
- Reece, Donna
- Wolf, Jeffrey
- Martin, Thomas
- Rosenbaum, Cara
- Jakubowiak, Andrzej J.
- Vij, Ravi
- Stockerl-Goldstein, Keith
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 25
- Issue
- 1
- Pages
- 91-101
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4241387
- OpenAlex
- W2059581635
- Cited by
- 988
- References
- 54
- Citations by year
- 2026: 28 · 2025: 36 · 2024: 55 · 2023: 56 · 2022: 98 · 2021: 97 · 2020: 107 · 2019: 91 · 2018: 101 · 2017: 92 · 2016: 92 · 2015: 81 · 2014: 52
- FWCI
- 74.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Conquer Cancer Foundation
- Multiple Myeloma Research Foundation
- World Health Organization
- Dana-Farber/Harvard Cancer Center
- Broad Institute
- National Institutes of Health
- National Cancer Institute (U54CA112962, P50CA100707, T32CA009172)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- multiple myeloma, tumor genetic heterogeneity, subclonal mutations, copy number alterations, homozygous deletion, loss of heterozygosity, KRAS mutation, NRAS mutation, BRAF mutation, TP53 mutation, FAM46C, DIS3, targeted therapy, in vitro tumor model, tumor suppressor
- MeSH terms
- Humans, Multiple Myeloma, Mutation, Blotting, Western, Sequence Analysis, DNA, Gene Dosage, Genetic Heterogeneity
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