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Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis
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Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy

Jens G Lohr1, Petar Stojanov1, Scott L Carter2

  • 1Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

Cancer Cell
|January 18, 2014
PubMed

Insights

Genomic sequencing of multiple myeloma (MM) revealed frequent mutations in key genes like KRAS and TP53, often within subclonal populations. Understanding this tumor heterogeneity is crucial for effective treatment strategies.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Multiple myeloma (MM) is a hematologic malignancy characterized by significant genetic heterogeneity.
  • Understanding the genomic landscape of MM is essential for developing targeted therapies and improving patient outcomes.

Purpose of the Study:

  • To identify significantly mutated genes and copy number alterations in multiple myeloma.
  • To discover putative tumor suppressor genes through homozygous deletions and loss of heterozygosity analysis.
  • To investigate the impact of genetic heterogeneity on treatment efficacy.

Main Methods:

  • Massively parallel sequencing of paired tumor/normal samples from 203 MM patients.
  • Analysis of gene mutations, copy number alterations, homozygous deletions, and loss of heterozygosity.
  • In vitro modeling to assess the efficacy of targeting subclonal mutations.

Main Results:

  • Frequent mutations were observed in KRAS, NRAS, BRAF, FAM46C, TP53, and DIS3, with specific patterns in previously treated or nonhyperdiploid MM.
  • Mutations were often present in subclonal populations, and concurrent mutations within the same pathway were common.
  • In vitro models indicated limited efficacy for targeting subclonal mutations and potential growth promotion of nonmutated subclones.

Conclusions:

  • Genomic heterogeneity, including subclonal mutations, is a significant feature of multiple myeloma.
  • Targeting subclonal mutations may have limited therapeutic benefit and could potentially promote the growth of resistant subclones.
  • Comprehensive analysis of tumor heterogeneity is critical for informing treatment decisions in MM.

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