Biological and Biomedical Science
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Matthew Meyerson

Department of Pathology
Dana-Farber Cancer Institute
Department of Medical Oncology
Dana Building, Room 1540
44 Binney Street
Boston, MA 02115
Tel: (617) 632-4768
Fax: (617) 582-7880
Email: matthew_meyerson@dfci.harvard.edu
12 postdoctoral fellows, 2 graduate students

We strive to discover genomic events that cause human cancers and infectious causes for diseases of unknown origin.  We then seek to apply these discoveries to improving diagnosis and treatment for these diseases.  Our particular focus is lung cancer pathogenesis.

Somatic genetic alterations in cancer: We use genome-scale approaches to discover chromosomal alterations and cancer-causing mutations, working closely with colleagues at the Broad Institute. Our group is active in The Cancer Genome Atlas project to perform multi-modality analyses of human cancers.

Using single-nucleotide polymorphism (SNP) arrays, we have analyzed copy number alterations in over 2,500 human cancer samples, and have defined both lineage-specific and cancer-universal regions of amplification and deletion.  Among recent findings, we have identified the most common DNA amplification in lung adenocarcinoma as targeting NKX2-1, a lung lineage-determining transcription factor (Weir et al., 2007).

By cancer sequencing, we identified mutations in the epidermal growth factor receptor tyrosine kinase gene, EGFR, in lung adenocarcinomas  (Paez et al., 2004), and in glioblastomas (Lee et al., 2006).  More recently, we have identified activating mutations of FGFR2 in multiple cancers (Dutt et al., 2008).  We pioneered the use of single-template sequencing in cancer genome analysis (Thomas et al., 2006) and are applying these methods widely. 

Functional analysis of lung cancer genes:  We work to understand transformation by the major oncogenes that cause lung cancer, focusing on EGFR, KRAS, and NKX2-1, and to apply this understanding to lung cancer therapy.  For EGFR, we demonstrated that distinct mutations are differentially sensitive or resistant to distinct inhibitors (Greulich et al., 2005), establishing the concept of mutant-selective therapy.  We are now studying a large number of novel oncogenic mutants identified in a genome sequencing screen (Ding et al., submitted).

Tumor suppressor proteins and chromatin modification: We have shown that several endocrine tumor suppressor proteins, including menin, the protein product of the MEN1 (multiple endocrine neoplasia type 1) tumor suppressor gene, and parafibromin, product of the HRPT2 (hyperparathyroidism and jaw tumor syndrome 2) gene, are associated with histone methylases (Hughes et al., 2004; Rozenblatt-Rosen et al., 2005).  We are now working to apply the modulation of histone methylation activity to treatment of endocrine tumors and leukemias.

Discovery of pathogenic microbes: We developed a genomic approach to discover microbial sequences in cryptic infectious diseases, by sequencing nucleic acids from diseased tissues and removing sequences that match the human genome computationally, leaving microbial sequences (Weber et al., 2002).  We are applying these methods to cancers and to inflammatory and auto-immune diseases (see MacConaill & Meyerson, 2008).

 

References:

  • Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee A, Biondi CA, Kay GF, Hayward NK, Hess JL, Meyerson M. (2004). Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell 13: 587-597.
  • Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497-1500.
  • Thomas RK et al. (2006) Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing. Nat Med 12: 852-855.
  • Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, … , Gabriel SB, Gibbs RA, Varmus HE, Wilson RK, Lander ES, Meyerson M. (2007). Characterizing the cancer genome in lung adenocarcinoma.  Nature 45:893-898.