Department of PathologyDana Farber Cancer Institute
Dana Bldg., Rm. 1540
450 Brookline Ave.
Boston, MA 02215
Assistant: Julie Hammond-Coiro
Lab Members: 15 postdoctoral fellows, 3 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. One particular focus is lung cancer pathogenesis and targeted therapy.
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 (TCGA) project to perform multi-modality analyses of human cancers.
Using single-nucleotide polymorphism (SNP) arrays, we have defined both lineage-specific and cancer-universal regions of amplification and deletion (Beroukhim et al., 2010). We identified the most common DNA amplification in lung adenocarcinoma as targeting NKX2-1, a lung lineage-determining transcription factor (Weir et al., 2007) and in squamous cell lung carcinoma as targeting SOX2, also a lineage-specific transcription factor (Bass et al., 2009).
By cancer sequencing, we identified activating 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), of FGFR2 in multiple cancers (Dutt et al., 2008), and of DDR2 in squamous cell lung carcinoma (Hammerman et al., 2011).
We pioneered the use of single-template sequencing in cancer genome analysis (Thomas et al., 2006) and are applying these methods widely. Through studies of the whole genome sequences of a variety of human cancer types we have identified recurrent translocations of TCF7L2 in colon cancer (Bass et al., 2011) and of AKT3 in breast cancer (Banerji et al., 2012) among other findings. As part of TCGA, we have identified loss-of-function mutations in the HLA-A gene in squamous cell lung cancers suggesting a role for immune evasion in this and other cancers.
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 genome sequencing screens (Ding et al., 2008 and Imielinski et al., submitted) and are continuing to pursue targeted therapies in the EGFR and FGFR pathways.
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 using next-generation sequencing. Recently, we identified an enrichment of Fusobacterium nucleatum in colorectal carcinoma (Kostic et al., 2011) and are studying the role of Fusobacterium in cancer pathogenesis.
Last Update: 1/13/2014