Genomic and functional studies of lung and other cancers
Somatic genetic alterations in cancer: We use genome-scale approaches to discover chromosomal alterations and cancer-causing mutations. I am a principal investigator for NCI’s “The Cancer Genome Atlas” project for comprehensive cancer genome characterization; this work is based at the Broad Institute. This year, we are publishing numerous manuscripts from TCGA studies; I am co-chair of the lung cancer disease working group for TCGA and corresponding author of the submitted manuscript on squamous cell lung carcinoma, in which we identified loss-of-function HLA-A mutations.
We developed the use of single-nucleotide polymorphism (SNP) arrays for human cancer genome analysis (Lindblad-Toh et al., 2000). We have now defined both lineage-specific and cancer-universal regions of amplification and deletion by SNP array analysis of over 2,500 cancer DNAs. Using SNP arrays, we identified the most common DNA amplification in lung adenocarcinoma, which targets the NKX2-1 pneumocyte-specifying transcription factor (Weir et al., 2007), common amplification of the SOX2 transcription factor in squamous cell carcinomas (Bass et al., 2009), and amplification of anti-apoptotic genes including MCL1,across multiple human cancers (Beroukhim et al., 2010).
Our cancer sequencing projects identified mutations in the epidermal growth factor receptor tyrosine kinase gene, EGFR, in lung adenocarcinomas, associated with clinical response to gefitinib and erlotinib (Paez et al., 2004), and in glioblastoma (Lee et al., 2006). We also identified activating mutations of FGFR2 in multiple cancers (Dutt et al., 2008) and of ALK in glioblastoma (George et al., 2008). With our colleagues, we recently reported statistically significant mutation of 26 genes in lung adenocarcinoma (Ding et al., 2008). In addition, we pioneered the use of single-template sequencing in cancer genome analysis (Thomas et al., 2006), which we are now applying widely. Ongoing projects have identified mutation of MAP3K1 and CBFB and translocation of AKT3 in breast carcinoma (Banerji et al., 2012), translocations of the TCF7L2 gene in colon carcinoma (Bass et al., 2011), and mutations of multiple genes including U2AF1 and RBM10 in lung adenocarcinoma (Imielinski et al., 2012).
Functional analysis of lung cancer genes: We study oncogenic transformation by the major oncogenes that cause lung cancer, including EGFR and NKX2-1. For EGFR, we demonstrated the concept of mutation-selective therapy: distinct mutations are differentially sensitive or resistant to inhibitors (Greulich et al., 2005) and transformed cells bearing distinct mutations can most effectively be killed by different small molecule inhibitors (Yuza et al., 2007). For NKX2-1, we have now identified LMO3 as a downstream target (Watanabe et al., 2013). We have also recently identified multiple drug-sensitive alterations in the squamous cell lung cancer genome: mutations of DDR2 (Hammerman et al., 2011), FGFR2 and FGFR3 (Liao et al., 2013) and amplifications of FGFR1 (Dutt et al., 2011).
Tumor suppressor proteins and chromatin modification: We showed that several endocrine tumor suppressor proteins, including menin and parafibromin, are associated with histone methyltransferases (Hughes et al., 2004; Rozenblatt-Rosen et al., 2005). We are now working to modulate histone methylation activity for treating endocrine tumors and leukemias, and have showed that deletion of the Rbp2 histone demethylase can reverse tumorigenesis by loss of the menin tumor suppressor (Lin et al., 2011).
Discovery of pathogenic microbes: We developed a genomic approach to discover microbial sequences in human disease, by sequencing nucleic acids from diseased tissues followed by computational subtraction of human sequences (Weber et al., 2002). We and others have applied our approach to cancers, inflammatory and auto-immune diseases. Recently, we have completed a new software approach for identifying pathogens using next-generation sequencing data (Kostic et al., 2011), have identified an association of Fusobacterium species with colorectal carcinoma (Kostic et al., 2012) and have demonstrated that Fusobacterium infection potentiates lung cancer in mouse models (Kostic et al., 2013). Finally, we have recently identified infection with Bradyrhizobium enterica in transplant-associated cord colitis syndrome (Bhatt et al., 2013).