Dana-Farber Cancer Institute

Research

Our laboratory focuses on identifying and understanding the genomic alterations that cause human cancers, with a particular focus on lung cancer.

Somatic gene alterations that cause cancer
We are applying genome-scale approaches to discover chromosomal alterations and cancer-causing mutations. We developed the use of single-nucleotide polymorphism (SNP) arrays to analyze loss of heterozygosity (LOH) and copy number alterations in human cancer samples, and have since discovered multiple regions of LOH and copy number change in human lung carcinomas.

Together with the Sellers laboratory and the Broad Institute, we are resequencing the human genome to identify oncogenic mutations in cancer, with an initial focus on protein kinase genes. In 2002, we identified oncogenic mutations in the BRAF serine-threonine kinase gene in human lung adenocarcinoma. More recently, working with the Sellers, Johnson, and Janne groups, we identified frequent mutations in the EGFR tyrosine kinase gene in lung adenocarcinomas. Mutations in the epidermal growth factor receptor are tightly associated with clinical response to the EGFR kinase inhibitors gefitinib and erlotinib. We are continuing functional and genomic experiments on EGFR. We have demonstrated that lung cancer-derived EGFR mutations are able to transform mammalian cells and are differentially sensitive to erlotinib and gefitinib. Through our kinase sequencing efforts, we have also assisted in additional cancer genome discoveries, most notably the identification of JAK2 mutations that cause polycythemia vera and other hemoproliferative disorders.

Tumor suppressor proteins and chromatin modification
Using a biochemical approach, we have identified the cellular function for menin, the protein product of the MEN1 (multiple endocrine neoplasia type 1) tumor suppressor gene. Menin is associated with a trithorax family complex that methylates histone H3 on lysine 4. Menin appears to promote the activity of target genes, including homeobox genes, and is physically associated with target gene loci. We have also found that a second tumor suppressor protein, parafibromin, is similarly associated with a chromatin-modifying activity, suggesting a broad role for histone modification in the development of cancer.

Discovery of pathogenic microbes
In other research, we have developed a genomic approach to discover microbial sequences in cryptic infectious diseases. In sequence-based computational subtraction, we generate and sequence libraries from diseased tissues. Sequences that match the human genome are removed computationally, leaving microbial sequences. We are applying these methods to a variety of human cancers, including lung cancers of nonsmokers.