It is well established that cancer is a genetic disease and the types of genetic changes that are present in a tumor provide an evolutionary history of that particular tumor. Knowledge about the cancer genome would help us understand the natural history of cancer and also provides valuable information about the prognosis for the patient with that tumor and in some instances the response profile of the tumor to different therapeutic interventions.
To generate a comprehensive understanding of human tumor genomes the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) have initiated the cancer genome atlas (TCGA) project and we are a part of this project. Together with colleagues at Harvard and other institutions around the country we are helping decipher the genomic architecture of several human solid tumors. We use whole genome sequencing to understand the copy number changes as well as structural aberrations in cancers.
We have a longstanding program to understand the role of genes involved in several human cancers with a focus on colorectal cancer. Towards this goal we have developed a large number of genetically engineered mouse strains each carrying a different genetic lesion that is known to be or suspected to be involved in the initiation or progression of cancer. Among the genes that we have studied are Adenomatous polyposis coli (APC) and two DNA mismatch repair genes Mut L homolog 1 (MLH1) and Mut S homolog 2 (MSH2). Mutations in the APC gene are known to be involved in the human cancer predisposition syndrome, familial adenomatous polyposis (FAP) and mutations in the two DNA mismatch repair genes are involved in another cancer predisposition syndrome hereditary non-polyposis colorectal cancer (HNPCC).
We have also developed conditional knock-out alleles of these genes and mice carrying these alleles are being used to model many different cancers including sporadic colorectal cancer, breast cancer and skin cancer. We are also using these mice to develop novel therapeutic approaches.
It is well known that activation mutations in one of the RAS family of oncogenes and other members in the RAS-Map Kinase pathway are involved in a large proportion of cancers of many tissue origins. Interestingly, germline mutations of several genes in this pathway also cause a number of human disorders including Noonan syndrome (NS). NS has many phenotypes and we have a program to gain a comprehensive understanding of the genetic basis of this disorder and in developing novel therapeutic approaches for this and related disorders.