Biography
Dr. Daniel Haber was born in Paris, France in 1957. He came to the US in 1973 to attend college at Massachusetts Institute of Technology, where he received BS and MS degrees. He continued his studies at Stanford University under the Medical Scientist Training Program. He obtained his PhD in the laboratory of Dr. Robert Schimke in 1981, studying gene amplification as a mechanism of chemotherapeutic drug resistance, and received his MD in 1983. He subsequently completed a medical internship and residency at Massachusetts General Hospital, followed by a clinical fellowship in medical oncology at Dana Farber Cancer Institute (1986). Dr. Haber then pursued postdoctoral research training with Dr. David Housman at MIT, working on the characterization of the Wilms Tumor suppressor gene WT1. He was appointed Assistant Professor of Medicine at Harvard Medical School in 1991, and established his laboratory at the Massachusetts General Hospital Cancer Center to study the genetics of Wilms tumor and breast cancer. He was promoted to Associate Professor in 1996 and Professor in 2001. In addition, Dr. Haber serves as Associate Chief for Research in the Hematology Oncology Unit at MGH, as Chair of the Cancer Genetics Program for the Dana Farber-Harvard Comprehensive Cancer Center, and as Director of the MGH Center for Cancer Risk Analysis. He is on the Editorial Board of Cell and Cancer Cell, and serves as Genetics Editor for the New England Journal of Medicine. He has received numerous awards, including the McDonnell Cancer Scholar Award (1990), the American Association for Cancer Research and National Foundation for Cancer Research Professorship in Basic Cancer Research (2000), and a MERIT Award from the National Cancer Institute (2002). He was elected to the American Society for Clinical Investigation in 1995. He is the author of 122 publications dealing with various aspects of the genetics of pediatric kidney cancer and adult breast cancer. The Doris Duke Distinguished Clinical Scientist Award was awarded for his work on the characterization of CHK2, a cell cycle checkpoint kinase that is mutated in the germline of women with predisposition to breast cancer.
Abstract
CHK2: A Common Low Penetrance Familial Breast Cancer Gene
Germline mutations in BRCA1 account for ~50% of high risk familial breast cancer, while mutations in BRCA2 are responsible for ~25% of cases. These findings have provided important insight into the pathogenesis of breast cancer, and they have made it possible to offer genetic counseling to family members at risk, with consideration of preventive surgery, hormonal chemoprophylaxis, intensive screening regimens, and eventually the possibility of genotype-directed therapy. The etiology of familial breast cancer cases lacking mutations in the BRCA genes is uncertain, and the absence of clear genetic linkage to a third locus has led to the suggestion that these cases may result from a number of lower penetrance genes, which in aggregate, may contribute to both breast cancer kindreds, as well as individuals with less dramatic family histories. A major step in this direction has been the observation that 1% of the population carries a specific truncating mutation in CHK2 (1100delC), while this mutation is present in 5% of familial breast cancer cases (ie. a common low penetrant mutation). CHK2 encodes a kinase, which itself is activated by the DNA damage responsive kinase ATM, and which is capable of phosphorylating p53, CDC25 and BRCA1. As such, CHK2 is positioned at the intersection between DNA damage response sensors and the effectors of cellular checkpoints implicated in cell cycle arrest, apoptosis and DNA damage repair. Our laboratory was the first to identify mutations in CHK2, including 100delC which we discovered in a family with the multicancer phenotype Li-Fraumeni Syndrome, but which lacked the characteristic mutation in p53. CHK2 has now been shown to phosphorylate p53 at the critical 20Serine residue required for its activation following DNA damage. The recent discovery that the specific CHK2 mutation 1100delC is common in the population and confers a moderate risk for breast cancer has raised the possibility that additional mutations in this gene and in other related genes may play a significant role in human breast cancer. In this proposal, we propose 1. to undertake mutational analyses of CHK2 and related genes in familial breast cancer cases lacking mutations in BRCA genes; 2. to define the penetrance (ie. breast cancer risk) and clinical phenotype associated with these mutations; 3. to develop functional assays that allow interpretation of CHK2 missense mutations present in familial breast cancer cases; and 4. to use CHK2 as a model with which to explore how analysis of low penetrance mutations should be integrated into clinical practice. These questions will have significant impact, both in terms of high risk breast cancer care, as well as the more general integration of increasingly complex genetic information into the clinic.