Professor of Genetics; Director, DNA Diagnostic Laboratory; Director, Cancer Genetics Program:

* B.S. Massachusetts Institute of Technology, 1975
* M.D. University of Massachusetts, 1979

Research Interests:

* Molecular Mechanisms of Cancer Predisposition and Developmental Defects
* DNA Diagnostics

My laboratory focuses on the relationship between neoplasia and development. We are interested in the molecular basis for hereditary syndromes that involve both cancer predisposition and birth defects. As the director of the DNA diagnostics laboratory, I am also involved in developing new techniques for the diagnosis of human genetic disorders.

Current Research

Genes involved in carcinogenesis often play a critical role in embryonic development and cellular differentiation. My laboratory focuses on analyzing the normal function of these genes and the mechanisms by which mutations lead to cancer. One emphasis of the laboratory is the gene underlying the nevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant disorder characterized by skin cancer, ovarian tumors, and brain tumors as well as developmental defects of the brain, bones, and teeth. We isolated the NBCCS gene by positional cloning and showed that it is homologous to Drosophila "patched". The Drosophila version of this gene encodes a cell surface protein that plays a role in segment polarity; i.e., distinguishing anterior from posterior in the developing fly. My laboratory is exploiting Drosophila and mouse models to develop new therapeutics to treat the cancers associated with patched mutations. Other disease genes under study in human and in Drosophila models include MEN1 (multiple endocrine neoplasia type 1) and BRCA1 (the main gene responsible for hereditary breast cancer).

A second area of interest is the application of new molecular techniques to clinical diagnosis of cancer predispostion syndromes, inborn errors of metabolism, muscular dystrophy, and fragile X-related mental retardation. Through collaboration with other investigators in the Department of Genetics and elsewhere in the medical school, we carry the most recent discoveries about genetic disorders and novel methodology from the research laboratory to the medical setting.

A hypothetical two-hit mechanism for developmental defects in Gorlin syndrome. An affected fetus inherits a germ-line mutation in one copy of the Gorlin syndrome gene. Through somatic mutations, cells in the developing fetus undergo a second hit resulting in dysregulated clones. These clones give rise to focal developmental defects such as jaw cysts, bifid ribs, and spina bifida occulta. Molecular studies showing allelic loss in jaw cysts support this model.