Cellular DNA damage responses; Breast cancer genetics; Genetics of type 1 diabetes

Biochemistry, Molecular Biology and Genetics
Research in our laboratory builds upon our prior genetic studies intended to map and identify the genes responsible for two very different types of inherited genetic disorders: rare recessive disorders such as ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) that are characterized by hypersensitivity to ionizing radiation, and the common, but genetically complex disorder type 1 diabetes (T1D) that disrupts the body's ability to metabolize glucose.  Nijmegen Breakage Syndrome (NBS) is a recessive inherited childhood disease characterized by microcephaly from birth, immunodeficiency, an increased incidence of malignancy and hypersensitivity to ionizing radiation.  In an international collaborative study, we positionally cloned the gene NBS1, which is mutated in this disorder.  Subsequently, we have used cell biology studies to develop an understanding the role of NBS1 in the complex signaling cascade that is elicited in mammalian cells when exposed to agents, such as ionizing radiation, that cause double strand breaks in DNA.  These studies have demonstrated that the product of the NBS1 gene, nibrin, acts in the same pathway as ATM, the gene mutated in A-T, and is both an activator of ATM and substrate for ATM's kinase activity.

Cancer Research-Molecular Medicine
Many of the DNA damage response proteins that take part in the signaling cascade elicited by cellular exposure to ionizing radiation, such as NBS1 and ATM, are also implicated in predisposition to cancer in the general population.  For susceptibility genes such as these, the low prevalence of mutation carriers and of exposure to environmental risk factors such as radiation limits the informativeness of standard case-control studies that use a random sample of subjects obtained from the general population (e.g., traditional case-control designs). To investigate the joint roles of mutations in DNA damage response genes and radiation exposure in breast cancer, we initiated the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study.  The primary hypothesis of the WECARE Study is that women who carry a deleterious allele in a DNA damage response gene, and who received radiation therapy as treatment for their first primary breast cancer, have an increased risk of developing a second primary breast cancer.  Thus, in the WECARE Study, women with bilateral breast cancer serve as cases and women with unilateral breast cancer serve as controls.  This design is based on the premise that by restricting consideration to women with a first primary breast cancer and then studying the determinants of developing a second primary breast cancer, the power to detect main effects of relatively rare genetic mutations and/or their interactions with environmental factors is considerably enhanced. Currently, we are examining the roles of variation in the ATM, BRCA1, BRCA2 and CHEK2 genes in the WECARE Study population.  Using cell lines from WECARE subjects, we are also exploring the functional consequences of variation in these genes for cellular radiation sensitivity.

Genetics of Autoimmunity-Microbiology, Immunology and Infectious Disease
Positional cloning of the mutated genes is relatively straightforward in a disorder like NBS where these alleles are highly penetrant, the disease follows a clear mode of inheritance, and there is little heterogeneity.  The genetics of a disorder such as type 1 diabetes (T1D) is considerably more complex and involves the actions and likely the interactions of multiple genes as well as unknown environmental factors, all of which conspire to drive the autoimmune destruction of the insulin-secreting Beta cells of the pancreas.  Loss of these cells results in a complete dependence on exogenously administered insulin for survival.  Identification of at least the genetic component of this disorder holds the promise of better disease prediction and a better understanding of the underlying pathology.  These factors are crucial to developing treatments for T1D that are preventive, rather than simply supportive. Our current studies on T1D are focused on mapping and identifying the major susceptibility genes for this disorder.  Some of these genes are known, and, in these cases, we are pursuing translational studies to connect risk genotypes with patient phenotypes.