Congenital Abnormalities; DNA; Fanconi Syndrome; Genetics; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Multiple Endocrine Neoplasia; Neoplastic Syndromes, Hereditary; Skin Neoplasms
Skin Diseases Research Center, Yale
My laboratory’s focus is hereditary cancer predisposition. One project in the laboratory arose from studies of the nevoid basal cell carcinoma syndrome (NBCCS), a human genetic disease characterized by skin cancer and brain tumors as well as a variety of birth defects. We isolated the NBCCS gene and showed that it is homologous to Drosophila "patched," a key gene in Drosophila embryonic development. We are now examining human homologs of other members
of the patched pathway and investigating their roles in human cancer. In addition, we have become involved in large molecular epidemiology studies, using high throughput sequencing to search in an unbiased way for novel skin cancer genes and the interaction between genes and environment in cancer causation.
Specialized Terms: Molecular Mechanisms of Cancer; Predisposition and Developmental Defects; DNA Diagnostics; Birth Defects; Cancer; Fanconi; Genetics; Hedgehog; Multiple Endocrine Neoplasia; Patched; Skin Cancer; Tumor Suppressor
Extensive Research Description
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. We are examining other segment polarity genes in human cancer. Other disease genes under study 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, such as high throughput sequencing, to clinical diagnosis of cancer predispostion syndromes. 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.
- Kottemann, M.C. and A.E. Bale, Characterization of DNA damage-dependent cell cycle checkpoints in a menin-deficient model. DNA Repair (2009) 8:944-952.
- Marek LR, Kottemann MC, Glazer PM, Bale AE (Mar 2008) MEN1 and FANCD2 mediate distinct mechanisms of DNA crosslink repair., DNA repair, 7(3)476-86
- Busygina, V., Kottemann, M.C., Scott, K.L., Plon, S.E., and Bale, A.E. (2006). Multiple endocrine Neoplasia Type 1 Interacts with forkhead transcription factor CHES1 in DNA damage response. Cancer Res. 66:8397-403.
- Cajaiba MM, Bale AE, Alvarez-Franco M, McNamara J, Reyes-Múgica M (Oct 2006) Rhabdomyosarcoma, Wilms tumor, and deletion of the patched gene in Gorlin syndrome., Nature clinical practice. Oncology, 3(10)575-80
- Cooper, A.F., et al. (2005). Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Dev. 132:4407-17.