Albert de la Chapelle, MD, PhD
College of Medicine
Molecular Virology, Immunology & Medical Genetics
Molecular Biology and Cancer Genetics
Colorectal Neoplasms, Hereditary Nonpolyposis, Chromosome Aberrations, Genetic Markers, Colorectal Neoplasms, Sex Chromosome Aberrations, Chromosome Deletion, Neoplasms, Microsatellite Instability, Chromosome Disorders, Leukemia
Research in Dr. de la Chapelle’s laboratory focuses on the mapping, cloning, and characterization of high-penetrance genes for cancer predisposition. Similar studies into low-penetrance genes, a relatively new concept, are also done. When new genes are identified, studies are directed to determine the pathophysiological role of the proteins they encode, and the mechanisms by which mutations in the genes contribute to the cancer phenotype. Finally, there is an emphasis on translational aspects of the research, viz. the exploitation of laboratory discoveries towards new diagnostic and therapeutic procedures. Diseases under study in the de la Chapelle laboratory include colorectal cancer, papillary thyroid cancer, and acute myeloid leukemia. Colorectal cancer is highly heritable; nevertheless only a small fraction of all predisposing genes have been detected so far. Two novel mechanisms of predisposition to colorectal cancer are presently being explored. In papillary thyroid cancer predisposing germline mutations are sought by a variety of methods, including linkage, allelic association, and the determination of allelic differences in gene expression. The role of non-coding RNA genes is emerging as a major cause of predisposition to papillary thyroid cancer. One microRNA, 146a, has been implicated. Carriers of a single nucleotide polymorphism in the pre-miR146a sequence have an elevated risk of thyroid cancer. It appears that heterozygotes for the polymorphism produce two abnormal mature miRs, whose target genes suggest the involvement of numerous downstream genes contributing to cancer development. In acute myeloid leukemia the group cloned a novel gene, BAALC for Brain and Acute Leukemia, Cytoplasmic that is expressed in early hematopoietic progenitor cells, and in a subset of the acute myeloid and lymphoid leukemias. Ongoing studies, including mouse modeling, aim at understanding the precise role of BAALC in leukemogenesis. The working hypothesis is that BAALC is a marker of, or even a contributor to, blocked differentiation of these cells.