Albert de la Chapelle, MD, PhD
College of Medicine
Cancer Biology and Genetics
Molecular Biology and Cancer Genetics
Cancer, Colorectal Cancer, Colorectal Cancer, Hereditary Nonpolyposis, Thyroid Cancer, Microsatellite Instability, Leukemia, Myeloid, Acute, Chromosome Aberrations, Leukemia, Genetic Markers, Endometrial Cancer
Research in Dr. de la Chapelle’s laboratory focuses on the mapping, cloning, and characterization of high-and low-penetrance genes for cancer predisposition. When new genes are identified, studies are directed to determine the pathophysiological role of the proteins or RNA molecules 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 research viz. the exploitation of laboratory discoveries towards new diagnostic and therapeutic procedures. Diseases under study include colorectal cancer, papillary thyroid cancer, acute myeloid leukemia and chronic lymphocytic leukemia. Colorectal cancer is highly heritable; but only a fraction of all predisposing genes have been detected so far. Even so, screening all colorectal and endometrial cancer patients for mutations in the mismatch repair genes (Lynch syndrome) is practically feasible and desirable, because it can save lives through clinical surveillance of targeted high-risk family members. A method of population-wide screening for Lynch syndrome has been developed and its nationwide use is being encouraged. 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 gens is emerging as a major cause of predisposition to papillary thyroid cancer. Several novel candidate genes are investigated that predispose to thyroid cancer. Two long noncoding RNA genes named Papillary Thyroid Carcinoma Susceptibility Candidate 2 (PTCSC2 in chromosome 9q22) and PTCSC3 (in chromosome 14q13) have been identified and implicated. One single nucleotide variant in an enhancer element located in chromosome 4q32 predisposes to thyroid cancer with apparently high penetrance but is utterly rare. Finally, a common variant in the pre-miR146a sequence causes low penetrance thyroid cancer predisposition. A challenge for present and future research is to identify the downstream target genes of these and other sequence variants. Second-generation deep sequencing is replacing previously used methods in the search for deleterious mutations. 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 acute myeloid and lymphoid leukemias. Ongoing studies 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. The novel miR-3151 is located in an intron of BAALC and is hypothesized to act as an independent oncogene in AML. The novel miR-3662 located in a major quantitative trait locus on chromosome 6q23 appears to act as a tumor suppressor that when downregulated conveys AML risk. In chronic lymphocytic leukemia the role of the proapoptotic gene DAPK1 is investigated, and in families with several affected individuals novel predisposing genes are sought by second-generation deep sequencing.