de la Chapelle Lab
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 the research, viz. the exploitation of laboratory discoveries toward 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. Even so, screening all colorectal and endometrial cancer patients for mutations in the mismatch repair genes (Lynch syndrome) is practically feasible, 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, the determination of allelic differences in gene expression, next generation sequencing (NGS) and genome-wide association studies (GWAS). 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. Moreover, in the case of two SNPs carrying risk for papillary thyroid cancer (by GWAS), a search for the causative mutation has led to the detection of previously unknown long intergenic noncoding RNAs (lincRNAs) that are implicated in the predisposition. In one family showing linkage to a chromosomal locus in chromosome 4q32, an enhancer is disrupted by a causative SNP. These and other leads are being investigated to determine the mechanisms causing increased risk of thyroid cancer. Second-generation deep sequencing is replacing previously used methods in the search for pathogenic mutations.
In acute myeloid leukemia, the group previously cloned a novel gene, BAALC (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 seek to understand the role of BAALC in leukemogenesis. The hypothesis is that BAALC is a marker of, or even a contributor to, blocked differentiation of these cells. Surprisingly, in vitro and in vivo studies have implicated miR-3151 in the development of acute myeloid leukemia. This miR is “hosted” by the BAALC gene being located in intron 1 of BAALC. It appears that the major pathogenic player is miR-3151 rather than BAALC.
Finally, in chronic lymphocytic leukemia (CLL) two particularly large families have been identified in which both CLL and its precursor, monoclonal B-cell lymphocytosis (MBL), appear to segregate in a Mendelian fashion. Members of the families have undergone Whole Genome Sequencing; the results are being evaluated. It is likely that, in both families, mutations in one or perhaps two genes will turn out to be causative.
Ann-Kathrin Eisfeld, MD, visiting scholar
Huiling He, MD, research scientist
Wei Li, MD, research associate
Sandya Liyanarachchi, MS, research scientist
Jan Lockman, BS, research associate, lab manager
Yanqiang Wang, PhD, postdoctoral researcher
Daniel Comiskey, PhD
Taina Nieminen, PhD