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 the 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. Novel sequencing techniques now allow several other hereditary cancers of the colorectum to be screened for.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. In all, some 10 variants showing high to moderate penetrance are being characterized. In addition some 15 variants showing moderate to low penetrance have been implicated in thyroid cancer risk. A challenge for present and future research is to identify the downstream target genes of these and other sequence variants. When target genes or binding elements are identified it becomes possible to assign the detected variants to already characterized signaling pathways. This in turn is a first step towards attempts to develop drugs that interfere with the abnormal signaling. The characterization of variants conferring thyroid cancer risk raises the possibility that these markers may be used in clinical work and prevention. The frequency of the variants in patients with thyroid cancer compared to healthy control individuals defines the magnitude of risk often expressed as odds ratio. While high-penetrance variants have high odds ratios, say, over 10, low-penetrance variants often display odds ratios <1.5. It is of considerable interest to determine whether the effect of variants is additive. Indeed, in a first study based on just 5 variants the group determined that carriers of 7 or more risk alleles had odds ratios ~13. This suggests that combining data from as many suitable variants as possible (presently ~15) will produce odds ratios high enough to be used in diagnostic work. Acute Myelogenous Leukemia (AML) is a life-threatening disease whose risk factors are poorly understood. The de la Chapelle lab collaborates with the renowned AML clinical research group at OSU in searching for predisposing genetic variants. Experiments essentially identical with those described above for thyroid cancer are underway and novel risk variants are being evaluated. A genome-wide association study (GWAS) involving >1000 AML cases and >1000 controls was completed in 2017. Novel risk alleles were detected and are being characterized.
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