Nathan A. Ellis, Ph.D.

Genomic Instability and Cancer Susceptibility in Digestive Diseases

Research Summary

The over-all research focus of the Ellis laboratory is the study of genomic instability and its relationship to cancer susceptibility. This focus includes the study of both high-penetrance and low-penetrance cancer-causing genes, population genetics of human cancer susceptibility alleles, and the molecular and cellular biology of the disease susceptibility genes themselves.

Regulation of homologous recombination in human cells
Cells contain numerous DNA repair systems that maintain the integrity of the genome. When a component of one of these systems is mutated, either somatically or in the germline, cells accumulate mutations and susceptibility to cancer increases. Homologous recombination (HR) is a high-fidelity pathway that can restart broken replication forks and repair DNA double-strand breaks. HR is carefully controlled so that it is called into play only when it is needed. In the autosomal recessive disorder Bloom's syndrome (BS), HR occurs excessively. The gene mutated in BS is BLM. BLM is a DNA helicase of the RecQ family, and it plays a critical role in controlling excessive HR. We are interested in how BLM’s function in HR is regulated. Our recent evidence indicates that BLM’s interaction with the recombination protein RAD51 is regulated by the protein modification SUMO (small ubiquitin-like modifier). We are investigating the mechanisms by which SUMO modification of BLM and other proteins regulates HR and DNA damage responses.

Genetic analysis of colorectal cancer susceptibility
Genetic risk factors play an important role in the development of colorectal cancer (CRC). Hereditary CRC syndromes have demonstrated the importance of DNA repair in CRC susceptibility, and many of the environmental factors that increase the risk of CRC development do so by causing increased DNA damage. While DNA damage and repair are clearly important, genetic factors that influence cell proliferation in the gut epithelium also can increase CRC risk. Our overall goals are (1) to identify clinically useful genetic risk factors that predict a person’s risk of developing CRC, (2) to elucidate the role these genetic risk factors play in disease pathogenesis, and (3) to develop a predictive model that takes into account both genetic and environmental factors in determining CRC risk. To address these goals, we are performing candidate gene and genome-wide association studies comparing CRC cases with cancer-free controls. Being located on the Southside of Chicago, our hospital sees a large contingent of African American (AA) patients. This patient base gives our studies a broader population perspective than most others. Moreover, because the AA population is enormously more diverse genetically than populations derived from Europe, through comparative studies we have a distinct advantage in the search for and elucidation of genetic risk factors. Finally, our work with AA CRC patients also examines population-specific factors in CRC incidence and hopefully will shed light on the causes of health disparities in this population.

Genetic factors and response to treatment in inflammatory bowel disease
Inflammatory bowel disease (IBD) is a disorder of the gut in which the host immune system is over-active, which is itself a potent risk factor for cancer development. Recent genetic studies have identified over 30 genetic risk variants that influence the development of IBD. However, while this information has helped us understand the fundamental causes of disease, there is enormous heterogeneity in the disease and many new treatment options that complicate clinical management. We are investigating genetic factors that influence response to therapy and outcome. For example, antibodies to tumor necrosis factor (TNF) have been successful in treating persons with severe disease who have failed other treatments, yet 20-30% of patients do not respond to anti-TNFs. Using genetic markers, we may be able to predict treatment response, and patients who would not respond could be spared exposure to complications of therapies and the possibility of success with another therapy. These studies are being carried out in the context of a large multi-center consortium, working closely with IBD clinicians.

Selected Papers

Peterlongo P, Mitra N, Chuai S, Kirchhoff T, Palmer C, Huang H, Nafa K, Offit K, Ellis NA. Frequency of MYH mutations in Caucasian and Jewish colorectal cancer cases and controls. Int J Cancer 2005;114:505-507

Shia J, Klimstra DS, Nafa K, Offit K, Guillem JG, Markowitz AJ, Gerald WL, Ellis NA. Value of immunohistochemical detection of DNA mismatch repair gene proteins in predicting germline mutation status in familial colorectal neoplasms. Am J Surg Path 2005; 29:96-104

Eladad, S, Ye TZ, Hu P, Leversha M, Beresten SF, Matunis M, Ellis NA. Intra-nuclear trafficking of the BLM helicase to DNA damage induced foci is regulated by SUMO-1. Hum Mol Genet 2005; 14:1351-1365

Ellis NA, Kirchhoff T, Mitra N, Ye TZ, Chuai S, Huang H, Nafa K, Norton L, Neuhausen S, Struewing JP, Narod S, Offit K. Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping. Genetic Epidemiology 2006 30:48-61

Peterlongo P, Mitra N, Sanchez de Abajo A, de la Hoya M, Bassi C, Bertario L, Radice P, Glogowski E, Nafa K, Caldes T, Offit K, Ellis NA. Increased frequency of disease-causing MYH mutations in colon cancer families. Carcinogenesis 2006; 27:2243-2249

German J, Ciocci S, Ye TZ, Sanz MM, Ellis NA. Syndrome-causing mutations at BLM in persons in the Bloom’s Syndrome Registry. Hum Mutation 2007; 28:743-753

Gold B, Kirchhoff T, Stefanov S, Lautenberger J, Viale A, Garber J, Friedman E, Narod S, Olshen A, Gregersen P, Kosarin K, Bergeron J, Ellis NA, Klein R, Clark A, Norton L, Dean M, Boyd J, Offit J. Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci USA 2008; 105:4340-4345

Ellis NA, Huo D, Yildiz O, Worrillow LJ, Banerjee M, Le Beau MM, Larson RA, Allan JM, Onel K. MDM2 SNP309 and TP53 Arg72Prointeract to alter therapy-related acute myeloid leukemia susceptibility. Blood 2008; 112:741-749

Zhu J, Zhu S, Guzzo CM, Ellis NA, Sung KS, Choi CY, Matunis MJ. Sumo binding determines substrate recognition and paralog-selective sumo modification. J Biol Chem 2008; 283:29405-29415

Ellis NA, Sander M, Harris CC, Bohr VA. Bloom's syndrome workshop focuses on the functional specificities of RecQ helicases. Mech Age and Develop 2008; 129:681-691