2. Genetic Risk Detection (Diagnosis)

The clinical utility of SNPs has been very limited due to the fact that they only have small impact on the disease risk. Ozcelik laboratory’s long-term interest has been to understand the contribution of genetic variation and environmental factors to the risk of developing disease in human populations. In the area of risk detection (diagnosis), his laboratory has been developing improved risk detection methodologies, contributing to the bridging of statistical genetics and biological findings, for effective translation to clinical care. Ozcelik lab has established long-term collaborations with genetic epidemiologists and biostatisticians to also study the cancer risk associated with gene-environment relationships including alcohol, smoking and diet.

    Selected Publications

Terry MB, Knight JA, Zablotska L, Wang Q, John EM, Andrulis IL, Senie RT, Daly M, Ozcelik H., Briollais L, Santella RM. "Alcohol metabolism, alcohol intake, and breast cancer risk: a sister-set analysis using the Breast Cancer Family Registry." Breast Cancer Res Treat (2007)

Pabalan N, Bapat B, Sung L, Jarjanazi H, Francisco-Pabalan O, Ozcelik H. "Cyclin D1 Pro241Pro (CCND1-G870A) polymorphism is associated with increased cancer risk in human populations: A meta-analysis." Cancer Epidemiol Biomarkers & Prev 17(10): 2773-2781, (2008)

Fehringer G, Boyd NF, Knight JA, Paterson AD, Dite GS, Giles GG, Southey MC, Andrulis IL, Hopper JL, Ozcelik H. "Family-based genetic association study of insulin-like growth factor I microsatellite markers and premenopausal breast cancer risk." Breast Cancer Res Treat 118(2): 415-424 (2009)

Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Hofmann W, Sutter C, Niederacher D, Deissler H, Caldes T, Kampjarvi K, Nevanlinna H, Simard J, Beesley J, Chen X, the Kathleen Cuningham Consortium for Research into Familial Breast Cancer; Neuhausen SL, Rebbeck TR, Wagner T, Lynch HT, Isaacs C, Weitzel J, Ganz PA, Daly MB, Tomlinson G, Olopad OI, Blum JL, Couch FJ, Peterlongo P, Manoukian S, Barile M, Radice P, Szabo CI, Pereira LHM, Greene MH, Rennert G, Lejbkowicz F, Barnett-Griness O, Andrulis IL, Ozcelik H, OCGN; Gerdes A-M, Laitman Y, Kaufman B, Milgrom R, Friedman E, The Swedish BRCA1 and BRCA2 study collaborators; Domchek SM, Nathanson KL, Osorio A, Llort G, Milne RL, Benitez J, Hamann U, Hogervorst FBL, Manders P, Ligtenberg MJL, van den Ouweland AMW, The DNA-HEBON collaborators; Peock S, Cook M, Platte R, Evans DG, Eeles R, Pichert G, Chu C, Eccles D, Davidson R, Douglas F, EMBRACE; Goodwin AK, Barjhoux L, Mazoyer S, Sobol H, Bourdon V, Eisinger F, Chompret A, Capoulade C, Bressac-de Paillerets B, Lenoir GM, Gauthier- Villars M, Houdayer C, Stoppa-Lyonnet S, GEMO; Chenevix-Trench G, Easton DF, on behalf of CIMBA. "Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers." Am J Hum Genet 82 (4): 937-948, (2008)

Pabalan, N., Francisco-Pabalan, O., Sung, L., Jarjanazi, H., Ozcelik H. "Meta-analysis of two ERCC2 (XPD) polymorphisms, Asp312Asn and Lys751 Gln, in breast cancer." Breast Cancer Res Treat epub Apr 9, (2010)

    Gene-Gene Interactions

In line with his interest in systems biology, Dr. Ozcelik’s work has recently demonstrated that gene-gene interactions are more likely to have higher impacts on the magnitude of the breast cancer risk in the population. Since the emergence of Genome Wide Association Studies (GWAS), his laboratory investigate genome wide data, using gene-set enrichment and pathway based analyses, to accelerate the discovery of critical biological and genetic information that may have overlooked. Using pathway based analysis and the available GWAS data, the laboratory comparing the similarities and differences among the biological processes associated with cancer, neurodegenerative and mental disorders, diabetes, heart and stroke disorders. These approaches will shed light into the biological mechanisms of disease, leading to better diagnosis and treatment modalities of complex disorders.

    Selected Publications

Savas S, Ahmad MF, Shariff M, Kim DY, Ozcelik H. "Candidate nsSNPs that can affect the functions and interactions of cell cycle proteins." Proteins, 58:697-705, (2005)

Onay VU, Briollais L, Knight JA, Shi E, Wang Y, Wells S, Li H, Rajendram I, Andrulis IL, Ozcelik H. "SNP-SNP interactions in breast cancer susceptibility." BMC Cancer, 6:114, (2006)

Onay UV, Aaltonen K, Briollais L, Knight JA, Pabalan N, Kilpivaara O, Andrulis IL, Blomqvist C, Nevanlinna H, Ozcelik H. "Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk. " BMC Cancer 8(1):6, (2008)

Briollais L, Wang Y, Rajendram I, Venus O, Shi E, Knight J, Ozcelik H. "Methodological issues in detecting gene-gene interactions in breast cancer susceptibility: a population-based study in Ontario." BMC Med 5(1): 22, (2007)

3. Genetic Response to Treatment

The wide range of individual variation in chemotherapy response among patients is well known and poses a serious problem in medicine. In the area of pharmacogenomics, he has also recently described a novel methodology using genetic data from drug treated NCI60 cell line panel to study candidate genes associated with variable drug response. He has also applied this methodology on the genome-wide level for the discovery of novel genes associated with resistance to well known cancer agents including Gemcitabine, Doxorubicin, Selenium and paclitaxel. The future aim is to improve the design of the clinical trials for effective study of the chemotherapeutic agents and thus provide a basis for individualized chemotherapy.

    Selected Publications

Jarjanazi H, Kiefer J, Savas S, Briollais L, Tuzmen S, Pabalan N, Ibrahim-Zada I, Mousses S, Ozcelik H. "Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine." Hum Mutat 29(4): 461-467, (2008)

Savas S, Briollais L, Ibrahim-zada I, Jarjanazi H, Choi YH, Musquera M, Fleshner N, Venkateswaran V, Ozcelik H. "A whole-genome SNP association study of NCI60 cell line panel indicates a role of Ca2+ signalling in selenium resistance." PLoS One 5(9): e12601, (2010)

Eng L, Ibrahim-Zada I, Jarjanazi H, Savas S, Meschian M, Pritchard KI, Ozcelik H. "Bioinformatic analyses identifies novel protein-coding pharmacogenomic markers associated with paclitaxel sensitivity in NCI60 cancer cell lines." BMC Med Genomics 4:18, (2011)