Research Statement (immediately below)

Research Staff

Research Statement
Our research has been focused on the identification of genetic alterations underlying tumor development and progression, and, in particular, the mapping and identification of putative tumor suppressor genes (TSG) on the short arm of chromosome 9 (9p). Our laboratory was the first to show that the putative TSG on 9p was involved in a wide variety of solid tumors and that the gene was likely to play a more general role in oncogenesis. Having defined the critical region on 9p in leukemias, gliomas, melanomas and lung cancers CDKN2A (p16INK4), a cell cycle regulator was eventually identified as the candidate gene. CDKN2A's candidacy as the sole TSG on 9p has been highly controversial because initial studies only demonstrated homozygous deletions in cell lines. Therefore, we have maintained our interest in characterizing additional genes on 9p. We have cloned the MTAP gene from the critical region on 9p, and are currently studying its possible role in determining tumor sensitivity to antimetabolite chemotherapy. In addition, we remain interested in studying the chromosomal mechanisms leading to the frequent deletion of such a large region on 9p in multiple tumor types, including breast cancer.

Our laboratory is also interested in the genetics of breast cancer, the leading cause of death among women 40-55 years of age. Our goal is to understand the genetic markers and pathways that characterize breast cancer development in order to generate clinical tools for prevention, prediction, and treatment of breast cancer. Although available evidence suggests that genetic factors may explain ethnic differences in the biology of breast cancers, little information is available regarding BRCA1 and BRCA2 mutations in ethnic groups other than Caucasians of Northern European Ancestry and Ashkenazi Jews. Our laboratory was the first to describe recurrent BRCA1 mutations in extended African American (AA) families with breast cancer. For AAs, this should be a high priority research question because the biology of BRCA1 associated breast cancers appears more closely related to the biology of tumors from AA women. BRCA1 associated tumors and tumors from AAs both occur at a younger age, have a high nuclear and histologic grade (excess of medullary histology), and are generally estrogen receptor negative. Many European mutations have been observed in the US or Canada, reflecting European migrations to North America. However, the nature of BRCA1 and BRCA2 mutations in Africa is just beginning to be revealed by the evaluation of families of combined African and European or American Ancestry. As a focus for our research, we continue to study the contribution of BRCA1 and BRCA2 to genetic susceptibility to breast cancer in AAs, as well as African women with breast cancer. We are also examining the secondary genetic alterations which characterize tumors from women with hereditary cancers.

In addition to inherited breast cancer factors, we are also examining the somatic genetic changes associated with breast tumor development. In particular, we are studying the mechanism of HER2/neu genomic amplification and its relationship to BRCA1 alterations. HER2/neu amplification status is a prognostic indicator of tumor aggressiveness as well as a predictor of responsiveness to certain therapies. Because some but not all patients with HER2/neu amplification respond to combination therapies that include Herceptin, we are characterizing the associated markers that will provide better predicting power in considering therapy strategies.

Other interests include characterization of genes involved in familial leukemia.

Selected References

1. Olopade OI, Jenkins R, Cowan JM, Linnenbach AJ, Pomykala H, Rowley JD, Diaz MO. Molecular analysis of deletion of the short arm of chromosome 9 in human gliomas. Cancer Res 2:2523-2529, 1992.

2. Olopade OI, Thangavelu M, Larson RA, Vardiman JW, Daley K, Le Beau MM. Clinico-pathological and cytogenetic characteristics of 26 patients with Erythroleukemia (AML-M6). Blood 79:2873-2883, 1992.

3. Ransom DT, Ritland SR, Moertel CA, Dahl RJ, O'Fallon JR, Scheithauer BW, Kimmel DW, Kelly PJ, Olopade OI, Diaz MO, Jenkins RB. Correlation of cytogenetic and loss of heterozygosity studies in human diffuse astrocytoma and mixed oligo-astrocytomas. Genes, Chrom Cancer 5:357-374, 1992.

4. Olopade OI, Buchhagen DL, Malik K, Sherman J, Nobori T, Gazdar AF, Minna JD, Diaz MO. Homozygous loss of the interferon genes defines the critical region on 9p that is deleted in lung cancers. Cancer Res 53:2410-2415, 1993.

5. Nobori T, Szinai I, Amox D, Parker B, Olopade OI, Buchhagen DL, Carson DA. Methylthioadenosine phosphorylase deficiency in human non-small cell lung cancers. Cancer Res 53:1098-1101, 1993.

6. Coleman A, Fountain JW, Nobori T, Olopade OI, Robertson G, Housman DE, Lugo TG. Distinct deletions of chromosome 9p associated with melanoma versus glioma, lung cancer and leukemia. Cancer Res, 54:344-348, 1994.

7. Stadler WM, Sherman J, Bohlander SK, Roulston D, Dreyling M, Rustalis, Olopade, OI. Homozygous deletions within chromosomal bands 9p21-22 in bladder cancer. Cancer Res 54:2060-2063, 1994.

8. Porterfield BW, Olopade OI, Rowley JD, Diaz MO. Analysis of a tumor suppressor gene on human chromosome 9 in mouse x human somatic cell hybrids. Somatic Cell and Molecular Genetics 20:391-400, 1994.

9. Cheng JQ, Jhanwar JS, Klein WM, Bell DW, Lee W-C, Altomare DA, Nobori T, Olopade OI, Buckler AJ, Testa JR. p16 alterations and deletion mapping of 9p21-p22 in malignant mesothelioma. Cancer Res 54:5547-5551, 1994.

10. Yaeger T, Stadler W, Belair C, Puthenveetti J, Olopade OI, Reznikoff C. Increased p16 levels correlate with pRB alterations in human urothelial cells. Cancer Res 55:493-497, 1995.

11. Dreyling MH, Bohlander SK, Adeyanju MO, Olopade OI. Detection of CDKN2 deletions in tumor cell lines and primary glioma by Interphase Fluorescence in situ Hybridization. Cancer Res 55:984-988, 1995.

12. Olopade OI, Pomykala H, Sveen L, Hagos F, Gursky S, Stadler W, Dreyling M, Le Beau MM, Bohlander SK. Construction of a 2.8 megabase YAC contig and cloning of the Methylthioadenosine Phosphorylase (MTAP) gene from the tumor suppressor region on 9p21. Proc. National Academy of Science, 92: 6489-6493, 1995.

13. Gupta E, Olopade OI, Ratain MJ, Mick R, Berezin FK, Benson III AB, and Dolan ME. Pharmacokinetics and pharmacodynamics of Oltipraz as a chemoprevention agent. Clin Cancer Res 1:1133-1138, 1995.

14. Dreyling MH, Olopade OI, Bohlander SK. A method for screening cosmid libraries with mega insert yeast artificial chromosomes. Nucleic Acids Res 23: 1085-1086, 1995.

15. Dreyling MH, Kobayashi H, Olopade OI, Le Beau MM, Rowley JD, Bohlander SK. Detection of 9p deletions in leukemia cell lines by interphase fluorescence in situ hybridization with YAC-derived probes. Cancer Genet Cytogenet 83:46-55, 1995.

16. Dreyling MH, Bohlander SK, Le Beau MM, Olopade OI. Refined mapping of genomic rearrangements involving the short arm of chromosome 9 in acute lymphoblastic leukemias and other hematologic malignancies. Blood 86: 1931-1938, 1995.

17. Schroeder M, Mathieu U, Dreyling MH, Bohlander SK, Hagemeijer A, Beverloo BH, Olopade OI, Stilgenbauer S, Fischer K, Bentz M. CDKN2 gene deletion is not found in chronic lymphoid leukemias of B- and T-cell origin but is frequent in acute lymphoblastic leukemia. Br Haematol 4:685-870, 1995.

18. Olopade OI, Roulston D, Baker T, Narvid S, Le Beau MM, Freireich EJ, Larson RA, Golomb HM. Familial myeloid leukemia associated with loss of the long arm of chromosome 5. Leukemia 10, 669-674, 1996.

19. Stadler WM, Olopade OI. The CDKN2 and CDKN2B loci in bladder cancer: Homozygous deletion is the most common mechanism of inactivation. Urol Res 24:239-224, 1996.

20. Brenner AJ, Paladugu A, Wang H, Olopade OI, Dreyling MH, Aldaz CM. Preferential loss of p16INK4a rather than p19ARF in Breast Cancer. Clin Cancer Res 2:1993-1998, 1996.

21. Olopade OI. BRCA1 testing in families with hereditary breast - ovarian cancer. JAMA 276:1138-1139, 1996.

22. Ong ST, Koeppen H, Larson RA, Olopade OI. Successful Treatment of Angioimmunoblastic Lymphadenopathy with Dysproteinaemia (AILD) with Fludarabine. Blood 88:2354-2355, 1996.

23. *Gao Q, Cummings S, Sveen L, Neuhausen S, Olopade OI. Recurrent germline BRCA1 mutations in extended African-American families with early-onset breast cancer. Am J Hum Genet 60:1233-1236, 1997.

24. *Olopade OI, Adeyanju MO, Safa AR, Hagos F, Mick R, Thompson CB, Recant WR. Overexpression of BCLX protein in primary breast cancer is associated with high tumor grade and nodal metastases. Cancer J. Sci Am 3: 3:230-237, 1997.

25. Dreyling MH, Olopade OI, Bohlander SK. Generation of small insert genomic FISH probes with high signal intensity suitable for deletion mapping. Cytogenet Cell Genet 77:202-205, 1997.

26. Reeder JE, Morreale JF, O'Connell MJ, Stadler WM, Olopade OI, Messing EM, Wheeless LL. Loss of the CDKN2/p16 locus detected in bladder irrigation specimens by fluorescence in situ hybridization. J Urol 158:1717-1721, 1997.

27. Zhi-Hao C, Olopade OI, Savarese TM. Expression of Methylthioadenosine Phosphorylase (MTAP) cDNA in p16, MTAP Malignant Cells: Restoration of MTAP-Dependent Salvage Pathways and Alterations of Sensitivity in Inhibitors of Purine de novo Synthesis. Mol Pharmacol 52:903-911, 1997.

28. Strissel PL, Dann HA, Pomykala HM, Diaz MO, Rowley JD, Olopade OI. Scaffold associated regions in the human type I interferon gene cluster on the short arm of chromosome 9. Genomics 47:217-229, 1998.

29. *Brunet JS, Ghadirian P, Rebbeck TR, Lerman C, Garber J, Tonin PN, Abrahamson J, Foulkes WD, Daly M, Wagner-Costalas J, Godwin A, Olopade OI, Moslehi R, Liede A, Futreal PA, Weber B, Lenoir GM, Lyncy HT, Narod SA. The effects of smoking on breast cancer incidence in BRCA1 and BRCA2 carriers. J Natl Cancer Inst 90:761-766, 1998.

30. Dreyling MH, Roulston D, Bohlander SK, Vardiman J, Olopade OI. Co-deletion of CDKN2 and MTAP genes in a subset of non-Hodgkin's lymphoma may be associated with histologic transformation from low grade to diffuse large cell lymphoma. Genes, Chromosomes and Cancer 22:72-78, 1998.

31. *Frank TS, Manley SA, Olopade OI, Cummings S, Garber JE, Bernhardt B, Antman K, Russo D, Wood ME, Mullineau L, Isaacs C, Peshkin B, Buys S, Venne V, Rowley PT, Loader S, Offit K, Hampel H, Brener D, Winer EP, Clark S, Weber B, Strong LC, Reiger P, McClure M, Ward B, Shattuck-Eidens D, Oliphant A, Skolnick MH, Thomas A. Sequence analysis of BRCA1 and BRCA2: Correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 279:2417-25, 1998.

32. *Walker AH, Jaffe JM, Gunasegaram S, Cummings SA, Huang CS, Chern HD, Olopade OI, Weber BL, Rebbeck TR. Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: Ethnic distribution and implications for prostate cancer risk. Human Mutation, 12:289-293, 1998.

33. *Narod SA, Risch H, Moslehi R, Dorum A, Neuhausen S, Olsson H, Provencher D, Radice P, Evans G, Bishop S, Brunet JS, Ponder BA and hereditary ovarian cancer clinical study group.Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 339:424-428, 1998.

34. *Rebbeck TR, Levin AM, Eisen A, Snyder C, Watson P, Cannon-Albright L, Isaacs C, Olopade O, Garber JE, Godwin AK, Daly MB, Narod SA, Neuhausen SL, Lynch HT, Weber BL. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst, 91:1475-9, 1999.

35. *Wang-Gohrke S, Weikel W, Risch H, Vesprini D, Abrahamson J, Lerman C, Godwin A, Moslehi R, Olopade O, Brunet JS, Stickeler E, Kieback DG, Kreienberg R, Weber B, Narod SA, Runnebaum IB Intron variants of the p53 gene are associated with increased risk for ovarian cancer but not in carriers of BRCA1 or BRCA2 germline mutations. Br J Cancer, 81:179-83, 1999.

36. *Jernstrom H, Lerman C, Ghadirian P, Lynch HT, Weber B, Garber J, Daly M, Olopade OI, Foulkes WD, Warner E, Brunet JS, Narod SA. Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet, 354:1846-50, 1999.

37. *Huo Z, Giger ML, Wolverton DE, Zhong W, Cummings S, Olopade OI. Computerized analysis of mammographic parenchymal patterns for breast cancer risk assessment: Feature Selection. Med Phys, 27: 1-9, 2000.

38. *Liede A, Cohen B, Black DM, Davidson RH, Hoodfar E, Olopade OI, Micek M, Anderson V, DeMey R, Fordyce A, Warner E, Dann JL, King MC, Weber B, Narod SA, Steel CM. Evidence of a Founder BRCA1 mutation in Scotland. Br J Cancer, 82:705-711, 2000.

39. *Gao Q, Horwitz M, Roulston D, Hagos F, Zhao N, Freireich EJ, Golomb H, Olopade OI. The Susceptibility Gene for Familial Acute Myeloid Leukemia Associated with Loss of 5q and/or 7 q Is not Localized on the commonly Deleted Portion of Chromosome 5. Genes Chrom Cancer 28:164-172, 2000.

40. *Gao Q, Tominson G, Das S, Cummings S, Sveen L, Fackenthal J, Schumm Ph, Olopade OI. Prevalence of BRCA1 and BRCA2 mutations among clinic-based African American families with breast cancer. Human Genetics DOI10.1007/s004390000290

41. *Pierce LJ, Strawderman M, Narod SA, Oliviotto I, Eisen A, Dawson L, Gaffney D, Solin LJ, Nixon A, Garber J, Berg C, Isaacs C, Heimann R, Olopade OI, Haffty B, Weber, BL. Effect of radiotherapy following breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations in press Journal of Clinical Oncology.

42. Poelman SM, Adeyanju, M, Recant, W, Olopade, OI, and Conzen, SD. Correlation of tumor Bcl-2 expression and response to paclitaxel therapy for metastatic breast cancer. Manuscript in press Clinical Cancer Research.

43. Gao Q, Adebamowo CA, Fackenthal J, Das S, Sveen L, Falusi AG, Olopade OI. Protein Truncating mutations BRCA1 and BRCA2 mutations in African women with pre-menopausal breast cancer. Human Genetics DOI10.1007/s004390000342.