HMGP - Marileila Garcia, Ph.D.

My research interests have been primarily directed at the development of molecular markers for early detection or monitoring recurrence in human neoplasias. Examples of scientific accomplishments are the development of effective fluorescence in situ hybridization (FISH)–based assays for detection of chromosomal imbalance in interphase cells. In aerodigestive cancers, for instance, FISH using dual-target DNA probes labeled in distinct colors were demonstrated as useful tools to detect sub-clinical tumorigenesis. The dual-target FISH assay was proposed as an important test for non-invasive screening of individuals at risk for these tumors and molecular investigation of the tumor margins. More recently, we have validated FISH probes for simultaneous detection of four DNA targets in multicolor FISH assay as a tool for detection of abnormal cells in bronchial epithelium of patients with or at risk for lung cancer. We optimized methodological conditions for successful detection of aneusomic cells in sputum and developed a test that could identify abnormal cells in heavy smoker individuals one year prior to the clinical diagnosis of lung cancer.

Our translational focus was also applied to detection of leukemia cells. One example is the D-FISH assay (double fusion signal) for monitoring residual AML FAB M2 associated with the t(8;21)(q22;q22), developed in collaboration with Dr. Harry Drabkin. This probe design allows the identification of both chimeric products of the chromosome translocation in interphase cells, therefore significantly increasing the specificity of the FISH assay. Another approach, the break-apart FISH assay, was developed for laboratorial diagnosis of ALL with rearrangements involving the E2A gene in 19p13, in collaboration with Dr.Stephen Hunger. The break-apart FISH design accesses chimeric fusions of a given gene, E2A in the case, with multiple partner genes, which allows the diagnostic of distinct translocations. Both D-FISH and break-apart FISH assays have been easy incorporated into clinical laboratory settings.

Moreover, we actively interact with researchers in multiple fields of cancer genetics. Aiming to better support the molecular targeted therapy approach and to efficiently identify patients who can profit from these special forms of treatment, we are investigating gene amplifications and protein overexpression in multiple metabolic pathways important in oncogenesis. Examples of molecules already addressed are the growth factor receptors HER-2/neu and epidermal growth factor receptor (EGFR) and cyclin D1 (CCND1). The gene status and mechanisms controlling expression of these molecules have been investigated in prostate and ovarian adenocarcinomas, glioblastomas, squamous cell esophageal carcinomas, and non-small cell lung carcinomas, in collaboration with numerous UCD investigators.

Publications:

Varella-Garcia M. Molecular cytogenetics in solid tumors: Laboratorial tool for diagnosis, prognosis and therapy. The Oncologist 8: 45-58, 2003.

Vendrame-Goloni CB, Varella-Garcia M, Carvalho-Salles AB, Ruiz MA, Ricci Jr O, Fett-Conte AC. Translocation (11;19)(q23;p13.3) associated with a novel t(5;16)(q13;q22) in patient with acute myeloid leukemia. Cancer Genet. Cytogenet. 141: 71-74 , 2003.

Romeo MS, Sokolova IA, Morrison LE, Zeng C, Barón AE, Hirsch FR, Miller YE, Franklin WA, Varella-Garcia M. Chromosomal abnormalities in non-small cell lung carcinomas and in bronchial epithelium of high risk smokers detected by multi-target interphase fluorescence in situ hybridization. J Mol Diagnostics 5: 103-112, 2003.

Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia M, Franklin WA. Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. Lung Cancer 41 Suppl 1:S29-42, 2003.

Suratt BT, Cool CD, Serls A, Varella-Garcia M, Chen L, Shpall EJ, Brown KK, Worthen GS Human pulmonary chimerism following hematopoietic stem cell transplantation. Am. J. Respir. Crit. Care Med. 168: 318-322, 2003.

van Bokhoven A, Caires A, Di Maria M, Passarini A, Lucia MS, Nordeen S, Miller GJ Varella-Garcia M. Spectral karyotype (SKY) analysis of human prostate carcinoma cell lines. Prostate, 57:226-244, 2003.

van Bokhoven A,Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL, Nordeen SK, Miller GJ, Lucia MS. Molecular Characterization of Human Prostate Carcinoma Cell Lines. The Prostate, 57:205-225, 2003.

Hirsch FR, Varella-Garcia M, Bunn, Jr PA, Di Maria M, Veve R, Bremnes R, Barón AE, Zeng C, Franklin WA. Epidermal growth factor receptor in non-small cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol, 21(20):3798-3807, 2003.

Li FX, Zhu JW, Tessem JS, Beilke J, Varella-Garcia M, Jensen J, Hogan CJ, DeGregori J. The development of diabetes in E2F1/E2F2 mutant mice reveals important roles for bone marrow derived cells in preventing islet cell loss. Proc Ntl Acad Sc USA, 100(22):12935-12940, 2003.

Varella-Garcia M, Akduman B, Sunpaweravong P, DiMaria M, Crawford DE.. The UroVysion fluorescence in situ hybridization assay is an effective tool for monitoring recurrence of bladder cancer. Urologic Oncology, 22(1):16-9., 2004.

Ziada A, Barqawi A, Glode LM, Varella-Garcia M, Crighton F, Majeski S, Rosemblum M, Kane M, Chen L, Crawford ED. The use of Trastuzumab in the treatment of hormone refractory prostate cancer: Phase II trial. Prostate, 60: 332-337, 2004.

Varella-Garcia M, Kittelson K, Passarini A, Vu KO, Wolf HJ, Zeng C, Byers T, Franklin WA Multi-target interphase fluorescence in situ hybridization assay increases sensitivity of sputum cytology as a predictor of lung cancer. Cancer Detect Prev, 28(4):244-51, 2004.

Sunpaweravong P, Sunpaweravong S, Puttawibul P, Mitranun W, Zeng C, Baron A, Franklin WA, Said S, Varella-Garcia M. Epidermal growth factor receptor and cyclin D1 are independently amplified and overexpressed in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2004 Oct 19 [Epub ahead of print]

Heinrich, JKR, Böttcher-Luiz F, Andrade LA, Vassalo J, Davidson S, Bonds L, Stephens J, Varella-Garcia M. HER2 and CA 125 evaluation in ovarian borderline tumors by immunohistochemistry and fluorescence in situ hybridization. International Journal of Gynecological Cancer, in press.