Biography

Dr. Garcia-Closas received an M.D. from the University of Barcelona in 1990, an M.P.H. in quantitative methods, and a Dr.P.H. in epidemiology from the Harvard School of Public Health in 1993 and 1996, respectively. She joined the Hormonal and Reproductive Epidemiology Branch (HREB) in 1996 as a post-doctoral fellow and is now a Senior Investigator in this branch. She received an NIH Merit Award in 2001, an NCI Intramural Research Award in 2004, and the DCEG Women Scientist Advisory in 2007. Dr. Garcia-Closas sits on the Etiology and Early Marker Studies Review Panel for PLCO studies, the Steering Committee of the Molecular Epidemiology Group, the Estrogen Receptor Negative Breast Cancer Health Disparities Working Group at NCI, and the Editorial Board of Cancer Epidemiology, Biomarkers & Prevention. She is also a lead organizer of the International Consortium of Case-Control Studies of Bladder Cancer, which was formed to facilitate large-scale collaborations.

Research Interests

We are interested in the application of biomarkers in molecular epidemiologic studies of breast, ovarian, endometrial and bladder cancers, with special emphasis on the study of genetic susceptibility, and etiologic heterogeneity of breast cancer. We have also conducted a series of methodological investigations to address relevant scientific questions derived from molecular epidemiologic studies. Recently, my work has focused on three major areas: assessment of false positive findings, collection and use of buccal cell DNA, and creation of pilot studies for biomarker development.

Molecular Epidemiology Studies of Breast, Ovarian and Endometrial Cancers

In 2000, we initiated the Polish Breast, Ovarian and Endometrial Cancer studies, a set of parallel, molecular epidemiologic studies targeting the three female tumors and including about 2,500 breast, 500 endometrial and 300 ovarian cancer cases. This complex study combines detailed exposure assessment and comprehensive collection of biological specimens. The main aims from this study are to evaluate suspected hormonal and environmental risk factors, markers for genetic susceptibility and etiologic heterogeneity of these diseases. In addition, we are collecting five-year follow-up data from breast cancer cases to evaluate determinants of survival and recurrence, including tumor characteristics and common genetic variation.

The discovery of susceptibility genes for cancer holds great promise for improving risk assessment and developing targeted preventive strategies, and also provides an opportunity to dissect the complex etiology of each cancer. In exploring genetic susceptibility of breast cancer, we have evaluated variation in genes in a number of candidate pathways including DNA repair, apoptosis, and regulation of telomere length. With the Breast Cancer Association Consortium (BCAC), a consortium of studies including over 20,000 breast cancer cases, we were able to uncover convincing evidence for modest associations between breast cancer risk and two common genetic variants, caspase 8 (CASP8 D302H) and transforming growth factor beta 1 (TGFB1 L10P; Cox A, Dunning AM, García-Closas M et al. Nature Genetics 2007). In addition, we are collaborating with two efforts to identify genetic susceptibility makers through genome wide association studies (GWAS) at the University of Cambridge, UK and the Cancer Genetic Markers of Susceptibility (CGEMS) project. Recent publications from these studies (Easton DF et. al. Genome-wide association study identifies breast cancer susceptibility loci. Nature, 2007; and Hunter D et al. A genome-wide association study identifies alles in FGFR2 associated with risk of sporadic post-menopausal breast cancer. Nature Genetics 2007) have identified five novel genetic susceptibility makers for breast cancer. Numerous other variants are likely to be identified in the coming years using this approach. Ongoing work following the initial identification of markers includes: fine mapping and functional studies to identify causative markers; and evaluation of how lifestyle factors affect the risk from genetic variants; how different genetic variants interact with each other in affecting risk; whether genetic variants are differentially associated with different types of breast cancer (with different clinical and pathologic features at presentation); and how variants affect survival.

My work related to etiologic heterogeneity of breast cancer in the Polish breast cancer study, is conducted in close collaboration with Dr. Mark Sherman, a pathologist in HREB who brings recognized expertise in breast, ovarian and endometrial cancers. In an initial investigation, we demonstrated substantial heterogeneity in breast cancer risk factors by histopathological tumor characteristics of clinical relevance, particularly tumor grade and size. We then used tissue microarray (TMA) blocks to obtain standardized, rapid, and cost-effective immunohistochemical characterization of many tumors. After overcoming technical difficulties identified in pilot studies, we successfully constructed TMA blocks of invasive carcinoma and non-invasive tissue targets. These arrays have been used to detect hormone-related and other markers identified in expression studies. We are evaluating relationship of these markers with known breast cancer risk factors. Current analyses are focusing on molecular subtypes of breast cancer, as defined in previous gene expression profiling studies, as well as on the evaluation of co-expression patterns.

Our initial work on ovarian and endometrial cancer is focusing on the evaluation of genetic variants in TP53, as well as on hormone metabolizing enzymes. We are also collaborating with two consortia, the Ovarian Cancer Association Consortium (OCAC) and the E2C2 consortium of endometrial cancer studies to identify genetic susceptibly markers for these disease using candidate gene and GWAS approaches

Molecular Epidemiology Study of Bladder Cancer

Occupational exposure to carcinogenic aromatic amines and tobacco use have been causally linked to bladder cancer, and polycyclic aromatic hydrocarbons (PAHs) are also thought to be bladder carcinogens. Given the relative homogeneity in bladder cancer histology (>95% of cancers are transitional cell carcinomas), the well-known environmental causes, and the substantial inter-individual variation in carcinogen metabolizing processes and in the repair of DNA damage caused by these compounds, bladder carcinogenesis is an excellent model for the evaluation of genetic susceptibility and gene-environment interactions.

The Spanish Bladder Cancer (SBC) study is an interdisciplinary collaborative effort between investigators at DCEG and epidemiologists and laboratory investigators at the Institut Municipal d’Investigació Mèdica (IMIM) in Barcelona, Spain. SBC is a large hospital-based case-control study with very high participation rates, high quality DNA, and detailed and innovative exposure assessment. The Spanish study combines state-of-the-art exposure assessment using a computer-assisted interview and collection of biological specimens. We intend to evaluate genetic susceptibility factors for bladder cancer and the interaction of those factors with environmental and occupational exposures.

Because of the central role of tobacco smoking in bladder carcinogenesis, we initially focused on polymorphisms in genes involved in carcinogen metabolism and DNA repair . Data from this study provided compelling evidence for the associations of N-acetyltransferase 2 (NAT2) slow acetylator and glutathione S-transferase (GSTM1) null genotype with increased risk of bladder cancer. The data also supported an interaction between smoking and NAT2 genotype, which is one of the few consistent gene-environment interactions described to date. In addition, we showed that common variants in the nucleotide excision repair pathway are likely to alter bladder cancer risk. More recently, we have evaluated data quality from a highly-multiplexed genotyping platform. We used this technology to explore associations between variants in cancer-related genes and bladder cancer. This resulted in the identification of novel genes that may be involved in bladder cancer etiology. We plan to follow-up findings from our candidate gene investigations in the recently formed International Consortium of Bladder Cancer Study. In addition, we are planning carry out a GWAS of bladder cancer in collaboration with other intramural and extramural studies.

Keywords

bladder cancer, breast cancer, endometrial and ovarian cancer, DNA collection, gene-environment interactions, genetic susceptibility, molecular epidemiology, molecular pathology

Selected Publications

• García-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW, Tardon A, Serra C, Carrato A, Garcia-Closas R, Lloreta J, Castano-Vinyals G, Yeager M, Welch R, Chanock S, Chatterjee N, Wacholder S, Samanic C, Tora M, Fernandez F, Real FX, Rothman N. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 2005;366:649-59.
• García Closas M, Malats N, Real FX, Yeager M, Welch R, Silverman D, Kogevinas M, Dosemeci M, Figueroa J, Chatterjee N, Tardón A, Serra C, Carrato A, García-Closas R, Murta-Nascimento C, Rothman N, Chanock SJ. Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk. PLoS Genet 2007;3:e29.
• Cox A, Dunning AM, García-Closas M et al. on behalf of the Breast Cancer Association Consortium for the Breast Cancer Association Consortium. A common coding variant in CASP8 is associated with breast cancer risk. Nature Genetics Published online 11 February 2007; doi:10.1038/ng1981.
• Yang XR, Sherman ME, Rimm DL, Lissowska J, Brinton LA, Peplonska B, Hewitt SM, Anderson WF, Szeszenia-Dabrowska N, Bardin-Mikolajczak A, Zatonski W, Cartun R, Mandich D, Rymkiewicz G, Ligaj M, Lukaszek S, Kordek R, García-Closas M. Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev 2007 Mar;16(3):439-43.
• García-Closas M, Brinton LA, Lissowska J, Sherman ME, Szeszenia-Dabrowska N, Peplonska B, Welch R, Yeager M, Zatonski W, Chanock SJ. Ovarian cancer risk and common variation in the sex hormone-binding globulin gene: a population-based case-control study. BMC Cancer 2007, 7:60 (5Apr2007).
• Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, Wareham N, Ahmed S, Healey CS, Bowman R, Luccarini C, Conroy D, Shah M, Munday H, Jordan C, Perkins B, West J, Redman K, Meyer KB, Haiman CA, Kolonel LK, Henderson BE, Le ML, Brennan P, Sangrajrang S, Gaborieau V, Odefrey F, Shen CY, Wu PE, Wang HC, Eccles D, Evans DG, Peto J, Fletcher O, Johnson N, Seal S, Stratton MR, Rahman N, Chenevix-Trench G, Bojesen SE, Nordestgaard BG, Axelsson CK, García-Closas M,et al.Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007;May 27 (E-pub).

Collaborators

DCEG Collaborators

• William Anderson, M.D., BB/DCEG
• Aaron Blair, Ph.D., OEEB/DCEG
• Mustafa Dosemeci, Ph.D., OEEB/DCEG
• Stephen Chanock, M.D., CGF/DCEG
• Nilanjan Chaterjee, Ph.D., BB/DCEG
• Ruth Pfeiffer, Ph.D., BB/DCEG
• Jay Lubin, Ph.D., BB/DCEG
• Nathaniel Rothman, M.D., M.Sc., OEEB/DCEG
• Sharon Savage, M.D., CGB/DCEG
• Debra Silverman, Sc.D., OEEB/DCEG
• Rose Yang, Ph.D., GEB/DCEG
• Sholom Wacholder, Ph.D., BB/DCEG.

Other NCI Collaborators

• Marc Cosentino, Ph.D. SAIC-Frederick
• Stephen Hewitt, M.D., TRAP/CCR
• Paul Meltzer, Ph.D., CMPC/CCR
• Jeffrey P. Struewing, M.D., LPG/CCR

Other Scientific Collaborators

• Douglas Easton, M.D., Ph.D., Cambridge University, UK
• Kathleen Egan, Ph.D., H. Lee Moffitt Cancer Center & Research Institute, FL
• Manolis Kogevinas, M.D., Ph.D. Municipal Institute for Medical Research, Barcelona, Spain
• Peter Laird Ph.D., University of Southern California
• Jolanta Lissowska, Ph.D., M. Slodowska-Curie Memorial Cancer Center and Institute of Oncology
• Nuria Malats, M.D., Ph.D. Municipal Institute for Medical Research, Barcelona, Spain
• Polly Newcomb, Ph.D., University of Washington
• Beata Peplonska, M.D., Nofer Institue of Occupational Medicine, Lodz, Poland
• Paul Pharaoh, M.D., Ph.D. Cambridge University, UK
• Paco Real, M.D., Ph.D. Municipal Institute for Medical Research, Barcelona, Spain
• David Rimm, M.D. Ph.D., Yale Medical School
• Frank Stanczyk, Ph.D. University of Southern California
• Neonila Szeszenia-Dabrowska, M.D., Nofer Institue of Occupational Medicine, Lodz, Poland
• Linda Titus-Ernstoff, Ph.D., Dartmouth University Witold Zatonski, M.D., Ph.D., M. Slodowska-Curie Memorial Cancer Center and Institute of Oncology