Patricia Dahia, M.D., Ph.D., Assistant Professor
University of Sao Paulo, Brazil, PhD 1994
Federal University of Paraiba, MD 1988

Department of Medicine and Cellular & Structural Biology, UTHSCSA
San Antonio Cancer Institute
(210) 567-4866
dahia@uthscsa.edu

Dr. Dahia joined the UTHSCSA faculty in August 2005 in the Department of Medicine with a joint appointment in the Department of Cellular and Structural Biology.

Research Interests:
The laboratory's main focus is the utilization of genomics-based approaches to study the genetics of cancer, to characterize interactions between oncogenic pathways, and to identify novel cancer-related genes.

We use hereditary neural crest-derived tumors, pheochromocytomas, as study models. These highly vascular, catecholamine-secreting tumors have been fundamental in providing insights into more common cancer forms and have served as engines of gene discovery for a variety of oncogenes and tumor suppressor genes. Currently the malignant potential of these tumors cannot be predicted on the basis of clinical or histological features.

In recently published studies using primary pheochromocytoma samples we found that:
1) pheochromocytomas of various genetic origins are distributed in one of two major transcriptional groups that encode unique biological signatures with high predictive value;
2) tumors with mutations in the VHL, SDHB and SDHD genes are transcriptionally linked.

The VHL tumor suppressor protein, mutated in the von Hippel-Lindau syndrome, is a key mediator of the hypoxia response via regulation of the hypoxia-inducible factor HIF1a, while SDH (succinate dehydrogenase), is an essential element of cellular energy metabolism and is both an enzyme of the tricarboxylic acid (TCA) cycle and complex II of the mitochondrial electron transport chain (ETC). The association between these distinct tumor types provides a relevant biological tool to study the molecular link between two seemingly independent pathways, namely the energy metabolism and hypoxia signals.

As follow-up to these findings, future studies will focus on:

• Dissection of the molecular basis for the interaction between hypoxia and mitochondrial energy pathways in cancer.
• Validation of biological signatures defined by cluster analysis as diagnostic and/or prognostic biomarkers in pheochromocytomas and other cancers.
• Identification of the genomic basis for the transcriptional clustering of cancers.

Another interest of the lab is the cloning of novel cancer-related genes. Using a combination of linkage, transcription profiling and genomewide SNP array mapping we recently identified a novel hereditary form of pheochromocytoma that is transmitted through a digenic recessive trait (Figure). One of our goals is to identify the two susceptibility genes involved in this trait and characterize their interaction.

Figure Legend. A novel form of familial pheochromocytoma (FP) is identified through an integrative genomics approach. A) Linkage analysis points to a digenic inheritance at chromosomes 2 and 16 in a kindred with pheochromocytoma (FP1); B) Expression profiling reveals that FP tumors overlap with MEN and NF1-type pheochromocytomas (FP/MEN/NF1 cluster), with high expression of genes involved in kinase signaling and protein translation, in contrast with other well characterized hereditary pheochromocytomas (VHL=V, SDHB=B, SDHD=D); C) FP1 tumors have loss of heterozygosity (LOH) at 2q (shown in blue), but not at the16p locus. Genotype screening of pheochromocytomas with an FP-similar transcription profiling (FP2 and sporadic cases) also share chromosome 2q LOH, indicating that they represent novel 'FP tumors'; the resulting minimal region of deletion represents the current length of the FP locus at 2q (black rectangle).

A broader goal of this research line is to apply a similar integrative genomics approach to identify novel tumor-related genes in other familial cancer syndromes. The knowledge acquired from these studies in hereditary model systems will offer insights into the biology of both familial and sporadic cancers and also serve as a platform to develop and test novel diagnostic tools and therapeutic targets for tumors.

Research Techniques:
Molecular Biology
Cellular Biology
Microarray-based Transcription Profiling
Linkage analysis
SNP-based genotyping and genomewide copy number mapping
Analysis of large-scale cancer datasets

PUBLICATIONS:
Dahia PL. (2006) Evolving concepts in pheochromocytoma and paraganglioma.Curr Opin Oncol. Jan;18(1):1-8.

Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M, Gimm O, Henley D, Herman P, Murday V, Niccoli-Sire P, Pasieka JL, Rohmer V, Tucker K, Jeunemaitre X, Marsh DJ, Plouin PF, Robinson BG. (2006) Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.J Clin Endocrinol Metab. Mar;91(3):827-36. Epub 2005 Nov 29.

Dahia PL, Hao K, Rogus J, Colin C, Pujana MA, Ross K, Magoffin D, Aronin N, Cascon A, Hayashida CY, Li C, Toledo SP, Stiles CD; Familial Pheochromocytoma Consortium. (2005) Novel pheochromocytoma susceptibility loci identified by integrative genomics.Cancer Res. Nov 1;65(21):9651-8.

Dahia PLM, Ross K, Wright ME, Hayashida CY, Santagata S, et al. (2005) A HIF1a regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 1: e8.

Sauvageot C, Dahia PL, Lipan O, Park JK, Chang MS, et al. (2005) Distinct temporal genetic signatures of neurogenic and gliogenic cues in cortical stem cell cultures. J Neurobiol 62: 121-133.