The University of Texas MD Anderson Cancer Center
Department of Epigenetics and Molecular Carcinogenesis
My laboratory has a long-standing interest in human genetics and cancer genomics. Over the years, my lab has focused on identifying and elucidating the role of key abnormalities that affect the genome of normal and premalignant cells towards cancer development and evolution. We were among the earliest to utilize high throughput sequencing approaches (serial analysis of gene expression) for functional genomics studies. We performed comprehensive studies for characterizing the genome, transcriptome and methylome of breast ductal carcinoma in situ (DCIS) lesions identifying key driver mutations, epigenetic changes and gene expression alterations that occur at pre-invasive stages of breast cancer progression. Among other studies, my lab was the first to clone and characterize a putative tumor suppressor gene which we named WWOX (WW domain-containing oxidoreductase), target of chromosomal fragile site 16D (FRA16D). WWOX is one of the largest human genes and FRA16D is the second most common site in the human genome for spontaneous chromosomal breakage and rearrangement. Germline and somatic copy number variation affecting the WWOX locus are common and intimately linked to an array of diverse human pathologies. My laboratory has published extensively on WWOX’s role in multiple diseases from cancer, metabolic conditions to CNS pathology. We have generated various molecular biology tools and reagents including valuable genetically engineered mouse models to analyze the effects of targeted Wwox ablation in tissues of relevance and knock-in mutations not only to understand the role of WWOX in cancer but now in rapidly emerging new fields of various pathologies associated with WWOX. Recently we and others have discovered that germline WWOX loss-of-function mutations are causally linked to various complex neurodevelopmental disorders including spinocerebellar ataxia, autosomal recessive type 12 (SCAR12, MIM #614322), developmental and epileptic encephalopathy 28 (DEE28, MIM#616211), developmental delay, intellectual disability and autism spectrum disorders. Importantly, WWOX has been recently identified as a novel risk gene for Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Thus, the spectrum of complex brain disorders associated with WWOX is broad and heterogeneous, and there is little understanding of the potential mechanisms at play. We are currently aiming to understand how WWOX loss-of-function is mechanistically related to disruption of excitatory/inhibitory neuronal homeostasis in the neocortex and cerebellum.
Education & Training
MD, University of Buenos Aires Medical School, 1980
PhD, University of Buenos Aires Medical School, 1983
Breast Cancer Genomics