Description of Research Expertise

Genetic Analysis of Predisposition to Retinoblastoma and Uveal Melanoma

Retinoblastoma is a childhood onset ocular cancer caused by mutations in tumor suppressor gene, RB1, present on chromosome 13.
RB1 was the first tumor suppressor gene identified and validated the two hit hypothesis of cancer proposed by Alfred Knudson. The burden of lost eye sight in early childhood is very high with this disease – it has been reduced remarkably in the developed countries, but still is a major concern in developing countries.
Thus there is a need to reduce the burden of blindness by developing treatment modality that will spare the infant eye and vision.

An interesting aspect of RB1 is that this gene is inactivated in half of all known cancer. Yet an individual born with a germline mutation in RB1 gene is predisposed to childhood onset eye tumor and a second cancer that can be osteosarcoma if exposed to radiation or melanoma. This means that the RB1 gene product has a very specific role in the development of the retina – a role that is not shared by other tissues.
However the cell of origin of retinoblastoma is not known. Therefore by studying the gene expression profile of enucleated retinoblastoma tumors we are attempting to answer a few clinical questions like the clinical response to different treatment options, potential for metastasis and molecular basis of other predictive clinical features. In addition we are trying to identify the expression profiles of genes characteristic of the progenitor cells for retina and define at which stage of retinal cell development does the process of tumorigenesis begin.


Another recent direction of research is in defining the molecular basis of uveal melanoma. Uveal melanoma is a rare form of ocular cancer in the Western world and the incidence rate is 1 in 100, 000. A significant observation is that almost half of all identified cases of uveal melanoma develop liver metastasis and die within a very short period after the initial diagnosis. Thus it is a major health care issue. The only prognostic features available at this time are monosomy for chromosome 3 along with alterations on chromosomes 1, 6 and 8 and are associated with bad prognosis. These features suggest an underlying genetic predisposition towards melanomas. Uveal melanoma can be mistaken for congenital nevi and may be undiagnosed or under diagnosed. The goals of this project are: i) To develop a gene signature that will be predictors of metastasis based on investigations on fine needle aspirates. ii) To understand the molecular mechanisms regulating the development of uveal melanomas.

Description of Clinical Expertise

As the co-director of the Genetic Diagnostic laboratory, Department of Genetics, I provide clinical molecular genetic testing services for hereditary forms of colon cancer, Li Fraumeni syndrome,Retinoblastoma(RB) and molecular profiling of sporadic uveal mealnoma, Hemophilia A, and Herediatry Hemorrhagic Telangiectasia (HHT or Osler Weber Rendu Syndrome). This laboratory is a reference laboratory for testing RB, HHT and Hemophilia A in the US.
This laboratory is also an ABMG accredited laboratory for training clinical molecular genetics fellows.

In addition, I am involved in a collaboration with Dr, Charles Stanley, Children's Hospital of Philadelphia, to undertsand the molecular genetics of congenital hyperinsulinism (CHI). We have recently identified a novel genomic region linked to autosomal dominant inheritance of CHI.