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.
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.
Selected Publications
Ganguly A., Citron M., Godmilow L., Ahrens M., Ganguly T.: A caucasian family with two independent mutations - 2594delC in BRCA1 and 5392delAG in BRCA2 gene. Am J Med Genet 2001.
MacMullen C., Fang J., Hsu BY., Kelly A., de Lonlay-Debeney P., Saudubray JM., Ganguly A., Smith TJ., Stanley CA., The Hyperinsulinism/hyperammonemia Contributing Investigators.: Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. Journal of Clinical Endocrinology & Metabolism 86(4): 1782-7, Apr 2001.
Hsu B., Koo-McCoy S., Wang1 Z., Cederbaum S., Iacobazzi V., Palmieri F., Stanley CA., Ganguly A.: Coding sequence mutations in carnitine transporter genes, CACT and OCTN2, exert long distance effects resulting in aberrant splicing and carnitine deficiency.
Am J Hum Genet 67(282), 2000.
Citron MP, Palmer SN., Verma S., Godmilow L., Ganguly T., Ganguly A.: Molecular genotyping Of hemophilia A: experience of a clinical testing laboratory. Am J Hum Genet 67(241), 2000.
Ganguly A., Palmer S., Godmillow L., Ganguly T.: Relevance of germline mutation in CDKN2A gene in breast cancer families with associated history of melanoma. Am J Hum Genet 65: A21, 1999.
Ganguly T., Dhulipala R., Godmilow L., Ganguly A.: High throughput fluorescence-based conformation-sensitive gel electrophoresis (F-CSGE) identifies six unique BRCA2 mutations and an overall low incidence of BRCA2 mutations in high-risk BRCA1-negative breast cancer families. Human Genetics 102(5): 549-56, May 1998.
Kuivaniemi, H, Marshall A, Ganguly A, Chu ML, Abbott W and Tromp, G.: Detection of sequence variants by direct sequencing and conformation sensitive gel electrophoresis(CSGE): Fibulin 2 exhibits high degree of variability but no structural changes concordant with abdominal aortic aneurisms. European Journal of Human Genetics 6: 642-646, 1998.
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Last updated: 03/16/2009
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