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Chromosome fragile sites and genome instability

Research Scholar

Seyed Ali Hosseini, Molecular Virology, Immunology and Medical Genetics (Iran)
Kay Huebner, Faculty Mentor

Biography

Seyed Ali Hosseini holds an MD from Bandar Abbas University of Medical Sciences, Iran (2002) and a PhD in Molecular Medical Genetics from Panjab University, India (2009). He joined the National Institute of Genetic Engineering and Biotechnology in Iran and served as an assistant professor in the Department of Genetic Disease, as well as chief of Medical Genetics Clinic, from 2009-2011. He is a member of the American Society of Human Genetics and American Association of Cancer Research. Hosseini has received a Junior Research Fellowship award in science from India and a Young Scientist award from Iran's Ministry of Science. Last year, he was elected for a postdoctoral Pelotonia Fellowship.

What is the issue or problem addressed in your research?

Common fragile sites are regions that show elevated susceptibility to DNA damage, leading to alterations that can contribute to cancer development. FRA3B, located at chromosome region 3p14.2, is the most frequently expressed human common fragile site in lymphoblast cells; however common fragile sites have not yet been mapped in epithelial cells. Knowledge of common fragile site expression in epithelial cells is important, as allelic losses at FRA3B have been observed in many types of cancer of epithelial origin.

What methodology did you use in your research?

Currently, we are mapping chromosome fragile sites in epithelial cells derived from breast and kidney tissue to determine if these are indeed the sites that are most frequently broken or mutated in cancer cells of epithelial organs from which most human cancers derive. Knowledge of the most fragile chromosome regions of epithelial cells will help us to understand the earliest genetic changes that occur in normal cells on the path to cancer development, so that we may eventually develop methods to prevent those changes. Additional work has focused on the role of Fhit protein on chromosome stability. The FHIT gene, encompassing the FRA3B region, is a tumor-suppressor gene; thus alterations at FRA3B can lead to loss of Fhit expression and promote tumorigenesis. We investigated chromosome instability in epithelial cells deficient for Fhit expression compared to Fhit-expressing cells. We observed increased aneuploidy, sister chromatid exchanges, chromosome breaks and gaps in Fhit-deficient cells.

What are the purpose/rationale and implications of your research?

We conclude that loss of Fhit expression in precancerous lesions, due to FRA3B fragility, can initiate chromosome and genome instability, a hallmark of cancer, early in the carcinogenic process.