LIFE09200604007 Tabish - Homi Bhabha National Institute

Discussion
Introduction
Squamous cell carcinomas of UADT are the most common cancers found in
India and occurrence of MPN in early stage survivors is presently one of the major
concerns. Predominant risk determinant for these cancers include exposure to
carcinogens like tobacco and alcohol, however only a fraction of exposed individuals
develop the disease suggesting the importance of interplay of intrinsic genetic
susceptibility to environmental genotoxic exposures. Since the time occurrence of MPN
in UADT cancers was discovered, numerous studies have been conducted in order to
investigate the association of genetic polymorphisms with risk of such multiple primary
cancers 10, 19, 126, 179, 190-192 .
Results from few such studies reveal association of genetic variants of
important genes like p53 and p73 with increased risk of second primary malignancies in
patients with index squamous cell carcinoma of the head and neck 190, 191, 193 . Whereas,
few other studies report involvement of polymorphisms in DNA repair genes with
approximately 2.4 fold increased risk of second primary neoplasms in UADT cancer
patients 19, 126 . Apart from this, genetic variation in carcinogen metabolising genes as
well as genes involved in cell death regulation are found to be associated with increased
risk of MPN 10, 44, 172, 179, 192 . However, all these studies have been conducted on
populations other than Indians. Previous reports from our group are the only studies
done on Indian patients with tobacco-related MPN where association of genetic
polymorphisms falling in major tobacco carcinogenesis pathways was studied with
occurrence of MPN in UADT 7, 11, 45 .
Similarly, there are studies where only phenotypic response with either
presence or absence of genotoxic exposure has been conducted in order to understand
susceptibility to MPN 194-199 . Such studies done specifically on UADT MPN cancers
reveal mutagen hypersensitivity as an indicator of genetic susceptibility to multiple
primary malignancies 198, 199 . Also, similar reports demonstrating association of altered
phenotype with occurrence of MPN in other cancers are available 194-197 . However, the
need for completely understanding the pathogenesis of UADT MPN warrants concerted
efforts focusing on developing a correlation between genotype and intermediate/
molecular phenotype, since such studies might lead to improved current understanding
of the disease perspective.
In the present study we have investigated the combined effect of multiple
genetic variations and phenotypic effects, after genotoxic exposure in vitro, in order to
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