Esophageal cancer in Kashmir [India]: an enigma for researchers

About 90% of esophageal cancers worldwide are Squamous Cell Carcinomas [SCC], mostly occurring in defined high-incidence areas of low and middle-resource countries. Historically, the highest incidences are reported in regions of Central Asia. One such region is Kashmir Valley in Northern India. In this review, we summarize a large body of epidemiological, toxicological and observational information on occurrence, dietary patterns and lifestyles to discuss factors that may be involved in the etiology of SCC in Kashmir Valley. To date, no single factor can be identified as the main cause of the excess incidence of SCC as compared to other regions of India. Three main components emerge as important factors: a societal component with poor, rural lifestyle and general deprivation, status in particular in vitamins and oligoelements; a lifestyle component with the use of copper utensil in cooking, the consumption of spicy, deep fried foodstuffs, and the drinking of hot salty tea; and an environmental component with exposure to high levels of dietary nitrosamines from diverse sources. Overall, these three components are similar to the general pattern of factors that have been involved in causing SCC in other high-incidence area in the so-called "esophageal cancer belt", namely in central China [Cixian, Lixian] and in Northern Iran [Golestan]. Further comparative studies between these regions are needed to identify the contributions of these various components

Combined impact of polymorphism of folate metabolism genes; glutamate carboxypeptidase, methylene tetrahydrofolate reductase and methionine synthase reductase on breast cancer susceptibility in Kashmiri women

Folate and methionine play a crucial role in DNA synthesis, repair and the epigenetic profile of cell. Hence, the alterations in the folate metabolism can lead to aberrant proliferation leading to neoplasia. Most of the studies have associated polymorphisms in methylene tetrahydrofolate reductase [MTHFR] and methionine synthase reductase [MTRR] genes with reduced risk of cervical and colorectal cancer. However, the association with breast cancer is still controversial. Further, the ivolvement of Glutamate carboxypeptidase II [GCPII] polymorphism in cancer is not known. In the present study, we analyzed if the individual and combined effects of polymorphisms in folate pathway genes viz., MTHFR 677C> T, MTHFR 1298A> C, MTRR 66A> G and GCP II 1561 C>T, have any role in altering the susceptibility to breast cancer. The DNA of 35 female breast cancer patients and 33 healthy individuals, in the Kashmiri population from India, were analyzed using a PCR-RFLP approach for the above mentioned polymorphisms. Individuals carrying the MTHFR 677CT/TT and GCPII 1561 CT genotype showed a 3.5 [95% CI: 3.1-3.7, P<0.02] and 7.7 [95% CI: 6.7-9.1, P<0.001] fold decreased risk for breast cancer than the wild types [MTHFR 677CC and GCPII 1561 CC]. Subjects with MTRR 66 G-allele showed a 4.5 fold decreased risk [OR: 0.22, 95% CI: 0.20, 0.24, P<0.0005] compared to the wild type [MTRR 66A]. Further, subjects with combined polymorphisms in MTHFR, GCPII and MTRR loci revealed a significant reduction of breast cancer risk. This study indicates [i] a protective role of polymorphisms in MTHFR, GCPII, MTRR against breast cancer in the study subjects, and [ii] combined effect of polymorphisms is more pronounced than single genetic polymorphism, thereby emphasizing the role of gene-gene interaction in the susceptibility to breast cancer