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

Mutations in epidermal growth factor receptor gene in esophageal squamous cell carcinoma patients in Kashmir: a high incidence area of India

Activating mutations in Epidermal Growth Factor Receptor [EGFR] are common in lung adenocarcinoma of never smokers but are rare in other types of cancer. Here we have analysed mutations in exons 19 to 21 of EGFR and in exons 19 and 20 of the EGFR homolog HER2 in 54 cases of Esophageal Squamous Cell Carcinomas [ESCC] from patients recruited in Kashmir, India, a region of high incidence for this cancer. We report the detection of 3 mutations [6%] in the ATP- binding regulatory loops of the tyrosine kinase domain of EGFR [deletion 746-750, p753L, G719D]. No mutation was found in HER2. This is the first report of activating EGFR mutations in ESCC, of the same type as those detected in lung adenocarcinoma of never-smokers. This suggests that a small portion of ESCC patients in this high incidence area may benefit from treatment with EGFR tyrosine kinase inhibitors

Association of Beta-catenin gene mutations and human papillomavirus in Carcinoma of Esophagus in a high-risk population of India

Background: Esophageal cancer [EC] is the sixth leading cause of death from cancer. In high-risk regions, squamous cell carcinoma is the most common type of EC, and its etiology remains poorly understood. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma [ESCC]. In the present investigation an attempt was made to study the role of -catenin mutations and human papillomavirus in 62 ESCC patients from Kashmir

Methods: The hot spot mutation region of -catenin exon 3 was evaluated in matched tumor and normal tissues using a combination of PCR-SSCP and direct sequencing. We used two different sets of consensus primers viz., GP5+ and GP6+; PGMY09 and PGMY11 in conjunction with reverse line blot assay to screen for human papillomavirus[HPV]

Results: None of the tumors showed the presence of commonly reported mutations in -catenin. In view of the fact that HPV has been linked to pathogenesis of EC, we screened all the tumor and control specimens for the presence of HPV and we didn't detect HPV in any of the matched tumor and control specimens in contrast to the positive controls we used

Conclusion: In conclusion our results suggest that squamous cell carcinoma of esophagus in Kashmir may arise independent of oncogenic Beta-catenin mutations and HPV is unlikely to be an etiologic factor for ESCC in this region

association of beta-catenin gene mutations and human papillomavirus in carcinoma of esophagus in a high-risk population of India

Esophageai cancer [EC] is the sixth leading cause of death from cancer. In high-risk regions, squamous cell carcinoma is the most common type of EC, and its etiology remains poorly understood. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma [ESCC]. In the present investigation an attempt was made to study the role of p-catenin mutations and human papillomavirus in 62 ESCC patients from Kashmir. The hot spot mutation region of p-catenin exon 3 was evaluated in matched tumor and normal tissues using a combination of PCR-SSCP and direct sequencing. We used two different sets of consensus primers viz., GP5+ and GP6+; PGMY09 and PGMY11 in conjunction with reverse line blot assay to screen for human papillomavirus [HPV]. None of the tumors showed the presence of commonly reported mutations in p-catenin. In view of the fact that HPV has been linked to pathogenesis of EC, we screened all the tumor and control specimens for the presence of HPV and we didn't detect HPV in any of the matched tumor and control specimens in contrast to the positive controls we used. In conclusion our results suggest that squamous cell carcinoma of esophagus in Kashmir may arise independent of oncogenic p-catenin mutations and HPV is unlikely to be an etiologic factor for ESCC in this region