Mutational and promoter hypermethylation status of FHIT gene in breast cancer patients of Kashmir.

OBJECTIVE: Fragile histidine triad (FHIT) gene located at chromosome 3p14.2 is a putative tumor suppressor gene involved in the pathogenesis of breast cancer. Both genetic and epigenetic alterations in FHIT have been implicated in breast carcinoma. In the present study, our main aim was to study the impact of these two kinds of alterations of FHIT gene in breast cancer patients of Kashmir. METHODS: We screened a total of 130 breast cancer patients of Kashmir by PCR-SSCP followed by direct sequencing and methylation specific PCR. RESULTS: Mutational screening of FHIT gene revealed significant amount of mutations [40.7% (53/130)] in five hot spot exons (exon 5-9), FHIT promoter was found to be hypermethylated in 59 of 130 [45.3%] breast cancer patients in our population. CONCLUSION: In the present study we have shown a significant association between the mutational and hypermethylation profile of FHIT gene. Hence, we provide the first evidence to our knowledge that the significant association of FHIT mutation and hypermethylation leads to the complete inactivation of FHIT gene in patients with breast cancer. Silencing of the FHIT gene by promoter hypermethylation occurs in breast carcinomas, especially those with the significant amount of mutations.

Molecular gate keepers succumb to gene aberrations in colorectal cancer in Kashmiri population, revealing a high incidence area.

BACKGROUND/AIM: Colorectal cancer (CRC) is one of the leading malignancies worldwide and has been reported to show geographical variation in its incidence, even within areas of ethnic homogeneity. The aim of this study was to identify p53 and K-ras gene mutations in CRC patients in a Kashmiri population, and to assess whether these mutations are linked with clinicopathological parameters. MATERIALS AND METHODS: Paired tumor and normal tissue samples from a consecutive series of 53 patients undergoing resective surgery for CRC were prospectively studied for p53 and K-ras gene mutations by PCR/single strand conformation polymorphism (SSCP). RESULTS: Less than half (45%, 19/42) of the patients presented mutations in the p53 gene. Twenty eight mutations were found in the p53 gene, which comprised of 23 substitutions (17 transitions + 6 transversions), and five insertions. The 23 substitutions constituted 18 missense mutations, two nonsense mutations, and three silent mutations. Of the 28 mutations (7.14%) observed in this study, 2 were not previously reported for CRC samples and were identified as novel p53 mutations. A few patients (22.64%, 12/53) presented with mutations in K-ras, constituting 13 missense mutations, out of which 11 were G-->A transitions, one was a G-->C transversion, and one a G-->T transversion. More than half (61.5%) of the mutations occurred in codon 12 whereas a few (38.5%) occurred in codon 13. One tumor contained missense mutations in both codons. Comparison of the mutation profiles of our patients with those of other ethnic populations and regions reflected both differences and similarities, indicating co-exposure to a unique set of risk factors. CONCLUSION: Mutations of the p53 and K-ras genes are some of the most common genetic changes in the development of human CRC. The high frequency of p53 gene mutations implicates p53 as a predominant factor for CRC in the high-risk ethnic Kashmiri population.