Significant Effect of Anti-tyrosine Kinase Inhibitor (Gefitinib) on Overall Survival of the Glioblastoma Multiforme Patients in the Backdrop of Mutational Status of Epidermal Growth Factor Receptor and PTEN Genes.

INTRODUCTION: We aimed to assess the effect of anti-tyrosine kinase inhibitors (TKIs) (gefitinib) in overall survival (OS) of the glioblastoma multiforme (GBM) patients in the backdrop of mutational status of epidermal growth factor receptor (EGFR) and PTEN genes. MATERIALS AND METHODS: All the patients subjected to resection or biopsies were put on gefitinib, and radiotherapy was delivered as per the hospital protocol. EGFR and PTEN mutational spectrum was performed by single-strand conformation polymorphism followed by DNA sequencing. RESULTS: In total, 50% GBM tumors had mutation either in EGFR or PTEN. Median progression-free survival (PFS) and OS observed in patients with EGFR +ve/PTEN -ve were significantly favorable (P < 0.05) which aggregated to 9(7, 11) months and 20 (16, 24) months, respectively, than 6 (4, 8) months and 13 (7, 19) months in patients with PTEN +ve/EGFR -ve. Patients positive for both EGFR/PTEN had lower disease-free survival and OS of 6 and 9 months as compared to 6 (5, 7) and 14 (12, 24) months for those negative for both EGFR/PTEN. CONCLUSIONS: We conclude that EGFR gene alterations with wild-type PTEN are associated with significantly better PFS and OS in patients treated with anti-TKIs (gefitinib). Combined EGFR and PTEN gene mutation is associated with significantly poor response to gefitinib in terms of median OS.

GSTP1 gene Ile105Val polymorphism causes an elevated risk for bladder carcinogenesis in smokers.

BACKGROUND: The glutathione S transferase (GST) family of enzymes plays a vital role in the phase II biotransformation of environmental carcinogens, pollutants, drugs and other xenobiotics. GSTs are polymorphic and polymorphisms in GST genes have been associated with cancer susceptibility and prognosis. GSTP1 is associated with risk of various cancers including bladder cancer. A case control study was conducted to determine the genotype distribution of GSTP1 A>G SNP, to elucidate the possible role of this SNP as a risk factor in urinary bladder cancer (UBC) development and to examine its correlation with clinico-pathologic variables inUBC cases. MATERIALS AND METHODS: Using the polymerase chain reaction-restriction fragment length polymorphism (PCR- RFLP) approach, we tested the genotype distribution of 180 bladder cancer patients in comparison with 210 cancer-free controls from the same geographical region with matched frequency in age and gender. RESULTS: We did not observe significant genotype differences between the control and bladder cancer patients overall with an odds ratio (OR)=1.23 (p>0.05). The rare allele (AG+GG) was found to be present more in cases (28.3%) than in controls (24%), though the association was not significant (p<0.05). However, a significant risk of more than 2-fold was found for the variant allele (AG+GG) with smokers in cases as compared to controls (p>0.05). CONCLUSIONS: Thus, it is evident from our study that GSTP1 SNP is not implicated overall in bladder cancer, but that the rare, valine-related allele is connected with higher susceptibility to bladder cancer in smokers and also males.

The XRCC1 Arg399Gln gene polymorphism and risk of colorectal cancer: a study in Kashmir.

BACKGROUND: The DNA repair gene XRCC1 Arg399Gln gene polymorphism has been found to be implicated in the development of various cancers, including colorectal cancer (CRC), in different populations. We aimed to determine any association of this polymorphism with the risk of CRC in Kashmir. MATERIALS AND METHODS: A total of 120 confirmed cases of CRC and 146 healthy cancer free controls from the Kashmiri population were included in this study. Genotyping was carried out by the polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Genotype frequencies of XRCC1 Arg399Gln observed in controls were 34.2%, 42.5% and 23.3% for GG (Arg/Arg), GA (Arg/Gln), AA( Gln/Gln), respectively, and 28.3%, 66.7% and 5% in cases, with an odds ratio (OR)=5.7 and 95% confidence interval (CI) =2.3-14.1 (p=0.0001). No significant association of Arg399Gln SNP with any clinicopathological parameters of CRC was found. CONCLUSIONS: We found the protective role of 399Gln allele against risk to the development of CRC. The XRCC1 heterozygote status appears to be a strong risk factor for CRC development in the Kashmiri population.

Lack of p16 gene mutations in gastric cancers in Kashmir.

BACKGROUND AND AIM: The focus of the study was to investigate the frequencies of homozygous deletions and mutations of p16 gene in gastric carcinomas in the Kashmiri population. METHODS: A total of 84 gastric carcinoma patients were screened by the single strand conformation polymorphism (SSCP) technique and later by DNA sequencing to detect mutations of the p16 gene. Also PCR was applied further to further detect any homozygous deletions. RESULTS: SSCP and DNA sequencing performed encompassing all the three exons of p16 gene could not detect any mutations in any ofl 84 cases. Though we could observe mobility shifts in SSCP of two samples, subsequent DNA sequencing did not show any mutation. Further PCR could not detect any homozygous deletion in P16 in any case. CONCLUSION: Though Kashmir is a high incidence area of gastric carcinomas, p16gene mutations /or deletions do not appear to be involved.

Activated H-ras gene mutations in transitional cell carcinoma of urinary bladder in a Kashmiri population.

AIMS AND BACKGROUND: The primary aim of the study was to evaluate the incidence of H-ras specific point mutations among a group of Kashmiri patients diagnosed with bladder cancer. We also explored the correlation of clinic-pathological status of the illness with these mutations. METHODS AND STUDY DESIGN: The DNA samples of both tumor and normal tissue were evaluated for the occurrence of H-ras activating mutations in exon 1 and 2 by PCR-SCCP and DNA sequencing. In addition, blood was also collected from all the cases to rule out any germ-line mutation. RESULTS: Point mutations of activated H-ras identified in bladder cancer patients were 14.5% (7 of 48), including four transversions (two G-->T and two A-->T) and three transitions (A-->G). Of the mutations, 71.4% were detected in codon 61 and 28.6% in codon 12. The pattern of mutation in the study showed a significant association with smoking in bladder tumors (P < 0.05). No correlation was found between tumor grade and/or stage and the presence of H-ras mutation. CONCLUSIONS: Activation of H-ras by mutation plays a less frequent role than other genetic events in the development of the most transitional cell tumors of the bladder in Kashmiri population.