In view of conducting HPV vaccination in India it is most important to understand the prevalence of HPV genotypes in this population, not only in squamous cell carcinoma of cervix and oral cavity but also in the general population. In this study we explored the prevalence and distribution of high-risk HPV types 16 and 18 in carcinoma of cervix, saliva of patients with oral squamous cell carcinoma and in general population in Karnataka.

The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys²⁷Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys²⁷Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys²⁷Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P=0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P=0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys²⁷Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival.

The aim of the study was to observe the variation of CD4(+)CD25(+) regulatory T cells in periphery blood and tumor microenvironment of non-small cell lung cancer (NSCLC) patients and the effects of CpG ODN. The proportion of CD4(+)CD25(+) regulatory T cells, Foxp3 gene expression, levels of tumor growth factor-β (TGF-β) and immunoreactive fibronectin-γ (IFN-γ) in the periphery blood of 30 NSCLC patients and 30 healthy volunteers were compared. These indicators were compared before and after CpG ODN treatment. Foxp3 gene expression in the tumor microenvironment of NSCLC patients was also observed. The results showed CD4(+)CD25(+) regulatory T cell proportion, Foxp3 expression and TGF-β levels in the periphery blood of NSCLC patients were higher than those of healthy volunteers (p < 0.05), and these indicators of patients were significantly decreased after CpG ODN 2006 treatment (p < 0.05). Foxp3 expression in the metastatic lymph nodes was higher than that in the non-metastatic ones of NSCLC patients (p = 0.000). In conclusion, a rise in the proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells was demonstrated in the periphery blood and tumor microenvironments of NSCLC patients. CpG ODN 2006 downregulated the CD4(+)CD25(+)Foxp3(+) regulatory T cells proportion and TGF-β levels in the periphery blood of these patients.

Because chemotherapy for metastatic breast cancer (MBC) is associated with relevant toxicity, sequential monotherapy trastuzumab followed by cytotoxic therapy at disease progression might be an attractive approach.

Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened.

TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP) T309G increases MDM2 activity and may reduce wild-type p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy.

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) represents a distinct disease entity whose molecular phenotype predicts exquisite sensitivity to the reversible EGFR-tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, primary or acquired resistance to these agents remains a major clinical problem. Afatinib is a novel dual irreversible EGFR/HER2 TKI that has been shown in preclinical studies to potentially prevent, delay or overcome resistance to reversible EGFR-TKIs. On this basis, the LUX-Lung clinical trial program has been recently launched for testing this molecule in advanced NSCLC patients. Notably, early results from the randomized LUX-Lung 1 trial indicate that afatinib significantly prolongs progression-free survival compared with placebo in pretreated patients with clinically acquired resistance to gefitinib or erlotinib. On the other hand, the LUX-Lung 2 trial shows that afatinib is highly active in the EGFR-mutant subgroup of patients. While these preliminary data open a new exciting scenario for the future development of anti-EGFR therapies in NSCLC, ongoing afatinib trials will definitively establish a role for this molecule in the treatment of advanced NSCLC.

Multiple endocrine neoplasia type 2 and a subset of apparently sporadic medullary thyroid carcinoma (AS-MTC) are caused by germ line activating point mutations of the rearranged during transfection (RET) proto-oncogene. RET encodes a receptor with tyrosine kinase activity that targets several intracellular signaling cascades, such as RAS-RAF-ERK1/2, PIK3-AKT, and STAT transcription factors. The objective of this study was to assess the function of three germ line RET variants Arg886Trp, Ser649Leu, and Glu511Lys of undetermined pathogenic significance, which were found in three kindreds of isolated AS-MTC. For this purpose, we employed vectors expressing each of the RET variants and measured the number of NIH3T3 transformation foci and soft agar colonies, the degree of activation of known RET intracellular signaling targets (ERK1/2, STAT1, STAT3, and TCF4), and the extent of ERK1/2 inhibition on sorafenib treatment. We found that RET variants Arg886Trp and Glu511Lys have shown increased in vitro transforming potential in a glial-derived neurotrophic factor-dependent manner. In contrast, the Ser649Leu variant did not significantly increased the number of foci and agar colonies relative to wild-type RET (RET-WT). The variants Glu511Lys and Arg886Trp showed 10- and 12.5-fold ERK1/2 activation respectively, that was significantly higher than that observed for RET-WT (fivefold). Increased levels of STAT1 and TCF4 activation were only observed for RET Arg886Trp (2.5- and 3-fold versus 1.2- and 2-fold in RET-WT respectively). The three RET variants analyzed here were sensitive to treatment with sorafenib. In conclusion, our results allow to classify previously uncharacterized RET genotypes, which may be of use to define follow-up and therapeutic regimens.

We present the rationale and study design of the Tarceva Italian Lung Optimization trial phase III, multicenter, open-label, randomized trial on efficacy of second-line therapies in different subgroups of non-small-cell lung cancer (NSCLC) patients identified using molecular and clinical evaluations. To date, we can assume that advanced NSCLC epidermal growth factor receptor (EGFR)-mutated patients benefit from EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, whereas their role in the treatment of patients who do not have EGFR mutations is controversial. The aim of this study is to assess whether it is possible to optimize second-line treatment in NSCLC patients with absence of EGFR mutations. Moreover, the predictive value of the K-ras mutation, EGFR protein expression, and EGFR gene copy number, as well as a smoking habit and histotype for determining a different effect of erlotinib compared with chemotherapy will be assessed in patients who do not have EGFR mutations. The primary endpoint is overall survival; the secondary endpoints are progression-free survival, response rate, quality of life, and toxicity. We have planned to collect blood samples to identify different prognosis-related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and K-ras mutations with respect to histologic samples.

A prognostic index for survival was constructed and validated from patient data from two European Organisation for Research and Treatment of Cancer (EORTC) radiation trials for low-grade glioma (LGG). We sought to independently validate this prognostic index with a separate prospectively collected data set (Intergroup 86-72-51).

H2AFX, a histone H2A gene family member X, is a key component in the detection of and response to DNA double-strand breaks (DSBs) caused by ionizing radiation (IR), a known risk factor for glioma. Thus, genetic variants in the H2AFX promoter region that may result in abnormal protein expression could confer susceptibility to glioma. In this case-control study, we genotyped three common single-nucleotide polymorphisms (SNPs) (rs643788, rs8551, and rs2509851) in the H2AFX promoter region in 669 adult glioma patients and 638 cancer-free controls. The associations between each SNP or haplotype and glioma risk were estimated by calculating odds ratios (ORs) and the corresponding 95% confidence interval (CI) using unconditional logistic regression models, with adjustment for age and sex. The H2AFX rs643788 A variant genotypes were significantly associated with reduced risk of glioma (GA versus GG: adjusted OR = 0.72, 95% CI = 0.56-0.94; GA/AA versus GG: adjusted OR = 0.75, 95% CI = 0.59-0.94), compared with the common GG genotype. Furthermore, this decreased risk was more evident among those aged ≥ 45 years (adjusted OR = 0.64, 95% CI = 0.45-0.90), male subjects (adjusted OR = 0.70, 95% CI = 0.50-0.96), and patients with glioblastoma (adjusted OR = 0.66, 95% CI = 0.46-0.94). These results suggest that a common variant in the H2AFX promoter region may modulate risk of glioma, particularly for adult glioma. However, our findings need to be replicated in other independent populations.

The response of colorectal tumours to chemotherapy is highly variable. Preclinical work has shown that the Kirsten ras (KRAS) oncogene sensitizes colorectal tumour cells to oxaliplatin and capecitabine in a wild-type tumour suppressor p53 (TP53)-dependent manner. Therefore, whether or not the combined mutation status of KRAS and TP53 could predict response to chemotherapy in metastatic colorectal cancer was tested.

The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken.

Optimizing treatment through microarray-based molecular subtyping is a promising method to address the problem of heterogeneity in breast cancer; however, current application is restricted to prediction of distant recurrence risk. This study investigated whether breast cancer molecular subtyping according to its global intrinsic biology could be used for treatment customization.

TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial.

Killer cell immunoglobulin-like receptors (KIRs) contribute to the pathogenesis of diverse kind of diseases. Previous studies have shown associations between KIR genes, their ligands and either protection or susceptibility to leukemias or virally associated solid tumors. However, the possible roles of KIR gene polymorphisms in the development of breast cancer remain largely unknown. To investigate the association of KIR gene polymorphisms with breast cancer, we carried out the present study on 33 breast cancer patients and 77 healthy controls by means of sequence-specific oligonucleotide probes analysis, and then all data were statistically analyzed by Fisher exact test. Our results showed that the frame genes KIR2DL4, 3DL2, 3DL3, and 3DP1 were found in all patients and all controls. The rate of activating KIR2DS1 was much higher in patients with breast cancer than that in healthy controls (P = 0.032) while the allelic types of activating 2DS4 (2DS4 003/4/6/7) were lower in patients with breast cancer compared with healthy controls (P = 0.028). Additionally, there was a statistically significant negative correlation between 2DL1 genes and breast cancer development (P = 0.025). In conclusion, this study suggests that the activating KIR2DS1 may trigger breast cancer development, while 2DL1 gene and 2DS4 003/4/6/7 alleles are possibly protectors for breast cancer.

Of the 200,000 U.S. men annually diagnosed with prostate cancer, approximately 20% to 30% will have clinically aggressive disease. Although factors such as Gleason score and tumor stage are used to assess prognosis, there are no biomarkers to identify men at greater risk for developing aggressive prostate cancer. We therefore undertook a search for genetic variants associated with risk of more aggressive disease.

Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide, and is the second leading cause of cancer death in Taiwan. E-cadherin is an epithelial cell adhesion molecule, and decreased E-cadherin expression in HCC is associated with a poor prognosis. This study investigates the effects of single nucleotide polymorphisms (SNPs) in the E-cadherin/CDH1 gene promoter on the risk and clinicopathological characteristics of HCC METHODS: 131 HCC patients and 347 controls were recruited for this study. Genetic polymorphisms of CDH1-160 and -347 were analyzed by PCR-RFLP genotyping analysis.

Background Allogeneic hematopoietic cell transplantation is considered the preferred post-remission therapy in patients with acute myeloid leukemia cytogenetically defined as being at high risk. To substantiate evidence for allogeneic hematopoietic cell transplantation in first complete remission in these high-risk patients we performed a landmark analysis within a single prospective multicenter treatment trial.

A single nucleotide polymorphism 61*G (rs4444903) in the epidermal growth factor (EGF) gene has been associated, in 2 case-control studies, with hepatocellular carcinoma (HCC). We tested associations between demographic, clinical, and genetic data and development of HCC, and developed a simple predictive model in a cohort of patients with chronic hepatitis C and advanced fibrosis.