Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: CCDC26 (cancer-related)
González-Castro TB, Juárez-Rojop IE, López-Narváez ML, et al.Genetic Polymorphisms of CCDC26 rs891835, rs6470745, and rs55705857 in Glioma Risk: A Systematic Review and Meta-analysis.
Biochem Genet. 2019; 57(4):583-605 [PubMed
] Related Publications
A genetic component is accepted in the etiology of the glioma. Evidence from candidate genes studies and GWAS reveal that CCDC26 gene could increase the risk of glioma. We performed a systematic review and up-to-date meta-analysis to explore if polymorphisms of CCDC26 gene (rs891835, rs6470745, and rs55705857) may be a susceptibility factor in developing glioma. An online search in PubMed, Web of Science, and SCOPUS up to September 2018 was performed. The pooled odds ratios were evaluated by fixed effects model and random effects model. Analyses of the overall sample and ethnic sub-groups were performed. In all the analyses, the allelic, additive, dominant, and recessive models were used. We found an association between all polymorphisms evaluated and an increased risk for glioma in the overall population in all the models studied. In sub-group analysis, we found that rs891835 and rs6470745 increased the risk of glioma in Europeans and Caucasians. On the other hand, the rs891835 polymorphism did not reveal any statistical association in Chinese population. Taken into consideration the limitations of this study, the present findings suggest a possible participation of rs891835, rs6470745, and rs55705857 as risk factors to develop glioma. Furthermore, it is possible that the involvement of CCDC26 variants depends on ethnicity. However, we recommend to perform further studies to have conclusive outcomes.
Shukla S, Pandey RK, Kant S, et al.Detection of Anaplastic Lymphoma Kinase Gene Re-Arrangement in Non-Small Cell Lung Carcinoma in the Indian Population: Comparison of Techniques and Immunohistochemistry Clones.
Turk Patoloji Derg. 2019; 35(1):36-45 [PubMed
] Related Publications
OBJECTIVE: Predictive and prognostic markers have revolutionized personalized therapy in non-small cell lung carcinoma (NSCLC). Crizotinib is now approved for locally advanced or metastatic NSCLC that is anaplastic lymphoma kinase (ALK) positive by either Fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC). The current study aimed to detect the incidence of ALK gene re-arrangement in the Indian population, to compare the various IHC antibodies with FISH as a gold standard, and to analyze the morphology of cases with ALK phenotype.
MATERIAL AND METHOD: A case series of 614 cases of NSCLC were included. IHC for detection of ALK phenotype was compared with FISH using 5A4 clone (Labvision, USA), ALK-1(Dako, Denmark) and D5F3 clone (Ventana, USA).
RESULTS: ALK gene rearrangement was evident in 4.07% of the cases. Cases with ALK phenotype had unique histomorphology with presence of mucin or signet ring cells in association with necrosis, high tumour grade and poor differentiation. Comparison of various antibody clones used in IHC revealed that the sensitivity and specificity using the D5F3 clone (100%, 100%) and 5A4 clone (87.5%, 100%) were similar while the ALK-1 clone had the lowest sensitivity and specificity (50%, 95.5%).
CONCLUSION: The incidence of ALK gene rearrangement in NSCLC in the current Indian study is within the worldwide reported range of 3-5%. This is the first study from the Indian subcontinent to compare various IHC antibodies used for detection of ALK phenotype. IHC using D5F3 clone and 5A4 clone may be considered as a rapid reliable and inexpensive method for detection of ALK gene rearrangement.
A small subpopulation of cancer stem-like cells (CSCs) present in almost all tumors is responsible for drug resistance and tumor recurrence. The role of NF-kB and miRNA in close association with essential risk factors, tobacco, alcohol and high risk HPV infection during oral carcinogenesis and its prognosis is not well understood. We have isolated cancer stem like SP cells from both HPV+/-ve oral squamous cell carcinoma (OSCC) cell lines and primary tumors, which formed orospheres, expressed stemness markers Oct4, Sox-2, CD133 and CD117. These cells showed differentially upregulated expression of NF-kB proteins and selective overexpression of viral oncogenes E6/E7 only in HPV16+ve cells which formed higher number of orospheres, overexpressed c-Rel and selectively activated p65 that heterodimerized with p50 to show higher DNA binding activity. Further, selective over expression of miR-21 and miR-155 and downregulation of miR-34a were demonstrated by HPV+ve CSCs which overexpress HPV16 oncogene E6 that is responsible for the maintenance of stemness. While, HPV-ve CSCs show exclusively p50 homodimeriztion, poor differentiation and worst prognosis, HPV infection induced participation of p65 along with deregulated expression of specific miRNAs led to well differentiation of tumors and better prognosis.
Jensen MB, Lænkholm AV, Nielsen TO, et al.The Prosigna gene expression assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer.
Breast Cancer Res. 2018; 20(1):79 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: The PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer.
METHODS: Prosigna assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF).
RESULTS: In total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P < 0.001 for disease-free survival (DFS), P = 0.001 for overall survival (OS)). No statistically significant interaction of continuous ROR score and treatment on DFS and OS was found. A highly significant association was observed between intrinsic subtypes and C/CMF treatment for DFS (P
CONCLUSION: The Prosigna ROR score and intrinsic subtypes were prognostic in high-risk premenopausal patients with breast cancer, and intrinsic subtypes identify high-risk patients with or without major benefit from adjuvant C/CMF treatment.
The standard treatment for high-grade serous ovarian cancer is primary debulking surgery followed by chemotherapy. The extent of metastasis and invasive potential of lesions can influence the outcome of these primary surgeries. Here, we explored the underlying mechanisms that could increase metastatic potential in ovarian cancer. We discovered that FABP4 (fatty acid binding protein) can substantially increase the metastatic potential of cancer cells. We also found that miR-409-3p regulates FABP4 in ovarian cancer cells and that hypoxia decreases miR-409-3p levels. Treatment with DOPC nanoliposomes containing either miR-409-3p mimic or FABP4 siRNA inhibited tumor progression in mouse models. With RPPA and metabolite arrays, we found that FABP4 regulates pathways associated with metastasis and affects metabolic pathways in ovarian cancer cells. Collectively, these findings demonstrate that FABP4 is functionally responsible for aggressive patterns of disease that likely contribute to poor prognosis in ovarian cancer.
Background: Incidence of Chronic Myeloid Leukemia (CML) is continuously increasing and expected to reach 100,000 patients every year by 2030. Though the discovery of Imatinib Mesylate (IM) has brought a paradigm shift in CML treatment, 20% patients show resistance to this tyrosine kinase inhibiter (TKI). Therefore, it is important to identify markers, which can predict the occurrence and prognosis of CML. Clinical Exome Sequencing, panel of more than 4800 genes, was performed in CML patients to identify prognostic and susceptibility markers in CML.
Methods: Enrolled CML patients (n=18) were segregated as IM responders (n=10) and IM failures (n=8) as per European Leukemia Net (ELN), 2013 guidelines. Healthy controls (n=5) were also enrolled. DNA from blood of subjects was subjected to Next Generation Sequencing. Rare mutations present in one patient group and absent in another group were considered as prognostic markers, whereas mutations present in more than 50% patients were considered as susceptibility markers.
Result: Mutations in genes associated with cancer related functions were found in different patient groups. Four variants: rs116201358, rs4014596, rs52897880 and rs2274329 in C8A, UNC93B1, APOH and CA6 genes, respectively, were present in IM responders; whereas rs4945 in MFGE8 was present in IM failures. Mutations in HLA-DRB1 (rs17878951), HLA-DRB5 (rs137863146), RPHN2 (rs193179333), CYP2F1 (rs116958555), KCNJ12 (rs76684759) and FUT3 (rs151218854) were present as susceptibility markers.
Conclusion: The potential genetic markers discovered in this study can help in predicting response to IM as frontline therapy. Susceptibility markers may also be used as panel for individuals prone to have CML.
Nanda SS, Gandhi AK, Rastogi M, et al.Evaluation of XRCC1 Gene Polymorphism as a Biomarker in Head and Neck Cancer Patients Undergoing Chemoradiation Therapy.
Int J Radiat Oncol Biol Phys. 2018; 101(3):593-601 [PubMed
] Related Publications
PURPOSE: We evaluated the correlation of the x-ray repair cross complementing gene 1 (XRCC1) Arg194Trp polymorphism with clinical outcomes in head and neck squamous cell carcinoma (HNSCC) patients treated with concurrent chemoradiation therapy (CCRT).
METHODS AND MATERIALS: In this prospective cohort study, we included 101 patients with HNSCC (oral cavity, pharynx, and larynx) who were aged ≥ 18 years, had stage III to IVB disease, had a Karnofsky Performance Status ≥ 80, and were deemed fit for CCRT. DNA extraction was done through polymerase chain reaction, and the genotypes of XRCC1 polymorphism were detected using designed restriction fragment length polymorphism. The genetic polymorphisms were classified into wild and polymorphic variants (Arg194Trp CT and TT). Radiation therapy was delivered with conventional parallel opposed lateral and low anterior neck fields with concurrent weekly cisplatin, 35 mg/m
RESULTS: Of the patients, 62 had the wild type and 39 had polymorphic variants. Patients with polymorphic variants had higher rates of grade > 2 oral mucositis, with 35.8% versus 16.0% (odds ratio [OR], 2.91; 95% confidence interval [CI], 1.13-7.46; P = .023); dermatitis, with 30.7% versus 8.0% (OR, 5.076; 95% CI, 1.62-15.8; P = .003); and laryngeal toxicity, with 25.6% versus 6.4% (OR, 5; 95% CI, 1.44-17.54; P = .006). Complete response rates in polymorphic versus wild variants were 76.9% versus 56.0% (P = .209). At a median follow-up of 21 months, the 2-year PFS and overall survival rates for patients with polymorphic versus wild variants were 57.0% versus 42.2% (P = .077) and 73.0% versus 55.5% (P = .143), respectively.
CONCLUSIONS: Polymorphic variant XRCC1 HNSCC patients treated with CCRT have significantly increased acute radiation morbidities and may have a trend toward better PFS in comparison with the wild variant.
Background: Radiation causes oxidative lesions and strand breaks in DNA of exposed cells. Extended length
PCR is a reliable method for assessing DNA damage. Longer DNA strands with DNA damage are difficult to amplify
compared to smaller DNA strands by PCR. The present study was aimed to evaluate DNA damage caused by ionising
radiation exposure in therapeutic and diagnostic medicine. Materials and Methods: The study group comprised 50
cases with low dose single exposure (LDS), low dose multiple exposure (LDM) and low dose angiography (LDA)
which were compared with 25 high dose controls (HDC) and 25 controls with no exposure (NEC). Blood samples were
collected within 1 hour of radiation exposure. DNA was isolated using a kit based protocol, 50 ng aliquots of DNA
were used to amplify a long 13kbp DNA fragment of the β-actin gene by conventional PCR and band intensity was
then quantified. Relative amplification was calculated and damage was expressed in terms of lesions per kilobase (kbp)
by assuming a Poisson distribution. Result: Relative amplification was found to be 1.0, 0.87, 0.86, 0.72 and 0.69 with
NEC, LDS, LDM, LDA and HDC groups, respectively. Cases undergoing angiography as well as high dose controls
had high values, compared to NEC. The lesions/kbp calculated for LDS was 0.13, for LDM 0.15, for LDA 0.32 and
for HDC 0.37 suggesting a linear increase in quantity with increasing radiation dose. Conclusion: DNA damage, even
at low doses of radiation can be assessed by quantitative extra long PCR.
Mishra S, Husain N, Awasthi NP, et al.Liquid-based cytology: do ancillary techniques enhance detection of epithelial abnormalities?
Arch Gynecol Obstet. 2018; 298(1):159-169 [PubMed
] Related Publications
PURPOSE: Cervical cancer is the fourth most common cancer in women worldwide with very high incidence in India. Liquid-based cytology (LBC) provides the use of ancillary techniques in addition to a good morphology and detection of cytologic abnormalities. The current study was designed to assess the diagnostics of P16INK4a immunoexpression, p16 promoter hypermethylation, human papilloma virus (HPV), and DNA ploidy in LBC samples with cervical precancer and cancer.
METHODS: A series of LBC samples categorised by Bethesda system including 22 atypical squamous cells of undetermined significance (ASC-US), 21 low-grade squamous intraepithelial lesion (LSIL), 41 high-grade squamous intraepithelial lesion (HSIL), 54 squamous cell carcinoma (SCC), and 26 controls with normal cytology were included. Ancillary techniques evaluated included P16INK4a immunoexpression, p16 promoter methylation DNA ploidy by flow cytometry, and HPV was detected using PGMY09/PGMY11 primers.
RESULTS: The test positivity rate of p16 expression in women with ASC-US, LSIL, HSIL, and SCC was 21.1, 39.0, 67.7, and 85.4%. For the p16 methylation the corresponding test positivity rate was 36.4, 76.2, 92.7, and 92.6%. The test positive rate of HPV in women with ASC-US, LSIL, HSIL, and SCC was 45.5, 76.2, 87.8, and 92.6%. Diploid G1 and diploid S values significantly (p < 0.05 or p < 0.01) discriminate LSIL versus HSIL and LSIL versus. SCC.
CONCLUSIONS: P16 gene promoter methylation and HPV seem more sensitive in detection of ASC-US and LSIL cytology with higher specificity. Diploid G1 and diploid S phase study provides progressive change in parameters with progression from LSIL to HSIL and SCC.
Prasad J, Goswami B, Gowda SH, et al.Does Hypoxia-Inducible Factor -1 α (HIF-1α) C1772T polymorphism predict short-term prognosis in patients with oral squamous cell carcinoma (OSCC)?
J Oral Pathol Med. 2018; 47(7):660-664 [PubMed
] Related Publications
BACKGROUND: Oral squamous cell carcinoma (OSCC) is a cancer of the oral cavity that is a major health problem in India. There is an urgent need to identify biomarkers that have prognostic significance. We studied HIF-1α levels as well as single-nucleotide polymorphism of HIF-1α gene in cancer and healthy controls.
METHODS: Fifty newly diagnosed OSCC patients and 50 age and sex-matched healthy control were included in the study. Serum concentrations of HIF-1α were measured by sandwich ELISA; whereas HIF-1α gene polymorphism study was performed using restriction enzyme digestion by HpH I.
RESULTS: The major genotype observed was CC genotype in both control (84%) and patients (86%) followed by CT genotype (control 16%, cases 14%). CT genotype led to more aggressive tumors. On subgroup analysis based on prognosis, the median overall survival of patients who were treatment responders was 488 days (16.2 months) and that of the patients with progressive disease was 365 days (12.1 months). The patients who expired during the study observation period had median survival of 330 days (11 months).
CONCLUSION: Our study showed that CT genotype for C1772T polymorphism of HIF-1α predisposes to aggressive tumor phenotype in patients with OSCC. Moreover, patients with CT genotype had poor survival rate as compared to CC genotype. A cut-off value of 460 pg/mL of HIF-1α can help to segregate patients with OSCC from healthy controls.
Cohen YC, Saranga A, Gatt ME, et al.Treatment patterns and clinical outcomes in high-risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi-center retrospective study.
Am J Hematol. 2018; 93(6):810-815 [PubMed
] Related Publications
Del17p is a genomic imbalance occurring in ∼7%-10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib-based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M-Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M-Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches.
The p53 tumor suppressor protein is the most well studied as a regulator of transcription in the nucleus, where it exists primarily as a tetramer. However, there are other oligomeric states of p53 that are relevant to its regulation and activities. In unstressed cells, p53 is normally held in check by MDM2 that targets p53 for transcriptional repression, proteasomal degradation, and cytoplasmic localization. Here we discovered a hydrophobic region within the MDM2 N-terminal domain that binds exclusively to the dimeric form of the p53 C-terminal domain in vitro. In cell-based assays, MDM2 exhibits superior binding to, hyperdegradation of, and increased nuclear exclusion of dimeric p53 when compared with tetrameric wild-type p53. Correspondingly, impairing the hydrophobicity of the newly identified N-terminal MDM2 region leads to p53 stabilization. Interestingly, we found that dimeric mutant p53 is partially unfolded and is a target for ubiquitin-independent degradation by the 20S proteasome. Finally, forcing certain tumor-derived mutant forms of p53 into dimer configuration results in hyperdegradation of mutant p53 and inhibition of p53-mediated cancer cell migration. Gaining insight into different oligomeric forms of p53 may provide novel approaches to cancer therapy.
Singh J, Thota N, Singh S, et al.Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations.
Breast Cancer Res Treat. 2018; 170(1):189-196 [PubMed
] Related Publications
PURPOSE: Breast and/or ovarian cancers are among the most common cancers in women across the world. In the Indian population, the healthcare burden of breast and/or ovarian cancers has been steadily rising, thus stressing the need for early detection, surveillance, and disease management measures. However, the burden attributable to inherited mutations is not well characterized.
METHODS: We sequenced 1010 unrelated patients and families from across India with an indication of breast and/or ovarian cancers, using the TruSight Cancer panel which includes 14 genes, strongly associated with risk of hereditary breast and/or ovarian cancers. Genetic variations were identified using the StrandNGS software and interpreted using the StrandOmics platform.
RESULTS: We were able to detect mutations in 304 (30.1%) cases, of which, 56 mutations were novel. A majority (84.9%) of the mutations were detected in the BRCA1/2 genes as compared to non-BRCA genes (15.1%). When the cases were stratified on the basis of age at diagnosis and family history of cancer, the high rate of 75% of detection of hereditary variants was observed in patients whose age at diagnosis was below 40 years and had first-degree family member(s) affected by breast and/or ovarian cancers. Our findings indicate that in the Indian population, there is a high prevalence of mutations in the high-risk breast cancer genes: BRCA1, BRCA2, TP53, and PALB2.
CONCLUSION: In India, socioeconomic inequality limiting access to treatment is a major factor towards increased cancer burden; therefore, incorporation of a cost-effective and comprehensive multi-gene test will be helpful in ensuring widespread implementation of genetic screening in the clinical practice for hereditary breast and/or ovarian cancers.
PURPOSE: Tumor-infiltrating lymphocytes (TILs) have an established impact on the prognosis of high-grade serous ovarian carcinoma (HGSOC), however, their role in recurrent ovarian cancer is largely unknown. We therefore systematically investigated TIL densities and MHC class I and II (MHC1, 2) expression in the progression of HGSOC.
EXPERIMENTAL DESIGN: CD3+, CD4+, CD8+ TILs and MHC1, 2 expression were evaluated by immunohistochemistry on tissue microarrays in 113 paired primary and recurrent HGSOC. TILs were quantified by image analysis. All patients had been included to the EU-funded OCTIPS FP7 project.
RESULTS: CD3+, CD4+, CD8+ TILs and MHC1 and MHC2 expression showed significant correlations between primary and recurrent tumor levels (Spearman rho 0.427, 0.533, 0.361, 0.456, 0.526 respectively; P<.0001 each). Paired testing revealed higher CD4+ densities and MHC1 expression in recurrent tumors (Wilcoxon P=.034 and P=.018). There was also a shift towards higher CD3+ TILs levels in recurrent carcinomas when analyzing platinum-sensitive tumors only (Wilcoxon P=.026) and in pairs with recurrent tumor tissue from first relapse only (Wilcoxon P=.031). High MHC2 expression was the only parameter to be significantly linked to prolonged progression-free survival after first relapse (PFS2, log-rank P=.012).
CONCLUSIONS: This is the first study that analyzed the development of TILs density and MHC expression in paired primary and recurrent HGSOC. The level of the antitumoral immune response in recurrent tumors was clearly dependent on the one in the primary tumor. Our data contribute to the understanding of temporal heterogeneity of HGSOC immune microenvironment and have implications for selection of samples for biomarker testing in the setting of immune-targeting therapeutics.
Miller KR, Patel JN, Zhang Q, et al.HOXA4/HOXB3 gene expression signature as a biomarker of recurrence in patients with high-grade serous ovarian cancer following primary cytoreductive surgery and first-line adjuvant chemotherapy.
Gynecol Oncol. 2018; 149(1):155-162 [PubMed
] Related Publications
OBJECTIVES: Aberrant homeobox (HOX) gene expression is reported in high-grade serous ovarian carcinoma (HGSOC), however, its prognostic significance remains unclear.
METHODS: HOX genes associated with progression-free survival (PFS) in a discovery cohort of primary HGSOC samples with RNA sequencing data, and those previously reported to be associated with clinical outcomes, were selected for qPCR testing in an independent training cohort of primary HGSOC samples (n=71). A prognostic model for PFS was developed using univariate and multivariate Cox regression. Patients were stratified into risk groups that optimized the test statistic. The model was tested in an independent HGSOC cohort from The Cancer Genome Atlas (TCGA) (n=320). The effect of selected HOX genes on drug sensitivity and reactive oxygen species (ROS) accumulation was examined in vitro.
RESULTS: Of 23 HOX genes tested in the training cohort, HOXA4 (HR=1.20, 95% CI=1.07-1.34, P=0.002) and HOXB3 (HR=1.09, 95% CI=1.01-1.17, P=0.027) overexpression were significantly associated with shorter PFS in multivariate analysis. Based on the optimal cutoff of the HOXA4/HOXB3 risk score, median PFS was 16.9months (95% CI=14.6-21.2months) and not reached (>80months) for patients with high and low risk scores, respectively (HR=8.89, 95% CI=2.09-37.74, P<0.001). In TCGA, the HOXA4/HOXB3 risk score was significantly associated with disease-free survival (HR=1.44, 95% CI=1.00-2.09, P=0.048). HOXA4 or HOXB3 overexpression in ovarian cancer cells decreased sensitivity to cisplatin and attenuated the generation of cisplatin-induced ROS (P<0.05).
CONCLUSIONS: HOXA4/HOXB3 gene expression-based risk score may be useful for prognostic risk stratification and warrants prospective validation in HGSOC patients.
BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex. In support of this, we also show that, in clinical tumor samples, BRD4 protein levels are negatively associated with outcome after prostate cancer (PCa) radiation therapy. Thus, in addition to regulating gene expression, BRD4 is also a central player in the repair of DNA DSBs, with significant implications for cancer therapy.
Zeng J, Luo Y, Yu M, et al.CCDC26 rs4295627 polymorphisms associated with an increased risk of glioma: A meta-analysis.
Adv Clin Exp Med. 2017; 26(8):1275-1281 [PubMed
] Related Publications
BACKGROUND: Gliomas are the most common primary brain tumor in adults. Many studies have revealed associations between the rs4295627 polymorphism in the coiled-coil domain containing 26 (CCDC26) gene and the risk of glioma. However, the conclusions are still unclear because some studies have reported inconsistent results.
OBJECTIVES: The aim of the present meta-analysis was to determine the relationship and quantitatively evaluate the effect of the rs4295627 polymorphism on the risk of glioma.
MATERIAL AND METHODS: Data was extracted from PubMed, EMBASE and Google Scholar, with the most recent search up to December, 2015. Odds ratios (OR) and their 95% CIs were used to evaluate the effect of CCDC26 rs4295627 polymorphisms on glioma. A test of heterogeneity and an assessment of publication bias were also performed.
RESULTS: A total of 11 studies (8292 cases and 12,419 controls) were selected for this meta-analysis. Significant associations were observed in all genetic analysis models (G vs T: OR = 1.26, 95% CI = 1.12-1.43; GG vs TT: OR = 1.72, 95% CI = 1.24-2.39; GT vs TT: OR = 1.33, 95% CI = 1.24-1.42; GG + GT vs TT: OR = 1.36, 95% CI = 1.20-1.53; GG vs GT + TT: OR = 1.65, 95% CI = 1.18-2.29, respectively).
CONCLUSION: The results of the present study clearly show that the G allele of the rs4295627 polymorphism significantly increases the risk of glioma. Nevertheless, well-designed large-scale studies are needed to further evaluate the effect of the rs4295627 polymorphism on different types or degrees of glioma in different ethnic groups as well as to measure the combined effects on glioma risk.
Lipper CH, Karmi O, Sohn YS, et al.Structure of the human monomeric NEET protein MiNT and its role in regulating iron and reactive oxygen species in cancer cells.
Proc Natl Acad Sci U S A. 2018; 115(2):272-277 [PubMed
] Free Access to Full Article Related Publications
The NEET family is a relatively new class of three related [2Fe-2S] proteins (CISD1-3), important in human health and disease. While there has been growing interest in the homodimeric gene products of CISD1 (mitoNEET) and CISD2 (NAF-1), the importance of the inner mitochondrial CISD3 protein has only recently been recognized in cancer. The CISD3 gene encodes for a monomeric protein that contains two [2Fe-2S] CDGSH motifs, which we term mitochondrial inner NEET protein (MiNT). It folds with a pseudosymmetrical fold that provides a hydrophobic motif on one side and a relatively hydrophilic surface on the diametrically opposed surface. Interestingly, as shown by molecular dynamics simulation, the protein displays distinct asymmetrical backbone motions, unlike its homodimeric counterparts that face the cytosolic side of the outer mitochondrial membrane/endoplasmic reticulum (ER). However, like its counterparts, our biological studies indicate that knockdown of MiNT leads to increased accumulation of mitochondrial labile iron, as well as increased mitochondrial reactive oxygen production. Taken together, our study suggests that the MiNT protein functions in the same pathway as its homodimeric counterparts (mitoNEET and NAF-1), and could be a key player in this pathway within the mitochondria. As such, it represents a target for anticancer or antidiabetic drug development.
Wang S, Hui Y, Li X, Jia QSilencing of lncRNA CCDC26 Restrains the Growth and Migration of Glioma Cells In Vitro and In Vivo via Targeting miR-203.
Oncol Res. 2018; 26(8):1143-1154 [PubMed
] Related Publications
Gliomas are the most common primary brain tumors with high mortality. The treatment for gliomas is largely limited due to its uncomprehending pathological mechanism. Here we aimed to investigate the effect of long noncoding RNA (lncRNA) coiled-coil domain-containing 26 (CCDC26) in glioma progression. In our study, the expression of CCDC26 was found upregulated in glioma tissues and cell lines compared with normal tissues and cell lines. Further exploration detected decreased cell proliferation and increased cell apoptosis in U-251 and M059J cells transfected with CCDC26-siRNA. In addition, the silencing of CCDC26 strongly reduced the wound closing rate and the number of invasive cells compared with the scramble group. Simultaneously, the expression of miR-203 was found suppressed in glioma tissues and cells lines. Suppressed level of miR-203 was then elevated in U-251 and M059J cells transfected with CCDC26-siRNA. The result of the luciferase activity assay also showed that the luciferase activity was strongly strengthened by adding the miR-203 inhibitor into the CCDC26 WT group. Moreover, CDCC26-siRNA counteracted the effect of the miR-203 inhibitor in facilitating cell viability and mobility in U-251 cells. The in vivo experiment also revealed that CCDC26-siRNA inhibited glioma growth and metastasis. Taken together, our research indicated a CCDC26/miR-203 pathway in regulating the growth and metastasis of gliomas, providing new viewpoints and promising targets for glioma therapy.
Singh MP, Rai S, Suyal S, et al.Genetic and epigenetic markers in colorectal cancer screening: recent advances.
Expert Rev Mol Diagn. 2017; 17(7):665-685 [PubMed
] Related Publications
INTRODUCTION: Colorectal cancer (CRC) is a heterogenous disease which develops from benign intraepithelial lesions known as adenomas to malignant carcinomas. Acquired alterations in Wnt signaling, TGFβ, MAPK pathway genes and clonal propagation of altered cells are responsible for this transformation. Detection of adenomas or early stage cancer in asymptomatic patients and better prognostic and predictive markers is important for improving the clinical management of CRC. Area covered: In this review, the authors have evaluated the potential of genetic and epigenetic alterations as markers for early detection, prognosis and therapeutic predictive potential in the context of CRC. We have discussed molecular heterogeneity present in CRC and its correlation to prognosis and response to therapy. Expert commentary: Molecular marker based CRC screening methods still fail to gain trust of clinicians. Invasive screening methods, molecular heterogeneity, chemoresistance and low quality test samples are some key challenges which need to be addressed in the present context. New sequencing technologies and integrated omics data analysis of individual or population cohort results in GWAS. MPE studies following a GWAS could be future line of research to establish accurate correlations between CRC and its risk factors. This strategy would identify most reliable biomarkers for CRC screening and management.
Katiyar T, Maurya SS, Hasan F, et al.Association of cytochrome P450 1B1 haplotypes with head and neck cancer risk.
Environ Mol Mutagen. 2017; 58(6):443-450 [PubMed
] Related Publications
Genetic polymorphisms have been reported in several cytochrome P450 (CYP) genes, including CYP1B1 which metabolically activates procarcinogens present in tobacco to carcinogenic intermediates. This study used a case-control approach in North Indian population to determine associations between genetic variants in CYP1B1 and risk of Head and Neck Squamous Cell Carcinoma (HNSCC). We examined the genotype and haplotype frequencies at various single-nucleotide polymorphisms (SNPs), including SNPs previously reported in the promoter region and intron 1 of CYP1B1 in Caucasians. Using cycle sequencing, 9 SNPs were identified in the promoter region, intron 1, and exons 2 and 3. Haplotype analysis revealed that 5 SNPs (those in the promoter region, intron, and Arg48Gly and Ala119Ser in exon 2) were in strong linkage disequilibrium (LD). Cases with the T-A-T-G-T haplotype were significantly associated with increased risk of HNSCC. Interestingly, qRT-PCR studies revealed a significant increase in mRNA expression of CYP1B1 in peripheral blood isolated from cases with the T-A-T-G-T haplotype compared with cases with the C-G-C-C-G haplotype, and in cases compared to controls for both main haplotypes. The data thus provide evidence that CYP1B1 haplotypes could be more effective in predicting HNSCC risk. Environ. Mol. Mutagen. 58:443-450, 2017. © 2017 Wiley Periodicals, Inc.
Treatment of pancreatic cancer with gemcitabine (GEM) is limited due to its rapid plasma metabolism and development of chemoresistance. MicroRNA (miRNA) regulates cancer stem cell (CSC) maintenance and induces chemoresistance in cancer cells. In this study, we observed differential downregulation of miR-205 (miR-205-5p) in human pancreatic cancer tissues and cells. Compared to GEM-sensitive MIA PaCa-2 cells, miR-205 was highly downregulated in GEM-resistant MIA PaCa-2R cells. Lentivirus-mediated overexpression of miR-205 inhibits MIA PaCa-2R cell proliferation after GEM-treatment. Further investigation confirmed that miR-205 alone significantly reduces the proliferation of CSCs and tumor growth in mouse models. However, miR-205 in combination with GEM was more efficient in reducing the proliferation of CSCs and 3D spheroids. Moreover, miR-205 overexpressing MIA PaCa-2R cells induced orthotopic tumor growth was significantly inhibited after intravenous administration of GEM-conjugated methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate)-graft-gemcitabine-graft-dodecanol (mPEG-b-PCC-g-GEM-g-DC) (mPEG-b-PCC-g-GEM-g-DC) polymeric micelles. Also, a reduction in CSCs, EMT and chemoresistance markers was observed in miR-205 overexpressing MIA PaCa-2R cells. Immunohistochemical analysis of orthotopic tumors showed a decrease in drug resistance protein caveolin-1 and cell proliferation marker Ki-67 in combination treatment. Overall, our findings suggest that miR-205 resensitizes GEM-resistant pancreatic cancer cells to GEM and acts as a tumor suppressor miRNA.
Ewing's sarcoma is a highly aggressive malignant tumour most commonly affecting long bones in children and adolescents. It is part of the Ewing's sarcoma family of tumours (ESFTs) that also include peripheral primitive neuroectodermal tumour and Askin's tumours. ESFTs share common cytogenetic aberrations, antigenic profiles and proto-oncogene expression with an overall similar clinical course. In 99% of ESFTs, genetic translocation with molecular fusion involves the EWSR1 gene on 22q12. Approximately 30% of ESFTs are extraosseous, most commonly occurring in the soft tissues of extremities, pelvis, retroperitoneum and chest wall. Primary presentation in solid organs is very rare but has been described in multiple sites including the pancreas. Accurate diagnosis of a Ewing's sarcoma in a solid organ is critical in facilitating correct treatment. We report the case of a 17-year-old girl with cytogenetically confirmed primary pancreatic Ewing's sarcoma and provide a brief review of the published literature.
Pal MK, Jaiswar SP, Dwivedi A, et al.Synergistic Effect of Graphene Oxide Coated Nanotised Apigenin with Paclitaxel (GO-NA/PTX): A ROS Dependent Mitochondrial Mediated Apoptosis in Ovarian Cancer.
Anticancer Agents Med Chem. 2017; 17(12):1721-1732 [PubMed
] Related Publications
BACKGROUND: Ovarian cancer is most lethal among all gynecologic malignancies. Paclitaxel (PTX) is well used chemotherapeutic regimen for cancer control; however its undesired toxicity has been a matter of concern for clinicians. Here, we used the graphene oxide coated nanotised apigenin (GO-NA) to enhance the efficacy of paclitaxel.
OBJECTIVE: The combined use of paclitaxel (PTX) and nanotised apigenin (NA) may reduce the PTX dose and increase the efficacy.
METHODS: GO and GO-Apigenin was prepared by modified Hummers method and the nanoparticles were characterized by dynamic light scattering and transmission electron microscopy. SKOV-3 cells were treated by DMSO, Group I (Control)-McCoy's 5A Medium, Group II-Paclitaxel (5nM), Group III- Nanotised Apigenin (GO-NA-10µM), Group IV- Paclitaxel (5nM) + GO-NA (10µM). Cell viability and IC-50 value were determined by MTT assay, synergism by Compusyn software, ROS by DCFH-DA assay, SOD activity by kit and MMP were examined by JC-1 and mitotracker/DAPI staining, cell cycle by flow cytometry, mRNA and protein level by Real Time-PCR and Western blot respectively Results: Results showed that GO-NA-PTX enhanced the anti-proliferative effect in synergistic manner as compare to GO-NA and PTX alone. GO-NA-PTX significantly suppressed the SOD activity, promotes the ROS accumulation, mitochondrial depolarization, DNA integrity and cell cycle arrest collectively accord the apoptosis. Results of immunocytochemistry, RT-PCR and western blot showed up-regulation of caspase-3, Bax, and down-regulation of Bcl-2.
CONCLUSION: The combination of PTX with GO-NA produces synergistic effects in SKOV-3 cells via the modulation of pro and anti-apoptotic gene and may reduce side effects of PTX.
Bogoch Y, Friedlander-Malik G, Lupu L, et al.Augmented expression of RUNX1 deregulates the global gene expression of U87 glioblastoma multiforme cells and inhibits tumor growth in mice.
Tumour Biol. 2017; 39(4):1010428317698357 [PubMed
] Related Publications
Glioblastoma multiforme is the most common and aggressive primary brain tumor in adults. A mesenchymal phenotype was associated with tumor aggressiveness and poor prognosis in glioblastoma multiforme patients. Recently, the transcription factor RUNX1 was suggested as a driver of the glioblastoma multiforme mesenchymal gene expression signature; however, its independent role in this process is yet to be described. Here, we assessed the role of RUNX1 in U87 glioblastoma multiforme cells in correspondence to its mediated transcriptome and genome-wide occupancy pattern. Overexpression of RUNX1 led to diminished tumor growth in nude and severe combined immunodeficiency mouse xenograft tumor model. At the molecular level, RUNX1 occupied thousands of genomic regions and regulated the expression of hundreds of target genes, both directly and indirectly. RUNX1 occupied genomic regions that corresponded to genes that were shown to play a role in brain tumor progression and angiogenesis and upon overexpression led to a substantial down-regulation of their expression level. When overexpressed in U87 glioblastoma multiforme cells, RUNX1 down-regulated key pathways in glioblastoma multiforme progression including epithelial to mesenchymal transition, MTORC1 signaling, hypoxia-induced signaling, and TNFa signaling via NFkB. Moreover, master regulators of the glioblastoma multiforme mesenchymal phenotype including CEBPb, ZNF238, and FOSL2 were directly regulated by RUNX1. The data suggest a central role for RUNX1 as master regulator of gene expression in the U87 glioblastoma multiforme cell line and mark RUNX1 as a potential target for novel future therapies for glioblastoma multiforme.
Treatment of prostate cancer with paclitaxel often fails due to the development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that codelivery of paclitaxel and 2'-hydroxy-2,4,4',5,6'-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes paclitaxel-resistant prostate cancer cells, killing both cancer stem-like cells (CSC) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells. Paclitaxel and rubone combination therapy inhibited tumor cell growth, migration, and CSC population growth. We synthesized poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol; PEG-PCD) to prepare micelles. The drug-loading capacities were 9.70% ± 0.10% and 5.34% ± 0.02% for paclitaxel and rubone, respectively, controlling a drug release of 60.20% ± 2.67% and 60.62% ± 4.35% release of paclitaxel and rubone at 24 hours. Delivery of miR-34a and rubone decreased PC3-TXR cell viability with increasing paclitaxel concentration. Coincubation with a miR-34a inhibitor diminished the effect of rubone. Paclitaxel IC
Jauhri M, Bhatnagar A, Gupta S, et al.Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing-based cohort study.
Tumour Biol. 2017; 39(2):1010428317692265 [PubMed
] Related Publications
Colorectal cancer incidences are on a rise in India. In this study, we have analyzed the mutation frequencies of six potential biomarkers, their coexistence, association with clinicopathological characteristics, and tumor location in Indian colorectal cancer patients. Next-generation sequencing was performed to identify mutations in the six potential biomarker genes using formalin-fixed paraffin-embedded tissue blocks of 112 colorectal cancer patients. The mutation frequency observed in KRAS, BRAF, PIK3CA, NRAS, TP53, and APC was 35.7%, 7.1%, 16.1%, 6.3%, 39.3%, and 29.5%, respectively. The significant associations of mutations were KRAS with age less than 60 years (p = 0.041), PIK3CA with males (p = 0.032), tumor stage I-II (p = 0.013), lack of metastasis in lymph nodes (p = 0.040), NRAS with rectum (p = 0.002), and APC with T2 stage of tumor growth (p = 0.013). No single patient harbored mutations in these six genes or any five genes simultaneously. Significance was noted in coexistence of KRAS with APC (p = 0.024) and mutual exclusion of KRAS with BRAF (p = 0.029). PIK3CA exon 9 was observed to be more frequently associated with KRAS mutations than PIK3CA exon 20 (p = 0.072). NRAS mutations were mutually exclusive with BRAF and PIK3CA mutations. As per our knowledge, this is the first next-generation sequencing-based biomarker study in Indian colorectal cancer patients. Frequent coexistence of gene mutations in pairs and triplets suggests that synergistic effect of overlapping mutations might further trigger the disease. In addition, infrequent coexistence of multiple gene mutations hints toward different signaling pathways for colorectal cancer tumorigenesis.
Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer.
Yang L, Achreja A, Yeung TL, et al.Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth.
Cell Metab. 2016; 24(5):685-700 [PubMed
] Related Publications
Reactive stromal cells are an integral part of tumor microenvironment (TME) and interact with cancer cells to regulate their growth. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets that make cancer cells vulnerable has remained challenging and elusive. Here, we identify a previously unrecognized mechanism whereby metabolism of reactive stromal cells is reprogrammed through an upregulated glutamine anabolic pathway. This dysfunctional stromal metabolism confers atypical metabolic flexibility and adaptive mechanisms in stromal cells, allowing them to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived conditions existing in TME. Using an orthotopic mouse model for ovarian carcinoma, we find that co-targeting glutamine synthetase in stroma and glutaminase in cancer cells reduces tumor weight, nodules, and metastasis. We present a synthetic lethal approach to target tumor stroma and cancer cells simultaneously for desirable therapeutic outcomes.