Research IndicatorsGraph generated 30 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 30 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (12)
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: XRCC1 (cancer-related)
Pak S, Kim W, Kim Y, et al.Dihydrotestosterone promotes kidney cancer cell proliferation by activating the STAT5 pathway via androgen and glucocorticoid receptors.
J Cancer Res Clin Oncol. 2019; 145(9):2293-2301 [PubMed
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PURPOSE: Androgen receptors (ARs) are expressed on a variety of cell types, and AR signaling plays an important role in tumor development and progression in several cancers. This in vitro study evaluated the effect of dihydrotestosterone (DHT) on the proliferation of renal cell carcinoma (RCC) cells in relation to AR status.
METHODS: Steroid hormone receptor expression was evaluated using RT-PCR and Western blotting. The effect of DHT on cell proliferation and STAT5 phosphorylation was evaluated in RCC cell lines (Caki-2, A498, and SN12C) and primary RCC cells using cell viability assays and Western blotting. ARs and glucocorticoid receptors (GRs) were knocked down with small interfering RNAs before assessing changes in cell proliferation and STAT5 activation.
RESULTS: DHT treatment promoted cell proliferation and increased STAT5 phosphorylation regardless of AR status. The AR antagonist bicalutamide reduced kidney cancer cell proliferation, regardless of AR status. AR and GR knockdown blocked STAT5 activation and reduced cell proliferation in all RCC cell lines. In patient-derived primary cells, DHT enhanced cell proliferation and this effect was diminished by treatment with the AR antagonists bicalutamide and enzalutamide and the GR antagonist mifepristone.
CONCLUSION: DHT promotes cell proliferation through STAT5 activation in RCC cells, regardless of AR status. DHT appears to utilize the AR and GR pathways to activate STAT5, and the inhibition of AR and GR showed antitumor activity in RCC cells. These data suggest that targeting AR and GR may be a promising new approach to the treatment of RCC.
Pyrroline-5-carboxylate reductase 1 (PYCR1) is an enzyme involved in cell metabolism and is upregulated in cancer. However, the correlations of PYCR1 expression with the clinicopathological features and prognosis of renal cell carcinoma (RCC) remain unclear. The purpose of this study was to identify the expression of PYCR1 and its clinical relevance in RCC patients.PYCR1 mRNA expression differences between RCC and the adjacent normal renal tissues were assessed using the Cancer Genome Atlas database (TCGA). Subsequently, the expression of PYCR1 mRNA and protein were evaluated by quantitative real-time polymerase chain reaction, Western blot, and immunochemistry using 30 paired frozen samples of RCC and the adjacent normal renal tissues. The protein expression of PYCR1 was evaluated by immunostaining formalin-fixed, paraffin-embedded sections of RCC samples from 96 patients who underwent radical nephrectomy, and its relationship with clinical features were analyzed. Nonpaired t tests were used to statistically analyze the differences between the 2 groups. Cox univariable and multivariable analyses of overall survival (OS) among RCC patients were performed.The expression of PYCR1 mRNA was significantly upregulated in RCC tissues compared to adjacent normal renal tissues in the TCGA database (P < .01). The area under the receiver operating characteristic curve value was 0.748. The expression of PYCR1 mRNA and protein was significantly upregulated in RCC compared with that in paired normal renal tissues (P < .01). Higher PYCR1 levels were associated with metastasis (P < .01). Kaplan-Meier survival curves indicated that higher PYCR1 expression was correlated with poorer OS. Therefore, PYCR1 may act as a novel prognostic marker and therapeutic target in the diagnosis and treatment of RCC.
Moy L, Lyons AB, Fox W, et al.Non-Invasive Buccal Swab Gene Testing for Skin Cancer Risk
J Drugs Dermatol. 2019; 18(5):448-453 [PubMed
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Background: Studies have identified numerous genetic polymorphisms associated with increased risk of melanoma and non-melanoma skin cancer (NMSC). In this pilot study, we aimed to examine whether previously identified melanoma and non-melanoma associated single nucleotide polymorphisms (SNPs) which were found to be associated with cutaneous malignancy were also present in a relatively heterogeneous population with a history of skin cancer versus an age and environmental matched controls. The undertaking of this project serves to further the current understanding of the genetic profile for those at higher risk for developing skin cancer.
Methods: Nineteen NMSC patients and their age-matched and environmental controls underwent genotyping of 7 previously discovered SNPs associated with melanoma and NMSC.
Results: In a random, heterogeneous population in Southern California, SNP’s Chr1, PAD16, PIGU, TDG had a similar association with NMSC previously reported in prior studies. Due to small trial size, no conclusions or observable associations could be drawn from the SNPs MC1R, TP53, and XRCC1.
Conclusion: This data supports that 4 of the 7 SNP’s studied had similar associations and could potentially be predictive tool of NMSC risk in this patient population. The remaining three SNP’s did not have a definitive association with malignancy. Larger studies are needed to further elucidate the specific roles of these SNPs collectively and ultimately to develop a genetic profile for those patients at increased risk of developing skin cancer.
J Drugs Dermatol. 2019;18(5):448-453.
Rudnicka K, Backert S, Chmiela MGenetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences.
Curr Top Microbiol Immunol. 2019; 421:53-76 [PubMed
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Helicobacter pylori infection is associated with the development of a chronic inflammatory response, which may induce peptic ulcers, gastric cancer (GC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic H. pylori infection promotes the genetic instability of gastric epithelial cells and interferes with the DNA repair systems in host cells. Colonization of the stomach with H. pylori is an important cause of non-cardia GC and gastric MALT lymphoma. The reduction of GC development in patients who underwent anti-H. pylori eradication schemes has also been well described. Individual susceptibility to GC development depends on the host's genetic predisposition, H. pylori virulence factors, environmental conditions, and geographical determinants. Biological determinants are urgently sought to predict the clinical course of infection in individuals with confirmed H. pylori infection. Possible candidates for such biomarkers include genetic aberrations such as single-nucleotide polymorphisms (SNPs) found in various cytokines/growth factors (e.g., IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFN-γ, TNF, TGF-β) and their receptors (IL-RN, TGFR), innate immunity receptors (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1) as well as glycoproteins (MUC1, PSCA), and DNA repair enzymes (ERCC2, XRCC1, XRCC3). Bacterial determinants related to GC development include infection with CagA-positive (particularly with a high number of EPIYA-C phosphorylation motifs) and VacA-positive isolates (in particular s1/m1 allele strains). The combined genotyping of bacterial and host determinants suggests that the accumulation of polymorphisms favoring host and bacterial features increases the risk for precancerous and cancerous lesions in patients.
Maleckaite R, Zalimas A, Bakavicius A, et al.DNA methylation of metallothionein genes is associated with the clinical features of renal cell carcinoma.
Oncol Rep. 2019; 41(6):3535-3544 [PubMed
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Metallothioneins are low‑weight cysteine‑rich proteins responsible for metal ion homeostasis in a cell and, thus, capable of regulating cell proliferation and differentiation. Deregulation of metallothionein genes has been reported in various human tumors. However, their role in renal cell carcinoma (RCC) has been poorly investigated. In the present study, we aimed to evaluate the importance of promoter DNA methylation of selected metallothionein genes for RCC. Based on the initial analysis of kidney renal clear cell carcinoma dataset from The Cancer Genome Atlas, genes MT1E, MT1F, MT1G and MT1M were selected for qualitative methylation analysis in 30 tumors (including 10 multifocal cases), 10 pericancerous, and 30 non‑cancerous renal tissues (NRT). Methylation of MT1E and MT1M was tumor‑specific (P=0.0056 and P=0.0486, respectively) and showed moderate interfocal variation in paired tumor foci. Methylated promoter status of the two genes was associated with larger tumor size (P=0.0110 and P=0.0156, respectively). Furthermore, aberrant MT1E methylation was more frequent in tumors having necrotic zones (P=0.0449) or characterized with higher differentiation grade (P=0.0144), while MT1M was more commonly methylated in tumors with higher Fuhrman grade (P=0.0272). Only unmethylated MT1F promoter status was observed in all analyzed samples. Gene expression analysis (51 RCC and 9 NRT) revealed MT1G downregulation in tumors (P<0.0001), while lower MT1E expression levels were associated with the promoter methylation (P=0.0077). In clear cell RCC, MT1E, MT1G and MT1M expression was higher than that noted in other histological tumor subtypes (all P<0.0500). In addition, some associations were observed between metabolic syndrome‑related clinical parameters and promoter methylation or gene expression. In conclusion, the present study revealed the potential role of MT1E and MT1M promoter methylation in RCC development.
Clear cell renal cell carcinoma (ccRCC) is the seventh most frequently diagnosed tumor in adults in Europe and represents approximately 2.5% of cancer deaths. The molecular biology underlying renal cell carcinoma (RCC) development and progression has been a key milestone in the management of this type of tumor. The discovery of Von Hippel Lindau (
BACKGROUND: In clinical practice, the detection of biomarkers is mostly based on primary tumors for its convenience in acquisition. However, immune checkpoints may express differently between primary and metastatic tumor. Therefore, we aimed to compare the differential expressions of PD-1, PD-L1 and PD-L2 between the primary and metastatic sites of renal cell carcinoma (RCC).
METHODS: Patients diagnosed with RCC by resection or fine needle aspiration of metastasis were included. Immunohistochemistry (IHC) was applied to detect PD-1, PD-L1 and PD-L2 expressions. SPSS 22.0 was applied to conduct Chi-square, consistency tests and Cox's proportional hazards regression models. GraphPad Prism 6 was used to plot survival curves and R software was used to calculate Predictive accuracy (PA).
RESULTS: In the whole cohort (N = 163), IHC results suggested a higher detection rate of PD-L1 in the metastasis than that of the primary site (χ2 = 4.66, p = 0.03), with a low consistent rate of 32.5%. Among different metastatic tumors, PD-1 was highly expressed in the lung/lymph node (65.3%) and poorly expressed in the brain (10.5%) and visceral metastases (12.5%). PD-L1 was highly expressed in lung/lymph node (37.5%) and the bone metastases (12.2%) on the contrary. In terms of survival analysis, patients with PD-1 expression either in the primary or metastasis had a shorter overall survival (OS) (HR: 1.59, 95% CI 1.08-2.36, p = 0.02). Also, PD-L1 expression in the primary was associated with a shorter OS (HR 2.55, 95% CI 1.06-6.15, p = 0.04). In the multivariate analysis, the predictive accuracy of the whole model for PFS was increased from 0.683 to 0.699 after adding PD-1.
CONCLUSION: PD-1, PD-L1 and PD-L2 were differentially expressed between primary and metastatic tumors. Histopathological examination of these immune check points in metastatic lesions of mRCC should be noticed, and its accurate diagnosis may be one of the effective ways to realize the individualized treatment.
Zhai W, Zhu R, Ma J, et al.A positive feed-forward loop between LncRNA-URRCC and EGFL7/P-AKT/FOXO3 signaling promotes proliferation and metastasis of clear cell renal cell carcinoma.
Mol Cancer. 2019; 18(1):81 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: The aberrant expression of long noncoding RNAs (lncRNAs) has recently emerged as key molecules in human cancers; however, whether lncRNAs are implicated in the progression of clear cell renal cell carcinoma (ccRCC) remains unclear.
METHODS: Candidate lncRNAs were selected using microarray analysis and quantitative real-time PCR (qRT-PCR) was performed to detect lncRNAs expression in human ccRCC tissues. Overexpression and knocking down experiments in vivo and in vitro were performed to uncover the biological roles of lncRNA-URRCC on ccRCC cell proliferation and invasion. Microarray, chromatin immunoprecipitation, Luciferase reporter assay and western blot were constructed to investigate the molecular mechanisms underlying the functions of lncRNA-URRCC.
RESULTS: The microarray analysis and qRT-PCR identified a new lncRNA, URRCC, whose expression is upregulated in RCC samples and associated with poor prognosis, leading to promote ccRCC cell proliferation and invasion. Mechanistically, URRCC enhances the expression of EGFL7 via mediating histone H3 acetylation of EGFL7 promoter, activation of P-AKT signaling, and suppressing P-AKT downstream gene, FOXO3. In return, FOXO3 could inhibit the transcription of URRCC via binding to the special region on the promoter of URRCC.
CONCLUSIONS: Our data suggests that targeting this newly identified feed-back loop between LncRNA-URRCC and EGFL7/P-AKT/FOXO3 signaling may enhance the efficacy of existing therapy and potentially imparts a new avenue to develop more potent therapeutic approaches to suppress RCC progression.
Mollica V, Di Nunno V, Gatto L, et al.Novel Therapeutic Approaches and Targets Currently Under Evaluation for Renal Cell Carcinoma: Waiting for the Revolution.
Clin Drug Investig. 2019; 39(6):503-519 [PubMed
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Management of metastatic renal cell carcinoma has drastically changed in the last few years, witnessing the advent of more and more target therapies and, recently, of immune-checkpoint inhibitors. On the other hand, the adjuvant setting still lacks a clear beneficial treatment. Medical treatment still remains a compelling challenge. A large number of clinical trials is ongoing with the aim to identify new therapeutic approaches to expand the options in our repertoire. Several strategies are under investigation in renal cell carcinoma (RCC). These include new targeted agents and combinations of target therapy and immunotherapy. Programmed death receptor-1 (PD-1), programmed death receptor ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are just part of the intricate network that regulates our immune response to cancer cells. Co-stimulators, such as glucocorticoid-induced TNFR-related protein (GITR) and tumor necrosis factor receptor superfamily, member 4 (OX40), and co-repressors, example.g. T cell immunoglobulin and mucin domain 3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3), also take part. As knowledge of the functioning of the immune system grows, so do these pathways to target with new drugs. This review is an overview of the current state of the clinical research, providing a report of ongoing Phase I, II and III clinical trials for localized and metastatic RCC, including novel target therapies, novel immunotherapy agents and new combinations strategies.
The anti-cancer properties of curcumin in vitro have been documented. However, its clinical use is limited due to rapid metabolization. Since irradiation of curcumin has been found to increase its anti-cancer effect on several tumor types, this investigation was designed to determine whether irradiation with visible light may enhance the anti-tumor effects of low-dosed curcumin on renal cell carcinoma (RCC) cell growth and proliferation. A498, Caki1, and KTCTL-26 cells were incubated with curcumin (0.1⁻0.4 µg/mL) and irradiated with 1.65 J/cm² visible light for 5 min. Controls were exposed to curcumin or light alone or remained untreated. Curcumin plus light, but not curcumin or light exposure alone altered growth, proliferation, and apoptosis of all three RCC tumor cell lines. Cells were arrested in the G0/G1 phase of the cell cycle. Phosphorylated (p) CDK1 and pCDK2, along with their counter-receptors Cyclin B and A decreased, whereas p27 increased. Akt-mTOR-signaling was suppressed, the pro-apoptotic protein Bcl-2 became elevated, and the anti-apoptotic protein Bax diminished. H3 acetylation was elevated when cells were treated with curcumin plus light, pointing to an epigenetic mechanism. The present findings substantiate the potential of combining low curcumin concentrations and light as a new therapeutic concept to increase the efficacy of curcumin in RCC.
Kelch‑like ECH‑associated protein 1 (Keap1)/nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling has a protective effect on normal cells. A number of previous studies demonstrated that Keap1/Nrf2 signaling is associated with drug resistance in numerous tumors. The aim of the present study was to investigate the roles of Keap1 in renal cell carcinoma (RCC) and its effect on sensitivity to chemotherapy. Reverse transcription‑quantitative polymerase chain reaction was used to detect the mRNA expression of Keap1 in 45 cases of RCC tumors and adjacent normal tissues. A total of five randomly selected patients with RCC, five RCC cell lines and normal renal tubular cells were examined to detect the protein and mRNA expressions of Keap1. The 5‑year survival rate was analyzed by Kaplan‑Meier analysis. The cell viability was assessed by a Cell Counting kit‑8 assay. The cell apoptosis and reactive oxygen species (ROS) were determined by flow cytometry. The expressions of associated proteins were determined by western blot analysis. It was identified that in RCC tissues and RCC cell lines, the expression of Keap1 was downregulated, which was considered to be associated with poor prognosis. In total, 1 µM Axitinib significantly decreased cell viability, promoted ROS release and induced cell apoptosis in ACHN cells. Silencing Keap1 was able to reverse the inhibitory effect of Axitinib and enhance the protein expressions of Nrf2, NAD(P)H dehydrogenase [quinone] 1 and heme oxygenase 1. However, silencing Nrf2 increased the cell sensitivity to Axitinib. Under Axitinib condition, overexpressing Nrf2 was able to increase cell viability; however, overexpressing Keap1 resulted in an opposite effect. Keap1 serves as a tumor suppressor; its low expression was associated with poor prognosis and a decreased sensitivity of RCC cells to Axitinib. A possible mechanism underlying Axitinib resistance may involve Nrf2 overexpression.
Clear cell renal cell carcinoma (ccRCC) was the most aggressive histological type of renal cell carcinoma (RCC) and accounted for 70-80% of cases of all RCC. The aim of this study was to identify the potential biomarker in ccRCC and explore their underlying mechanisms. Four profile datasets were downloaded from the GEO database to identify DEGs. GO and KEGG analysis of DEGs were performed by DAVID. A protein-protein interaction (PPI) network was constructed to predict hub genes. The hub gene expression within ccRCC across multiple datasets and the overall survival analysis were investigated utilizing the Oncomine Platform and UALCAN dataset, separately. A meta-analysis was performed to explore the relationship between the hub genes: EGFR and ccRCC. 127 DEGs (55 upregulated genes and 72 downregulated genes) were identified from four profile datasets. Integrating the result from PPI network, Oncomine Platform, and survival analysis, EGFR, FLT1, and EDN1 were screened as key factors in the prognosis of ccRCC. GO and KEGG analysis revealed that 127 DEGs were mainly enriched in 21 terms and 4 pathways. The meta-analysis showed that there was a significant difference of EGFR expression between ccRCC tissues and normal tissues, and the expression of EGFR in patients with metastasis was higher. This study identified 3 importance genes (EGFR, FLT1, and EDN1) in ccRCC, and EGFR may be a potential prognostic biomarker and novel therapeutic target for ccRCC, especially patients with metastasis.
The microbiome research is going through an evolutionary transition from focusing on the characterization of reference microbiomes associated with different environments/hosts to the translational applications, including using microbiome for disease diagnosis, improving the effcacy of cancer treatments, and prevention of diseases (e.g., using probiotics). Microbial markers have been identified from microbiome data derived from cohorts of patients with different diseases, treatment responsiveness, etc, and often predictors based on these markers were built for predicting host phenotype given a microbiome dataset (e.g., to predict if a person has type 2 diabetes given his or her microbiome data). Unfortunately, these microbial markers and predictors are often not published so are not reusable by others. In this paper, we report the curation of a repository of microbial marker genes and predictors built from these markers for microbiome-based prediction of host phenotype, and a computational pipeline called Mi2P (from Microbiome to Phenotype) for using the repository. As an initial effort, we focus on microbial marker genes related to two diseases, type 2 diabetes and liver cirrhosis, and immunotherapy efficacy for two types of cancer, non-small-cell lung cancer (NSCLC) and renal cell carcinoma (RCC). We characterized the marker genes from metagenomic data using our recently developed subtractive assembly approach. We showed that predictors built from these microbial marker genes can provide fast and reasonably accurate prediction of host phenotype given microbiome data. As understanding and making use of microbiome data (our second genome) is becoming vital as we move forward in this age of precision health and precision medicine, we believe that such a repository will be useful for enabling translational applications of microbiome data.
Immune infiltration of tumors is closely associated with clinical outcome in renal cell carcinoma (RCC). Tumor-infiltrating immune cells (TIICs) regulate cancer progression and are appealing therapeutic targets. The purpose of this study was to determine the composition of TIICs in RCC and further reveal the independent prognostic values of TIICs. CIBERSORT, an established algorithm, was applied to estimate the proportions of 22 immune cell types based on gene expression profiles of 891 tumors. Cox regression was used to evaluate the association of TIICs and immune checkpoint modulators with overall survival (OS). We found that CD8+ T cells were associated with prolonged OS (hazard ratio [HR] = 0.09, 95% confidence interval [CI].01-.53; P = 0.03) in chromophobe carcinoma (KICH). A higher proportion of regulatory T cells was associated with a worse outcome (HR = 1.59, 95% CI 1.23-.06; P < 0.01) in renal clear cell carcinoma (KIRC). In renal papillary cell carcinoma (KIRP), M1 macrophages were associated with a favorable outcome (HR = .43, 95% CI .25-.72; P < 0.01), while M2 macrophages indicated a worse outcome (HR = 2.55, 95% CI 1.45-4.47; P < 0.01). Moreover, the immunomodulator molecules CTLA4 and LAG3 were associated with a poor prognosis in KIRC, and IDO1 and PD-L2 were associated with a poor prognosis in KIRP. This study indicates TIICs are important determinants of prognosis in RCC meanwhile reveals potential targets and biomarkers for immunotherapy development.
Wang L, Wang LL, Shang D, et al.Gene polymorphism of DNA repair gene X-ray repair cross complementing group 1 and xeroderma pigmentosum group D and environment interaction in non-small-cell lung cancer for Chinese nonsmoking female patients.
Kaohsiung J Med Sci. 2019; 35(1):39-48 [PubMed
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An association between genetic polymorphisms in encoding X-ray repair cross complementing group 1 (XRCC1) and encoding xeroderma pigmentosum group D (XPD) and risks of non-small-cell lung cancer (NSCLC) in East Chinese Han population has been observed. Herein we hypothesized that genetic polymorphisms in these two DNA repair genes are likely to be important in the NSCLC in Chinese nonsmoking female patients. We recruited 327 nonsmoking female patients with NSCLC and 342 individuals with benign lung diseases or healthy controls. Genotype frequencies of XRCC1 T-77C, Arg194Trp, Arg280His and Arg399Gln, Pro206Pro, and XPD Asp312Asn and Lys751Gln were calculated after Polymerase Chain Reaction amplification and sequencing. Generalized multifactor dimensionality reduction (GMDR) was used to detect the interactive effect of XRCC1 and XPD gene polymorphisms. The ratio of cooking oil mist exposure history and soot exposure history, and the gene frequencies of XRCC1 T-77C TC + CC, XRCC1 AG + GG, XRCC1 399Gln/Gln, and XPD 751Gln/Gln were higher in female patients with NSCLC than those with benign lung diseases or healthy controls. The haplotypes of XRCC1 T-Arg-Arg-Gln and XRCC1 C-Arg-Arg-Arg were positively associated with the NSCLC occurrence in nonsmoking female patients. GMDR discovered that there was an interactive model of XRCC1 and XPD genes in multiple gene loci. Logistic regression analysis showed that XRCC1 T-77C, XRCC1 Pro206Pro polymorphism, cooking oil mist and soot exposure history and tumor-node-metastasis (TNM) stage were related to NSCLC occurrence for nonsmoking female patients. Taken together, XRCC1 and XPD polymorphisms, cooking oil mist, and soot exposure history may be interactively correlated with NSCLC incidence for nonsmoking female patients.
BACKGROUND: Transcriptional dysregulation drives cancer formation but the underlying mechanisms are still poorly understood. Renal cell carcinoma (RCC) is the most common malignant kidney tumor which canonically activates the hypoxia-inducible transcription factor (HIF) pathway. Despite intensive study, novel therapeutic strategies to target RCC have been difficult to develop. Since the RCC epigenome is relatively understudied, we sought to elucidate key mechanisms underpinning the tumor phenotype and its clinical behavior.
METHODS: We performed genome-wide chromatin accessibility (DNase-seq) and transcriptome profiling (RNA-seq) on paired tumor/normal samples from 3 patients undergoing nephrectomy for removal of RCC. We incorporated publicly available data on HIF binding (ChIP-seq) in a RCC cell line. We performed integrated analyses of these high-resolution, genome-scale datasets together with larger transcriptomic data available through The Cancer Genome Atlas (TCGA).
FINDINGS: Though HIF transcription factors play a cardinal role in RCC oncogenesis, we found that numerous transcription factors with a RCC-selective expression pattern also demonstrated evidence of HIF binding near their gene body. Examination of chromatin accessibility profiles revealed that some of these transcription factors influenced the tumor's regulatory landscape, notably the stem cell transcription factor POU5F1 (OCT4). Elevated POU5F1 transcript levels were correlated with advanced tumor stage and poorer overall survival in RCC patients. Unexpectedly, we discovered a HIF-pathway-responsive promoter embedded within a endogenous retroviral long terminal repeat (LTR) element at the transcriptional start site of the PSOR1C3 long non-coding RNA gene upstream of POU5F1. RNA transcripts are induced from this promoter and read through PSOR1C3 into POU5F1 producing a novel POU5F1 transcript isoform. Rather than being unique to the POU5F1 locus, we found that HIF binds to several other transcriptionally active LTR elements genome-wide correlating with broad gene expression changes in RCC.
INTERPRETATION: Integrated transcriptomic and epigenomic analysis of matched tumor and normal tissues from even a small number of primary patient samples revealed remarkably convergent shared regulatory landscapes. Several transcription factors appear to act downstream of HIF including the potent stem cell transcription factor POU5F1. Dysregulated expression of POU5F1 is part of a larger pattern of gene expression changes in RCC that may be induced by HIF-dependent reactivation of dormant promoters embedded within endogenous retroviral LTRs.
Hong X, Yu JJSilencing of lysyl oxidase‑like 2 inhibits the migration, invasion and epithelial‑to‑mesenchymal transition of renal cell carcinoma cells through the Src/FAK signaling pathway.
Int J Oncol. 2019; 54(5):1676-1690 [PubMed
] Free Access to Full Article Related Publications
The aim of the present study was to investigate the effects of lysyl oxidase‑like 2 (LOXL2) on the invasion, migration and epithelial‑to‑mesenchymal transition (EMT) of renal cell carcinoma (RCC) cells through the steroid receptor coactivator (Src)/focal adhesion kinase (FAK) signaling pathway. RCC tissues and adjacent normal tissues were collected from 80 patients with RCC. Immunohistochemistry was used to determine the positive expression rate of the LOXL2 protein. The expression levels of LOXL2 in the HK‑2, 786‑O, ACHN, Caki1 and A498 cell lines were detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The high LOXL2‑expressing 786‑O cells were selected for gene silencing experiments, whereas Caki1 cells, which exhibited low LOXL2 expression, were used for overexpression experiments. RT‑qPCR and western blot analysis were applied to determine the expression of LOXL2, FAK, Src, matrix metalloproteinase (MMP)‑9, epithelial (E)‑cadherin, neuronal (N)‑cadherin and vimentin. A MTT assay, a Transwell assay, a wound healing assay and flow cytometry were performed to detect cell proliferation, invasion, migration, cell cycle distribution and apoptosis, respectively. The protein expression rate of LOXL2 in RCC tissues was higher compared with that in adjacent normal tissues. Compared with adjacent normal tissues, the mRNA and protein expression levels of LOXL2, FAK, Src, MMP‑9, N‑cadherin and vimentin and the levels of FAK and Src phosphorylation were increased, while the mRNA and protein expression levels of E‑cadherin were decreased in RCC tissues. Following the transfection of 786‑O cells with small interfering (si) RNA against LOXL2, the mRNA and protein expression levels of FAK, Src, MMP‑9, N‑cadherin and vimentin and the levels of phosphorylated FAK and Src were notably decreased in the si‑LOXL2 and PP2 inhibitor treated groups, while that of E‑cadherin was substantially increased. Additionally, cell proliferation, invasion, migration and the percentage of RCC cells in the G1 phase were reduced, and cell apoptosis was increased. Additionally, Caki1 cells transfected with LOXL2 exhibited an opposite trend. In summary, these results indicate that LOXL2 silencing inhibits the invasion, migration and EMT in RCC cells through inhibition of the Src/FAK signaling pathway.
Osako Y, Yoshino H, Sakaguchi T, et al.Potential tumor‑suppressive role of microRNA‑99a‑3p in sunitinib‑resistant renal cell carcinoma cells through the regulation of RRM2.
Int J Oncol. 2019; 54(5):1759-1770 [PubMed
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Sunitinib is the most common primary molecular‑targeted agent for metastatic clear cell renal cell carcinoma (ccRCC); however, intrinsic or acquired sunitinib resistance has become a significant problem in medical practice. The present study focused on microRNA (miR)‑99a‑3p, which was significantly downregulated in clinical sunitinib‑resistant ccRCC tissues in previous screening analyses, and investigated the molecular network associated with it. The expression levels of miR‑99a‑3p and its candidate target genes were evaluated in RCC cells, including previously established sunitinib‑resistant 786‑o (SU‑R‑786‑o) cells, and clinical ccRCC tissues, using reverse transcription‑quantitative polymerase chain reaction. Gain‑of‑function studies demonstrated that miR‑99a‑3p significantly suppressed cell proliferation and colony formation in RCC cells, including the SU‑R‑786‑o cells, by inducing apoptosis. Based on in silico analyses and RNA sequencing data, followed by luciferase reporter assays, ribonucleotide reductase regulatory subunit‑M2 (RRM2) was identified as a direct target of miR‑99a‑3p in the SU‑R‑786‑o cells. Loss‑of‑function studies using small interfering RNA against RRM2 revealed that cell proliferation and colony growth were significantly inhibited via induction of apoptosis, particularly in the SU‑R‑786‑o cells. Furthermore, the RRM2 inhibitor Didox (3,4‑dihydroxybenzohydroxamic acid) exhibited anticancer effects in the SU‑R‑786‑o cells and other RCC cells. To the best of our knowledge, this is the first report demonstrating that miR‑99a‑3p directly regulates RRM2. Identifying novel genes targeted by tumor‑suppressive miR‑99a‑3p in sunitinib‑resistant RCC cells may improve our understanding of intrinsic or acquired resistance and facilitate the development of novel therapeutic strategies.
Al-Maghrabi J, Mufti S, Gomaa WThe incidence of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion in Saudi adult patients with renal cancer: a retrospective tissue microarray analysis.
Pol J Pathol. 2018; 69(4):376-383 [PubMed
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Renal cell carcinoma (RCC) is the most common renal tumour. RCC with Xp11.2 translocation/TFE3 (transcription factor E3) gene fusions (Xp11.2 RCC) is positive for immunostain labelling by TFE3 antibody. This tumour is rarely described in adults. This study aims to evaluate the frequency of RCC with Xp11.2 in a subset of Saudi adult patients with RCC. 112 RCCs diagnosed in 1995-2016 were retrieved from the Department of Pathology at King Abdulaziz University and King and Faisal Specialist Hospital and Research Centre, Saudi Arabia. Tissue microarrays were constructed and TFE3 immunostaining was performed. TFE3 immunostaining was considered positive when diffuse strong nuclear immunostaining was detected. TFE3 immunostaining-positive tumours were confirmed by fluorescence in situ hybridisation. 4.5% of RCCs were shown to be Xp11.2 RCC by TFE3 immunostaining. TFE3-positive tumours have a papillary configuration, nested pattern, or both. Positive tumours show male predominance, more occurrences in middle age, high grade, and large-sized tumours with necrosis. Two tumours were FISH-positive. Xp11.2 RCC is rare in Saudi adult patients. Xp11.2 RCCs tend to be large sized and higher grade. TFE3 immunostaining should be considered in RCC that are histologically suggestive to confirm the diagnosis of Xp11.2.
Zhao TL, Gan XX, Bao Y, et al.GRK5 promotes tumor progression in renal cell carcinoma.
Neoplasma. 2019; 66(2):261-270 [PubMed
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GRK5 is a multifunctional protein that is able to move within the cell in response to various stimuli to regulate key intracellular signaling from receptor activation, on plasmamembrane, to gene transcription, in the nucleus. Thus, GRK5 is involved in the development and progression of several pathological conditions including cancer. Here, we report an important tumor-promoting role for GRK5 in renal cell carcinoma (RCC). We investigated the expression pattern, clinical significance, and function of GRK5 in RCC. By using quantitative real-time polymerase chain reaction (qRT-PCR) and tissue microarray (TMA) immunohistochemistry (IHC), we first demonstrated that compared with paired adjacent nontumor (NT) tissues, RCC tissues presented with higher GRK5 expression. Moreover, we found that GRK5 upregulation was associated with poor clinical outcomes in RCC patients. In vitro, we found that GRK5 knockdown reduced viability, invasive ability, migratory ability, and decreased proportion of cells in S phase, with concomitant increase in G1 phase in RCC cell lines, while GRK5 overexpression promoted tumor cell proliferation, cell invasion, migration and increased proportion of cells in S phase, with concomitant decrease in G1 phase. Collectively, our findings describe the tumour-promoting role of GRK5 in RCC and thus provide molecular evidence for new therapeutic options in RCC.
Li H, Pan X, Gui Y, et al.Upregulation of miR-183-5p predicts worse survival in patients with renal cell cancer after surgery.
Cancer Biomark. 2019; 24(2):153-158 [PubMed
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OBJECTIVE: Renal cell carcinoma (RCC) is one of the most common genitourinary cancers, and advanced RCC usually leads to poor prognosis. Therefore, identifying novel biomarkers for predicting the progression and prognosis of RCC is essential. The present study aims to evaluate the clinical value of miR-183-5p in RCC development and prognosis after surgery.
MATERIALS AND METHODS: We enrolled a total of 284 patients who received partial or radical nephrectomy from April 2003 to May 2013 at a single institution. The clinical and pathological characteristics of the patients were collected, including age, gender, tumor size, tumor stage, as well as follow-up information. The expression levels of miR-183-5p of all the patients were calculated from FFPE specimens. Cox regression analyses were performed to approve the effect of miR-183-5p expression on patient survival. Kaplan-Meier method was used to analyze the patient survival curves.
RESULTS: After controlling for gender, age, tumor size and tumor stage in the multivariate analysis, we found that high expression of miR-183-5p was independently associated lower overall survival (HR = 0.550, 95% CI = 0.364-0.832, p= 0.005). The Kaplan-Meier analysis also showed that patients with high expression of miR-183-5p had a significantly poor prognosis (p= 0.006). These results was verified by analyzing the data of 506 cases from The Cancer Genome Atlas database (TCGA).
CONCLUSION: Our results indicated that the high miR-183-5p expression is an independent factor for predicting RCC's worse prognosis.
Objective: The tumor susceptibility gene 101 (TSG101) is closely associated with various tumor types, but its role in the pathogenesis of renal cell carcinoma (RCC) is still unknown. This study used RNA interference to silence the expression of TSG101 in RCC cell lines and explore the role of TSG101 in RCC.
Methods: Immunohistochemistry and western blot were performed to detect the expression of TSG101 in 15 paired renal tumor samples. A small interfering RNA (siRNA) targeting TSG101 was transfected into A498 and 786-O cell lines. The Cell Counting Kit-8 (CCK-8) assay and colony formation assay were used to observe the changes in cell proliferation after transfection. Flow cytometry was used to detect the effect on the cell cycle. Western blot was conducted to study the changes of related functional proteins.
Results: The expression of TSG101 was higher in RCC tissues than in adjacent normal tissues. The CCK-8 assay showed that the proliferation and colony formation of the A498 and 786-O cell lines were attenuated after suppression of TSG101. Flow cytometry showed that silencing of TSG101 induced G0/G1 arrest. The western blot results revealed that the levels of cell cycle-related proteins (c-myc, cyclin E1 and cyclin-dependent kinase 2 (CDK2)) were markedly decreased in the siRNA groups.
Conclusions: TSG101 promotes proliferation of RCC cells. This positive effect on tumor growth involves activation of c-myc and cyclin E1/CDK2 and their effect on cell cycle distribution.
Bi-allelic inactivation of the VHL gene on chromosome 3p is the characteristic feature in most clear cell renal cell carcinomas (ccRCC). Frequent gene alterations were also identified in SETD2, BAP1 and PBRM1, all of which are situated on chromosome 3p and encode histone/chromatin regulators. The relationship between gene mutation, loss of protein expression and the correlations with clinicopathological parameters is important for the understanding of renal cancer progression. We analyzed PBRM1 and BAP1 protein expression as well as the tri-methylation state of H3K36 as a surrogate marker for SETD2 activity in more than 700 RCC samples. In ccRCC loss of nuclear PBRM1 (68%), BAP1 (40%) and H3K36me3 (47%) expression was significantly correlated with each other, advanced tumor stage, poor tumor differentiation (P < .0001 each), and necrosis (P < .005) Targeted next generation sequencing of 83 ccRCC samples demonstrated a significant association of genetic mutations in PBRM1, BAP1, and SETD2 with absence of PBRM1, BAP1, and HEK36me3 protein expression (P < .05, each). By assigning the protein expression patterns to evolutionary subtypes, we revealed similar clinical phenotypes as suggested by TRACERx Renal. Given their important contribution to tumor suppression, we conclude that combined functional inactivation of PBRM1, BAP1, SETD2 and pVHL is critical for ccRCC progression.
BACKGROUND: Due to the significant heterogeneity of renal cell carcinoma (RCC), immune checkpoints may express differently between primary and metastatic tumor. We aimed to evaluate the differential expression of TIM-3 between the primary and metastatic sites of RCC.
METHODS: Cases of RCC with metastases resected or biopsied at West China Hospital between January 2009 and November 2016 were included. Clinicopathological parameters were retrospectively extracted. SPPS 22.0, GraphPad Prism 6 and R statistical software were applied for data analysis.
RESULTS: A total of 163 cases were included. Immunohistochemical results showed that the overall detection rate of TIM-3 was 56.4% (92/163). The detection rate of TIM-3 in the primary (53.0%, 44/83) was numerically higher than that of the metastasis (42.6%,79/174). Although the concordance rate of TIM-3 between the primary and metastasis was as high as 66.3% (55/83) in the paired cohort, a significant statistically difference of TIM-3 expression between the primary and metastasis was observed (χ2 = 4.664, p = 0.002), with a poor consistency (Kappa = 0.331, p = 0.002). Subsequent survival analysis suggested that TIM-3 expression either in the primary or metastatic tumor was associated with longer progression-free survival (PFS) (HR: 0.67, 95% CI 0.45-0.99, P = 0.02) and overall survival (OS) (HR: 0.52, 95% CI 0.33-0.82, P < 0.001). The expressions of TIM-3 in the primary, metastatic tumors and patients treated with targeted agents all played as favorable factors for PFS and OS. Further multivariate analysis showed that, in the whole cohort, TIM-3 expression in metastatic tumor increased the predicted accuracy (PA) of the whole model of PFS from 74.7 to 75.6% (P = 0.02). For OS, the PA of whole model was increased from 78.1 to 81.1% by adding TIM-3 expression in the metastasis (P = 0.005). The same trends were also observed in paired patients and patients treated with targeted agents. In conclusion, the expression difference between the primary and metastatic tumor of TIM-3 was significant. Biopsy or resection of the metastases may provide a more accurate biological information for clinician's decision-making and the patient's prognosis. What's more, the role of TIM-3 in the RCC still remains controversy, further study are needed to verify the conclusion.
Miikkulainen P, Högel H, Seyednasrollah F, et al.Hypoxia-inducible factor (HIF)-prolyl hydroxylase 3 (PHD3) maintains high
J Biol Chem. 2019; 294(10):3760-3771 [PubMed
] Article available free on PMC
after 08/03/2020 Related Publications
Most clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), resulting in the accumulation of hypoxia-inducible factor α-subunits (HIF-α) and their downstream targets. HIF-2α expression is particularly high in ccRCC and is associated with increased ccRCC growth and aggressiveness. In the canonical HIF signaling pathway, HIF-prolyl hydroxylase 3 (PHD3) suppresses HIF-2α protein by post-translational hydroxylation under sufficient oxygen availability. Here, using immunoblotting and immunofluorescence staining, qRT-PCR, and siRNA-mediated gene silencing, we show that unlike in the canonical pathway, PHD3 silencing in ccRCC cells leads to down-regulation of HIF-2α protein and mRNA. Depletion of other PHD family members had no effect on HIF-2α expression, and PHD3 knockdown in non-RCC cells resulted in the expected increase in HIF-2α protein expression. Accordingly, PHD3 knockdown decreased HIF-2α target gene expression in ccRCC cells and expression was restored upon forced HIF-2α expression. The effect of PHD3 depletion was pinpointed to
Liu GC, Zhou YF, Su XC, Zhang JInteraction between TP53 and XRCC1 increases susceptibility to cervical cancer development: a case control study.
BMC Cancer. 2019; 19(1):24 [PubMed
] Article available free on PMC
after 08/03/2020 Related Publications
BACKGROUND: Cervical cancer is the 4th highest cause of female reproductive tract malignancies. Multiple loci have been identified as important determinant factors for tumor susceptibility. In this report, we aimed to explore the roles of gene polymorphisms affecting x-ray repair cross complementing 1 (XRCC1), the tumor protein p53 (TP53), and fibroblast growth factor receptor 3 (FGFR3) in the context of susceptibility to cervical cancer. Additionally, we assessed the impact of single nucleotide polymorphism-single nucleotide polymorphism (SNP-SNP) interaction of these three genes in the context of cervical cancer risk in Chinese women.
METHODS: A case-control study consisted of 340 women located in Chongqing. Of these women, 121 were diagnosed with cervical cancer, 118 served as healthy controls, and 101 were specifically recruited elderly patients above the age of 80 who showed no history of cervical cancer. Three SNPs (XRCC1 rs25487, TP53 rs1042522, and FGFR3 rs121913483) were examined using mutation analysis of mismatch amplification PCR (MAMA-PCR) on samples obtained from peripheral blood.
RESULTS: Our results indicated that females from southwestern China all exhibited a wild-type phenotype at FGFR3 rs121913483. We also observed that the rs25487 mutation was significantly increased within the cervical cancer population. A 2-locus SNP-SNP interaction pattern (rs25487 and rs1042522) was significantly associated with cervical cancer risk (cases vs. negative controls: OR = 4.63, 95% CI = 1.83-11.75; cases vs. elderly group: OR = 17.61, 95% CI = 4.34-71.50).
CONCLUSIONS: This is the first study to identify a novel interaction between the XRCC1 and TP53 genes that is highly associated with susceptibility to cervical cancer risk in a female population in southwestern China.
Luo AJ, Tan J, He LY, et al.Suppression of Tescalcin inhibits growth and metastasis in renal cell carcinoma via downregulating NHE1 and NF-kB signaling.
Exp Mol Pathol. 2019; 107:110-117 [PubMed
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BACKGROUND: Renal cell carcinoma (RCC) is the most common form of kidney cancer. Recent studies reported that Tescalcin was overexpressed in various tumor types. However, the status of Tescalcin protein expression in RCC and its biological function is uncertain. This study was designed to investigate the expression of Tescalcin in human RCC and its biological function.
METHODS: shRNA transfection was performed to abrogates the expression of Tescalcin. Quantitative real time PCR and western blotting assays were used to determine mRNA and protein expression levels, respectively. The cell viability was analyzed by MTT and colony formation. Cell flow cytometry was used to assess pHi value and cell apoptosis. Cell invasive and migratory ability was measured with modified Boyden chamber assay. Xenograft model was setup to evaluate tumor growth.
RESULTS: Tescalcin was overexpressed in RCC tissues compared with matched normal tissues. It was also overexpressed in RCC cell lines relative that of normal cells. Suppression Tescalcin with specific shRNA resulted in the inhibition of cell proliferation, migration, invasion and apoptosis of RCC cells. Additionally, silencing of Tescalcin also caused the inhibition of the tumor growth in nude mice. Mechanistic study showed that Tescalcin regulated cell proliferation, migration and invasion via NHE1/pHi axis as well as AKT/NF-κB signaling pathway.
CONCLUSIONS: These findings demonstrate that atopic expression of Tescalcin facilitates the survival, migration and invasion of RCC cells via NHE1/pHi axis as well as AKT/ NF-κB signaling pathway, providing new perspectives for the future study of Tescalcin as a therapeutic target for RCC.
Smal MP, Kuzhir TD, Savina NV, et al.BER gene polymorphisms associated with key molecular events in bladder cancer.
Exp Oncol. 2018; 40(4):288-298 [PubMed
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AIM: Base excision repair (BER) gene polymorphisms are known to play an independent role in predisposition to developing different cancers as well as to be associated with clinicopathological traits of the disease modifying its clinical outcomes. One of the underlying mechanisms is presumed to include interplay between BER gene polymorphisms and key mutational, epigenetic and chromosomal events in tumor tissues. The present study was aimed at elucidating potential gene-gene interaction and assessing their mutual effects in bladder cancer (BC).
MATERIALS AND METHODS: The earlier obtained data on genotyping patients with verified diagnosis of BC for OGG1 rs1052133 (Ser326Cys) and XRCC1 rs25487 (Arg399Gln) polymorphisms were used for this study. The tumor tissue samples from the same patients were analyzed for mutations, epigenetic variations and losses of heterozygosity in some key genes involved in divergent pathogenic pathways of BC.
RESULTS: It was shown that the OGG1 (326 codon) heterozygous genotype as well as the minor 326Cys allele can intensify a mutational response of the RAS locus in urothelial carcinomas in the total cohort of patients simultaneously decreasing the mutation rates in the PIK3CA locus in smokers. The XRCC1 (399 codon) heterozygous genotype as well as the minor 399Gln allele reduced the frequency of LOH in the PTEN and TNKS genes, but did not affect the mutational variability in any locus tested. Both polymorphisms influenced the methylation status, carriers of OGG1 326Ser/Cys or Ser/Cys+Cys/Cys genotypes demonstrating increased frequency of methylated RUNX3 and ISL1 genes whereas the similar effect of XRCC1 polymorphism concerning methylation of p16 and TIMP3 genes. When dividing the total cohort into groups based on the extent of tumor spread, the observed associations were characteristic of non-muscle invasive BC.
CONCLUSION: The BER gene polymorphisms contributed to modification of key molecular events in urothelial carcinomas. Their mutual effects mainly manifested in non-muscle invasive BC. The underlying mechanisms as well as possible clinical outcomes need to be further explored to propose novel prognostic biomarkers for BC.
Imperial R, Ahmed Z, Toor OM, et al.Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles.
Mol Cancer. 2018; 17(1):177 [PubMed
] Article available free on PMC
after 08/03/2020 Related Publications
Right-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors.