Comprehensive identification of FGFR1-4 alterations in 5 557 Chinese patients with solid tumors by next-generation sequencing

xlomafota13 shared this article with you from Inoreader Comprehensive identification of <em>FGFR1-4</em> alterations in 5 557 Chinese patients with solid tumors by next-generation sequencing Via American Journal of Cancer Research Am J Cancer Res. 2021 Aug 15;11(8):3893-3906. eCollection 2021. ABSTRACT Deregulation of fibroblast growth factor receptor (FGFR) network is common in cancer due to activating mutations, gene amplifications and chromosomal translocations. Currently, various FGFR inhibitors are being developed. In order to optimize their clinical applications, understanding the frequencies and types of FGFR alterations in multiple cancer types appears to be extremely important. This study characterized FGFR1-4 alterations in solid tumors by next-generation sequencing (NGS). Between Jun. 2019 and Aug. 2020, the sequencing data of 5 557 solid tumors of diverse types in the database of Simcere Diagnostics, Inc. (Nanjing, China) were retrospectively analyzed. A panel-based NGS assay was used to detect FGFR1-4 alterations in tumor samples. 9.2% of cancer cases had FGFR1-4 alterations, in which gene amplifications (51.5%) and mutat ions (40.7%) were frequent, whereas gene rearrangements were less common (10.0%). FGFR1 was involved in 4.6% of 5 557 cases, FGFR2 in 2.1%, FGFR3 in 1.6%, and FGFR4 in 1.4%. Of patients with FGFR1-4 alterations, TP53, MUC16, NSD3, MYC and LRP1B genes were the top 5 mutant genes. FGFR1-4 aberrations occurred in almost every type of solid tumors, with the most common tumor being endometrial carcinoma (22.2%), followed by sarcoma (17.3%), breast cancer (13.2%), gastric cancer (12.2%), and more. 0.6% of cancer cases harbored FGFR1-4 fusions, with the most common fusion partner being TACC3. Two cases of GBM harboring FGFR3-TACC3 fusions were responsive to anlotinib treatment. In conclusion, FGFR1-4 alterations are prevalent in solid tumors of diverse types, with the majority being gene amplifications and mutations. FGFR1-4 fusions only occur in a minority of cancer cases, and t hose with glioblastoma harboring FGFR3-TACC3 fusions may benefit from anlotinib. PMID:34522456 | PMC:PMC8414391 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

DNA damage in cancer development: special implications in viral oncogenesis

xlomafota13 shared this article with you from Inoreader DNA damage in cancer development: special implications in viral oncogenesis Via American Journal of Cancer Research Am J Cancer Res. 2021 Aug 15;11(8):3956-3979. eCollection 2021. ABSTRACT DNA lesions arise from a combination of physiological/metabolic sources and exogenous environmental influences. When left unrepaired, these alterations accumulate in the cells and can give rise to mutations that change the function of important proteins (i.e. tumor suppressors, oncoproteins), or cause chromosomal rearrangements (i.e. gene fusions) that also result in the deregulation of key cellular molecules. Progressive acquisition of such genetic changes promotes uncontrolled cell proliferation and evasion of cell death, and hence plays a key role in carcinogenesis. Another less-studied consequence of DNA damage accumulating in the host genome is the integration of oncogenic DNA viruses such as Human papillomavirus, Merkel cell polyomavirus, and Hepatitis B virus. This critical step of viral-induced carcinogenesis is thought to be particularly facilitated by DN A breaks in both viral and host genomes. Therefore, the impact of DNA damage on carcinogenesis is magnified in the case of such oncoviruses via the additional effect of increasing integration frequency. In this review, we briefly present the various endogenous and exogenous factors that cause different types of DNA damage. Next, we discuss the contribution of these lesions in cancer development. Finally, we examine the amplified effect of DNA damage in viral-induced oncogenesis and summarize the limited data existing in the literature related to DNA damage-induced viral integration. To conclude, additional research is needed to assess the DNA damage pathways involved in the transition from viral infection to cancer. Discovering that a certain DNA damaging agent increases the likelihood of viral integration will enable the development of prophylactic and therapeutic strategies designed specifically to prevent such integration, with an ultimate goal of reducing or eliminating these vi ral-induced malignancies. PMID:34522461 | PMC:PMC8414375 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Role of hypoxia in inhibiting dendritic cells by VEGF signaling in tumor microenvironments: mechanism and application

xlomafota13 shared this article with you from Inoreader Role of hypoxia in inhibiting dendritic cells by VEGF signaling in tumor microenvironments: mechanism and application Via American Journal of Cancer Research Am J Cancer Res. 2021 Aug 15;11(8):3777-3793. eCollection 2021. ABSTRACT The tumor microenvironment (TME) plays a central role in tumor initiation, development, immune escape, and clinical treatment. Hypoxia, an important characteristic of the TME, mediates vascular endothelial factor (VEGF) signaling through direct or indirect mechanisms. Directly, hypoxia promotes the expression of VEGF through hypoxia-inducible factor (HIF) induction. Indirectly, VEGF inhibits dendritic cell (DC) maturation and function by binding to VEGF receptors (VEGFRs) and co-receptors expressed on cell membranes. Additionally, HIF can bypass VEGF/VEGFR and activate downstream signaling factors to promote tumor development. Currently, DC vaccine, anti-HIF and anti-VEGF therapies are widely used in clinical treatment, but their long-term effects remain limited. Therefore, a further understanding of the effects of hypoxia and VEGF signaling on DCs will help in th e development of innovative combination therapies and the identification of new targets. PMID:34522449 | PMC:PMC8414384 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Genetically predicted high circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 increase the risks of soft tissue sarcoma

xlomafota13 shared this article with you from Inoreader Genetically predicted high circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 increase the risks of soft tissue sarcoma Via American Journal of Cancer Research Am J Cancer Res. 2021 Aug 15;11(8):3980-3989. eCollection 2021. ABSTRACT Insulin growth factor-1 (IGF-1) plays important roles in carcinogenesis. Previous studies have linked circulating IGF-1 and its main binding protein, insulin-like growth factor-binding protein-3 (IGFBP-3), to cancer risks. However, no study has been conducted in soft tissue sarcoma (STS). In this study, we investigated the relationship of genetically predicted circulating IGF-1 and IGFBP-3 with STS risks. Recent large genome-wide association studies (GWAS) have identified 413 single nucleotide polymorphisms (SNPs) associated with IGF-1 and 4 SNPs associated with IGFBP-3. We genotyped these SNPs in 821 patients and 851 healthy controls. We constructed weighted genetic risk scores (GRS) to predict circulating IGF-1 and IGFBP-3. We determined the associations of individual SNPs and GRS with the risks of STS using multivariate logistic regression analysis. We found hi gh genetically predicted circulating IGF-1 and IGFBP-3 were both associated with increased STS risks. Dichotomized at the median values of IGF-1 and IGFBP-3 in controls, individuals with high level of IGF-1 exhibited a 27% increased risk of STS (odds ratio [OR]=1.27, 95% confidence interval [CI]=1.04-1.54, P=0.017), whereas the OR for high IGFBP-3 was 1.45 (95% CI=1.20-1.77, P<0.001). Interestingly, the significant association between IGFBP-3 and STS risk was only evident in women (OR=1.88, 95% CI=1.42-2.49, P<0.001), but not in men (OR=1.00, 95% CI=0.75-1.33, P=0.992). In stratified analyses by major STS subtypes, the strongest associations were observed in angiosarcoma for IGF-1, leiomyosarcoma for IGFBP-3, and gastrointestinal stromal tumors for IGFBP-3 in women. In conclusion, high circulating IGF-1 and IGFBP-3 levels were both associated with increased STS risks. PMID:34522462 | PMC:PMC8414386 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Downregulation of NEAT1 sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis

xlomafota13 shared this article with you from Inoreader Downregulation of NEAT1 sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis Via American Journal of Cancer Research Am J Cancer Res. 2021 Aug 15;11(8):3841-3856. eCollection 2021. ABSTRACT Chemoresistance is a major cause of treatment failure in pancreatic cancer (PC). It has been demonstrated that epithelial-to-mesenchymal transition (EMT) is closely related to drug resistance in PC; however, the underlying mechanisms are not yet fully understood. Recently found evidence has suggested that nuclear-enriched abundant transcript 1 (NEAT1) is involved in the development of chemoresistance. However, the role and mechanism of NEAT1 in PC gemcitabine resistance remain unknown. In the present study, we first established two independent gemcitabine-resistant (GR) PC cell lines, PANC-1/GR and SW1990/GR. We found that GR cells displayed markedly enhanced migration and invasion abilities, decreased expression of E-cadherin, and upregulation of N-cadherin, Vimentin, Snail, ZEB1, and ZEB2. Our findings suggested that downregulation of NEAT1 enhanced the sensitiv ity of GR cells to gemcitabine by reversing the EMT process. Mechanistically, NEAT1 mediates ZEB2 mRNA expression through sponging miR-506-3p. Downregulation of NEAT1 can reverse the EMT process of GR PC cells by reducing the expression of ZEB2, thus enhancing the sensitivity of GR PC cells to gemcitabine. These findings were further confirmed in a nude mouse xenograft model. Taken together, downregulation of NEAT1 sensitized the GR PC cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis. These results provide the novel evidence for understanding the function and molecular mechanism of NEAT1, and a new direction for improving the chemotherapeutic effects in PC. PMID:34522453 | PMC:PMC8414385 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Diagnosis of 'cribriform' prostatic adenocarcinoma: an interobserver reproducibility study among urologic pathologists with recommendations

xlomafota13 shared this article with you from Inoreader Diagnosis of "cribriform" prostatic adenocarcinoma: an interobserver reproducibility study among urologic pathologists with recommendations Via American Journal of Cancer Research Am J Cancer Res. 2021 Aug 15;11(8):3990-4001. eCollection 2021. ABSTRACT Accurate diagnosis of cribriform Gleason pattern 4 (CrP4) prostate adenocarcinoma (PCa) is important due to its independent association with adverse clinical outcomes and as a growing body of evidence suggests that it impacts clinical decision making in PCa management. To identify reproducible features for diagnosis of CrP4, we assessed interobserver agreement among 27 experienced urologic pathologists of 60 digital images from 44 radical prostatectomies (RP) that represented a broad spectrum of potential CrP4. The following morphologic features were correlated with the consensus diagnosis (defined as 75% agreement) for each image: partial vs. transluminal glandular bridging, intraglandular stroma, <12 vs. ≥12 lumina, well vs. poorly formed lumina, mucin (mucinous fibroplasia, extravasation, or extracellular pool), size (compared to benign glands and number o f lumina), number of attachments with gland border by tumor cells forming a "glomeruloid-like" pattern, a clear luminal space along the periphery of gland occupying <50% of glandular circumference, central nerve, dense (cell mass occupying >50% of luminal space) vs. loose, and regular vs. irregular contour. Interobserver reproducibility for the overall diagnostic agreement was fair (k=0.40). Large CrP4 had better agreement (k=0.49) compared to small CrP4 (k=0.40). Transluminal bridging, dense cellular proliferation, a clear luminal space along the periphery of gland occupying <50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were significantly associated with consensus for CrP4. In contrast, partial bridging, majority of intraglandular cells in contact with stroma, mucinous fibroplasia, only one attachment to the gland border by tumor cells forming a "glomeruloid-like" pattern, and a clear luminal space along the periphery of gland accounting for >50% of the glandular circumference were associated with consensus against CrP4. In summary, we identified reproducible morphological features for and against CrP4 diagnosis, which could be used to refine and standardize the diagnostic criteria for CrP4. PMID:34522463 | PMC:PMC8414383 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

bFGF-mediated phosphorylation of δ-catenin increases its protein stability and the ability to induce the nuclear redistribution of β-catenin

xlomafota13 shared this article with you from Inoreader bFGF-mediated phosphorylation of δ-catenin increases its protein stability and the ability to induce the nuclear redistribution of β-catenin Via American Journal of Cancer Research Am J Cancer Res. 2021 Aug 15;11(8):3877-3892. eCollection 2021. ABSTRACT Recently, we have shown that δ-catenin strengthened the epidermal growth factor receptor (EGFR)/Erk1/2 signaling pathway through the association between EGFR and δ-catenin. Now, we further analyzed the correlation between basic fibroblast growth factor (bFGF)/fibroblast growth factor receptor 1 (FGFR1) and δ-catenin in prostate cancer and investigated the molecular mechanism underlying the role of bFGF/FGFR1 modulation in CWR22Rv-1 (Rv-1) cells. Here, we demonstrated that bFGF phosphorylated the tyrosine residues of δ-catenin in Rv-1 cells and further proved that the bFGF mediated FGFR1/δ-catenin tyrosine phosphorylation was time dependent. Furthermore, we demonstrated that bFGF stabilized the expression of δ-catenin through weakening its association with GSK3β and enhancing its stability to induce β-catenin into the nuclear by strengthening the processing of E-cadherin. In a word, these results indicated that bFGF/FGFR1 signaling pathway could enhance the tumor progression of prostate cancer via δ-catenin. PMID:34522455 | PMC:PMC8414378 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.