MicroRNAs (miRNAs) play important roles in the cancer biology such as proliferation, differentiation, and apoptosis. The pivotal roles that miRNA expression plays, make them ideal candidates for detection of cancer progression as well as cancer metastasis. Especially for breast, lung and prostate cancer which are originated from soft tissues and prone to metastasis. Thus, the aim of this study is to evaluate the expression level of miR-145-3p which is a shared potential biomarker identified by meta-analysis of breast, prostate and lung cancer data sets. Six different data sets representative of three different cancer types were analyzed. These data sets are pooled together to have a master metamiRNA list while getting rid of the platform differentiations between them. As a result, 24 common differentially expressed miRNAs are determined in which miR-145-3p has the topmost rank. To mimic in vivo cancer microenvironment, hypoxia and serum deprivation were used to induce metastasis in breast (MCF-7, MDA-MB-231, MDA-MB-453), prostate (PC3, LNCaP, DU145), lung (A549, NCIH82,) cancer cell lines and noncancerous cell lines of the coresponding tissues (MCF10A, RWPE-1, MRC-5). miR-145-3p expression levels were determined by qRT-PCR. It has been shown that it is down regulated by the induction of metastasis in cancer cell lines while it is up regulated in normal cell lines to suppress the tumor formation. As a conclusion, as representing the same results in three different cancer cell types, miR-145-3p will be a promising biomarker to follow up its expression to detect cancer metastasis.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.

Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAF

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.

Epithelial ovarian cancer generally presents at an advanced stage and is the most common cause of gynaecological cancer death. Treatment requires expert multidisciplinary care. Population-based screening has been ineffective, but new approaches for early diagnosis and prevention that leverage molecular genomics are in development. Initial therapy includes surgery and adjuvant therapy. Epithelial ovarian cancer is composed of distinct histological subtypes with unique genomic characteristics, which are improving the precision and effectiveness of therapy, allowing discovery of predictors of response such as mutations in breast cancer susceptibility genes BRCA1 and BRCA2, and homologous recombination deficiency for DNA damage response pathway inhibitors or resistance (cyclin E1). Rapidly evolving techniques to measure genomic changes in tumour and blood allow for assessment of sensitivity and emergence of resistance to therapy, and might be accurate indicators of residual disease. Recurrence is usually incurable, and patient symptom control and quality of life are key considerations at this stage. Treatments for recurrence have to be designed from a patient's perspective and incorporate meaningful measures of benefit. Urgent progress is needed to develop evidence and consensus-based treatment guidelines for each subgroup, and requires close international cooperation in conducting clinical trials through academic research groups such as the Gynecologic Cancer Intergroup.

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.
METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.
RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10
CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

The present study evaluated the association between single nucleotide polymorphism (SNP) rs3746444 and the risk of non‑small cell lung carcinoma (NSCLC) in a Chinese population. Computational analyses and luciferase assays were performed to investigate the regulatory relationship between miR‑499a and CD200. In addition, reverse transcription‑quantitative polymerase chain reaction and western blot assays were performed to examine the effect of rs3746444 on the expression of miR‑499a and CD200. The results demonstrated a significant difference in the smoking history of patients carrying malignant pulmonary nodules and those carrying benign pulmonary nodules. Furthermore, CD200 was demonstrated to be a direct target of miR‑499a, and a miR‑499a binding site was located in the 3'UTR of CD200. Notably, the levels of miR‑499a in malignant pulmonary nodules were higher compared with benign pulmonary nodules, while the levels of CD200 were higher in benign pulmonary nodules compared with malignant pulmonary nodules. In addition, the subjects carrying the AA genotype of SNP rs3746444 exhibited upregulated miR‑499a expression and reduced CD200 expression, compared with the subjects carrying AG and GG genotypes. These findings indicate that the SNP rs3746444 in miR‑499a could affect the prognosis of NSCLC patients by regulating the expression of CD200.

Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.

BACKGROUND: Differential gene expression patterns are commonly used as biomarkers to predict treatment responses among heterogeneous tumors. However, the link between response biomarkers and treatment-targeting biological processes remain poorly understood. Here, we develop a prognosis-guided approach to establish the determinants of treatment response.
METHODS: The prognoses of biological processes were evaluated by integrating the transcriptomes and clinical outcomes of ~26,000 cases across 39 malignancies. Gene-prognosis scores of 39 malignancies (GEO datasets) were used for examining the prognoses, and TCGA datasets were selected for validation. The Oncomine and GEO datasets were used to establish and validate transcriptional signatures for treatment responses.
FINDINGS: The prognostic landscape of biological processes was established across 39 malignancies. Notably, the prognoses of biological processes varied among cancer types, and transcriptional features underlying these prognostic patterns distinguished response to treatment targeting specific biological process. Applying this metric, we found that low tumor proliferation rates predicted favorable prognosis, whereas elevated cellular stress response signatures signified resistance to anti-proliferation treatment. Moreover, while high immune activities were associated with favorable prognosis, enhanced lipid metabolism signatures distinguished immunotherapy resistant patients.
INTERPRETATION: These findings between prognosis and treatment response provide further insights into patient stratification for precision treatments, providing opportunities for further experimental and clinical validations. FUND: National Natural Science Foundation, Innovative Research Team in University of Ministry of Education of China, National Key Research and Development Program, Natural Science Foundation of Guangdong, Science and Technology Planning Project of Guangzhou, MRC, CRUK, Breast Cancer Now, Imperial ECMC, NIHR Imperial BRC and NIH.

Precise, analogue regulation of gene expression is critical for cellular function in mammals. In contrast, widely employed experimental and therapeutic approaches such as knock-in/out strategies are more suitable for binary control of gene activity. Here we report on a method for precise control of gene expression levels in mammalian cells using engineered microRNA response elements (MREs). First, we measure the efficacy of thousands of synthetic MRE variants under the control of an endogenous microRNA by high-throughput sequencing. Guided by this data, we establish a library of microRNA silencing-mediated fine-tuners (miSFITs) of varying strength that can be employed to precisely control the expression of user-specified genes. We apply this technology to tune the T-cell co-inhibitory receptor PD-1 and to explore how antigen expression influences T-cell activation and tumour growth. Finally, we employ CRISPR/Cas9 mediated homology directed repair to introduce miSFITs into the BRCA1 3'UTR, demonstrating that this versatile tool can be used to tune endogenous genes.

We are increasingly accumulating molecular data about a cell. The challenge is how to integrate them within a unified conceptual and computational framework enabling new discoveries. Hence, we propose a novel, data-driven concept of an integrated cell, iCell. Also, we introduce a computational prototype of an iCell, which integrates three omics, tissue-specific molecular interaction network types. We construct iCells of four cancers and the corresponding tissue controls and identify the most rewired genes in cancer. Many of them are of unknown function and cannot be identified as different in cancer in any specific molecular network. We biologically validate that they have a role in cancer by knockdown experiments followed by cell viability assays. We find additional support through Kaplan-Meier survival curves of thousands of patients. Finally, we extend this analysis to uncover pan-cancer genes. Our methodology is universal and enables integrative comparisons of diverse omics data over cells and tissues.

The immune response to melanoma improves the survival in untreated patients and predicts the response to immune checkpoint blockade. Here, we report genetic and environmental predictors of the immune response in a large primary cutaneous melanoma cohort. Bioinformatic analysis of 703 tumor transcriptomes was used to infer immune cell infiltration and to categorize tumors into immune subgroups, which were then investigated for association with biological pathways, clinicopathologic factors, and copy number alterations. Three subgroups, with "low", "intermediate", and "high" immune signals, were identified in primary tumors and replicated in metastatic tumors. Genes in the low subgroup were enriched for cell-cycle and metabolic pathways, whereas genes in the high subgroup were enriched for IFN and NF-κB signaling. We identified high MYC expression partially driven by amplification, HLA-B downregulation, and deletion of IFNγ and NF-κB pathway genes as the regulators of immune suppression. Furthermore, we showed that cigarette smoking, a globally detrimental environmental factor, modulates immunity, reducing the survival primarily in patients with a strong immune response. Together, these analyses identify a set of factors that can be easily assessed that may serve as predictors of response to immunotherapy in patients with melanoma. SIGNIFICANCE: These findings identify novel genetic and environmental modulators of the immune response against primary cutaneous melanoma and predict their impact on patient survival.

BRCA1/BRCA2 genes were discovered in early 1990s and clinical testing for these has been available since the mid-1990s. National Institute of Health and Care Excellence (NICE) and other international guidelines recommend genetic-testing at a ~10% probability threshold of carrying a BRCA-mutation. A detailed three generation family-history (FH) of cancer is used within complex mathematical models (e.g. BOADICEA, BRCAPRO, Manchester-Scoring-System) or through standardized clinical-criteria to identify individuals who fulfil this probability threshold and can be offered genetic-testing. Identification of unaffected carriers is important given the high risk of cancer in these women and the effective options available for clinical management which can reduce cancer risk, improve outcomes and minimise burden of disease. This article is protected by copyright. All rights reserved.

OBJECTIVE: To evaluate factors affecting unselected population-based BRCA testing in Ashkenazi Jews (AJ).
DESIGN: Cohort-study set within recruitment to the GCaPPS trial (ISRCTN73338115).
SETTING: North London AJ population.
POPULATION OR SAMPLE: Ashkenazi Jews women/men >18 years, recruited through self-referral.
METHODS: Ashkenazi Jews women/men underwent pre-test counselling for BRCA testing through recruitment clinics (clusters). Consenting individuals provided blood samples for BRCA testing. Data were collected on socio-demographic/family history/knowledge/psychological well-being along with benefits/risks/cultural influences (18-item questionnaire measuring 'attitude'). Four-item Likert-scales analysed initial 'interest' and 'intention-to-test' pre-counselling. Uni- and multivariable logistic regression models evaluated factors affecting uptake/interest/intention to undergo BRCA testing. Statistical inference was based on cluster robust standard errors and joint Wald tests for significance. Item-Response Theory and graded-response models modelled responses to 18-item questionnaire.
MAIN OUTCOME MEASURES: Interest, intention, uptake, attitude towards BRCA testing.
RESULTS: A total of 935 individuals (women = 67%/men = 33%; mean age = 53.8 (SD = 15.02) years) underwent pre-test genetic-counselling. During the pre-counselling, 96% expressed interest in and 60% indicated a clear intention to undergo BRCA testing. Subsequently, 88% opted for BRCA testing. BRCA-related knowledge (P = 0.013) and degree-level education (P = 0.01) were positively and negatively (respectively) associated with intention-to-test. Being married/cohabiting had four-fold higher odds for BRCA testing uptake (P = 0.009). Perceived benefits were associated with higher pre-counselling odds for interest in and intention to undergo BRCA testing. Reduced uncertainty/reassurance were the most important factors contributing to decision-making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional impact/inability to prevent cancer/marriage ability/ethnic focus/stigmatisation) were significantly associated with lower odds of uptake of BRCA testing, and discriminated between acceptors and decliners. Male gender/degree-level education (P = 0.001) had weaker correlations, whereas having children showed stronger (P = 0.005) associations with attitudes towards BRCA testing.
CONCLUSIONS: BRCA testing in the AJ population has high acceptability. Pre-test counselling increases awareness of disadvantages/limitations of BRCA testing, influencing final cost-benefit perception and decision-making on undergoing testing.
TWEETABLE ABSTRACT: BRCA testing in Ashkenazi Jews has high acceptability and uptake. Pre-test counselling facilitates informed decision-making.

Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer.

Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4

BACKGROUND: Structural variants (SVs) are known to play important roles in a variety of cancers, but their origins and functional consequences are still poorly understood. Many SVs are thought to emerge from errors in the repair processes following DNA double strand breaks (DSBs).
RESULTS: We used experimentally quantified DSB frequencies in cell lines with matched chromatin and sequence features to derive the first quantitative genome-wide models of DSB susceptibility. These models are accurate and provide novel insights into the mutational mechanisms generating DSBs. Models trained in one cell type can be successfully applied to others, but a substantial proportion of DSBs appear to reflect cell type-specific processes. Using model predictions as a proxy for susceptibility to DSBs in tumors, many SV-enriched regions appear to be poorly explained by selectively neutral mutational bias alone. A substantial number of these regions show unexpectedly high SV breakpoint frequencies given their predicted susceptibility to mutation and are therefore credible targets of positive selection in tumors. These putatively positively selected SV hotspots are enriched for genes previously shown to be oncogenic. In contrast, several hundred regions across the genome show unexpectedly low levels of SVs, given their relatively high susceptibility to mutation. These novel coldspot regions appear to be subject to purifying selection in tumors and are enriched for active promoters and enhancers.
CONCLUSIONS: We conclude that models of DSB susceptibility offer a rigorous approach to the inference of SVs putatively subject to selection in tumors.

Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements. We identified a mean of 4.4 driver events per tumor, which were derived more commonly from mutations than copy number alterations, and compared the prevelence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS). We observed mutual exclusivity or co-occurrence of events within and between several dysregulated EAC pathways, a result suggestive of strong functional relationships. Indicators of poor prognosis (SMAD4 and GATA4) were verified in independent cohorts with significant predictive value. Over 50% of EACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated with clinically relevant sensitivity in a panel of EAC cell lines and organoids.

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r

BACKGROUND: Tumour hypoxia is a driver of breast cancer progression associated with worse prognosis and more aggressive disease. The cellular response to hypoxia is mediated by the hypoxia-inducible transcription factors HIF-1 and HIF-2, whose transcriptional activity is canonically regulated through their oxygen-labile HIF-α subunits. These are constitutively degraded in the presence of oxygen; however, HIF-1α can be stabilised, even at high oxygen concentrations, through the activation of HER receptor signalling. Despite this, there is still limited understanding on how HER receptor signalling interacts with HIF activity to contribute to breast cancer progression in the context of tumour hypoxia.
METHODS: 2D and 3D cell line models were used alongside microarray gene expression analysis and meta-analysis of publicly available gene expression datasets to assess the impact of HER2 overexpression on HIF-1α/HIF-2α regulation and to compare the global transcriptomic response to acute and chronic hypoxia in an isogenic cell line model of HER2 overexpression.
RESULTS: HER2 overexpression in MCF7 cells leads to an increase in HIF-2α but not HIF-1α expression in normoxia and an increased upregulation of HIF-2α in hypoxia. Global gene expression analysis showed that HER2 overexpression in these cells promotes an exaggerated transcriptional response to both short-term and long-term hypoxia, with increased expression of numerous hypoxia response genes. HIF-2α expression is frequently higher in HER2-overexpressing tumours and is associated with worse disease-specific survival in HER2-positive breast cancer patients. HER2-overexpressing cell lines demonstrate an increased sensitivity to targeted HIF-2α inhibition through either siRNA or the use of a small molecule inhibitor of HIF-2α translation.
CONCLUSIONS: This study suggests an important interplay between HER2 expression and HIF-2α in breast cancer and highlights the potential for HER2 to drive the expression of numerous hypoxia response genes in normoxia and hypoxia. Overall, these findings show the importance of understanding the regulation of HIF activity in a variety of breast cancer subtypes and points to the potential of targeting HIF-2α as a therapy for HER2-positive breast cancer.

Glioblastoma (GBM) is the most aggressive malignant glioma and most lethal form of human brain cancer (Clin J Oncol Nurs. 2016;20:S2). GBM is also one of the most expensive and difficult cancers to treat by the surgical resection, local radiotherapy, and temozolomide (TMZ) and still remains an incurable disease. Oncomine platform analysis and Gene Expression Profiling Interactive Analysis (GEPIA) show that the expression of transcription factor EB (TFEB) was significantly increased in GBMs and in GBM patients above stage IV. TFEB requires the oligomerization and localization to regulate transcription in the nucleus. Also, the expression and oligomerization of TFEB proteins contribute to the resistance of GBM cells to conventional chemotherapeutic agents such as TMZ. Thus, we investigated whether the combination of vorinostat and melatonin could overcome the effects of TFEB and induce apoptosis in GBM cells and glioma cancer stem cells (GSCs). The downregulation of TFEB and oligomerization by vorinostat and melatonin increased the expression of apoptosis-related genes and activated the apoptotic cell death process. Significantly, the inhibition of TFEB expression dramatically decreased GSC tumor-sphere formation and size. The inhibitory effect of co-treatment resulted in decreased proliferation of GSCs and induced the expression of cleaved PARP and p-γH2AX. Taken together, our results definitely demonstrate that TFEB expression contributes to enhanced resistance of GBMs to chemotherapy and that vorinostat- and melatonin-activated apoptosis signaling in GBM cells by inhibiting TFEB expression and oligomerization, suggesting that co-treatment of vorinostat and melatonin may be an effective therapeutic strategy for human brain cancers.

Interferon-induced transmembrane protein 3 (IFITM3) is a component of ISG (Interferon-Stimulated Gene) family. The association between IFITM3 and hepatocellular carcinoma (HCC) has been reported. While the relationship between this genetic variation and the progress of HCC remains unclear. To address this issue, we explore the relationship between the IFITM3-rs12252 genetic variants and the progression of HCC in this study.A total of 336 candidates were enrolled in the study, including 156 patients with HBV related HCC and 180 patients with chronic Hepatitis B infections or liver cirrhosis. Liver cirrhosis or chronic hepatitis B were diagnosed with clinical characteristics and staging, laboratory testing, and imaging results of viral infection and hepatic damage. Polymerase chain reaction (PCR) was employed to determine the gene polymorphism of IFITM3, and analyzed with the GraphPad Prism v 5.The patients with HCC had a significantly higher proportion of IFITM3 rs12252-CC as compared with the patients with chronic HBV infection or liver cirrhosis. Moreover, the distribution of CC genotype in HCC patients with low differentiation was significantly higher than that in those with high differentiation. Furthermore, the patients with CC genotype were found with bigger tumor size, higher percentage of vascular thrombosis, higher distribution of low differentiation and higher 5-year relapse rate than those with CT/TT genotypes.This study indicates a correlation between the IFITM3-rs12252 CC genotype and the progression of HCC.

BACKGROUND: The risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate; previous efforts have been limited to in-vitro or in-vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant aromatase inhibitor therapy were characterised as a novel clinical model.
METHODS: Consecutive tumour samples from 62 patients undergoing extended (4-45 months) neoadjuvant aromatase inhibitor therapy with letrozole were subjected to transcriptomic and proteomic analysis, representing before (≤ 0), early (13-120 days), and long-term (> 120 days) neoadjuvant aromatase inhibitor therapy with letrozole. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as "dormant", and the remaining 20 patients as "acquired resistant".
RESULTS: Changes in gene expression in dormant tumours begin early and become more pronounced at later time points. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to the resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. The DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared with dormant tissues after extended letrozole treatment.
CONCLUSIONS: This is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients, supporting a potential role for therapy targeted at these epigenetic alterations in the management of resistance to oestrogen deprivation therapy.

We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4 and MED24. We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML.

Objective: This study aims to investigate the distribution of HLA-A genes and identify alleles related to cervical cancer.
Materials and Methods: A total of 252 cervical cancer patients (56 Han ethnic and 196 Uyghur ethnic) and 213 controls (103 Han ethnic and 110 Uyghur ethnic) were recruited in this study. HLA-A alleles were examined by polymerase chain reaction with sequence-specific primers. The frequencies of different HLA-A alleles were compared between the two ethnic groups as well as patients and controls. The correlation of HLA-A frequencies with various clinical characteristics and short-term treatment efficacy was analyzed.
Results: (1) Significantly higher frequencies of HLA-A*03:01 and HLA-A*03:02 and lower frequencies of HLA-A*11:01, HLA-A*24:02, and HLA-A*30:01 were observed in the Uyghur control groups than in Han control groups (P ≤ 0.05). (2) The frequency of HLA-A*01:01 in patients was significantly higher than controls. In contrast, the frequencies of HLA-A*30:01 and HLA-A*33:03 were lower in patients (P ≤ 0.05). (3) The frequency of HLA-A*30:01 in Han patients was lower than Han control group (P ≤ 0.05). However, there was no statistically significant in the frequency of HLA-A between Uyghur patients and controls (P > 0.05). (4) There was no significant association between HLA-A alleles and HPV16 or squamous cell carcinoma antigen levels (P > 0.05). (5) The frequency of HLA-A*30:01 allele in complete response + partial response group was higher than stable disease + progressive disease group (P ≤ 0.05).
Conclusions: People from two ethnic groups displayed different HLA-A gene distribution. HLA-A*30:01 and HLA-A*33:03 alleles are the protective factors to cervical cancer patients from Xinjiang while HLA-A*01:01 serves as the susceptible gene.

BACKGROUND: Interleukin-32 (IL-32) has been associated with various diseases. Previous studies have shown that IL-32 inhibited the development of several tumors. However, the role of IL-32γ, an isotype of IL-32, in skin carcinogenesis remains unknown.
METHODS: We compared 7,12-Dimethylbenz[a]anthracene/12-O-Tetradecanoylphorbol-13-acetate (DMBA/TPA)-induced skin carcinogenesis in wild type (WT) and IL-32γ-overexpressing mice to evaluate the role of IL-32γ. We also analyzed cancer stemness and NF-κB signaling in skin cancer cell lines with or without IL-32γ expression by western blotting, quantitative real-time PCR and immunohistochemistry analysis.
RESULTS: Carcinogen-induced tumor incidence in IL-32γ mice was significantly reduced in comparison to that in WT mice. Infiltration of inflammatory cells and the expression levels of pro-inflammatory mediators were decreased in the skin tumor tissues of IL-32γ mice compared with WT mice. Using a genome-wide association study analysis, we found that IL-32 was associated with integrin αV (ITGAV) and tissue inhibitor of metalloproteinase-1 (TIMP-1), which are critical factor for skin carcinogenesis. Reduced expression of ITGAV and TIMP-1 were identified in DMBA/TPA-induced skin tissues of IL-32γ mice compared to that in WT mice. NF-κB activity was also reduced in DMBA/TPA-induced skin tissues of IL-32γ mice. IL-32γ decreased cancer cell sphere formation and expression of stem cell markers, and increased chemotherapy-induced cancer cell death. IL-32γ also downregulated expression of ITGAV and TIMP-1, accompanied with the inhibition of NF-κB activity. In addition, IL-32γ expression with NF-κB inhibitor treatment further reduced skin inflammation, epidermal hyperplasia, and cancer cell sphere formation and downregulated expression levels of ITGAV and TIMP-1.
CONCLUSIONS: These findings indicated that IL-32γ suppressed skin carcinogenesis through the inhibition of both stemness and the inflammatory tumor microenvironment by the downregulation of TIMP-1 and ITGAV via inactivation of NF-κB signaling.

Major tumor suppressor and transcription factor p53 coordinates expression of many genes hence affecting critical cellular functions including cell cycle, senescence, and apoptosis. The NR4A family of orphan receptors (NR4A1-3) belongs to the superfamily of nuclear receptors. They regulate genes involved in proliferation, cell migration, and apoptosis. In this study, we report an identification of NR4A3 as a direct transcriptional target of p53. Using various techniques, we showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. Functionally, over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. Knockdown of NR4A3 reversed these phenotypes. Importantly, NR4A3 exhibited tumor suppressive functions both in p53-dependent and independent manner. In addition, NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis. These observations were corroborated by the bioinformatics analysis, which demonstrated a correlation between high levels of NR4A3 expression and better survival of breast and lung cancer patients. Collectively, our studies revealed a novel transcriptional target of p53, NR4A3, which triggers apoptosis and thus likely has a tumor suppressive role in breast and lung cancers.

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.