SPARC promotes pancreatic cancer cell proliferation and migration through autocrine secretion into the extracellular milieu

SPARC is a secreted glycoprotein that plays a complex and multifaceted role in tumour formation and progression. However, whether SPARC is an oncogene or a tumour suppressor is still unclear. Moreover, SPARC demonstrates potential in clinical pancreatic adenocarcinoma (PAAD) treatment, although it has been identified as an oncogene in some studies and a tumor suppressor in others. In the present study, a pan-cancer analysis of SPARC was carried out using The Cancer genome Atlas data, which demonstrated that SPARC was an oncogene in most cancer types and a cancer suppressor in others. In addition, SPARC expression was significantly upregulated in PAAD and associated with poor prognosis. SPARC also promoted the proliferation and migration of PANC-1 and SW1990 cell lines in vitro. SPARC was detected in the culture supernatant of PAAD cells and pancreatic acinar AR42J cells. SPARC regulated PAAD cell proliferation only when secreted into the extracellular milieu, thus explaining why the prognosis of patients with PAAD is correlated with the SPARC expression of both tumour cells and stromal cells. Collectively, the present findings demonstrated that the function of SPARC was associated with tumour type and that SPARC may represent an important oncogene in PAAD that merits further study.     

The clinical applications of The Cancer Genome Atlas project for bladder cancer

Introduction: Knowledge of the molecular subtypes of bladder cancer enables powerful generalizations involving the distinctive biology and pathways driving different disease subsets.

Areas covered: In this review, we summarize the findings of a number of published studies exploring the molecular landscape of bladder cancer by analysis of genomic data from The Cancer Genome Atlas (TCGA). TCGA project has provided a comprehensive data resource of 412 muscle-invasive bladder cancers as characterized by multiple molecular analytical platforms. These data have been and will continue to be utilized in numerous subsequent studies aimed at better understanding the molecular basis of bladder cancer. The catalog of DNA-level alterations can greatly inform personalized and precision medicine approaches. Molecular subtypes of bladder cancer include distinct ‘basal/squamous’ and ‘luminal’ subtypes, cancers with papillary histology, disease subsets with prominent leukocyte infiltration and immune checkpoint marker expression, and a ‘neuronal’ subtype lacking small cell or neuroendocrine histology. The gene-level alterations and subtypes as revealed by TCGA data are relevant from the standpoint of both basic biology and clinical trial studies.

Expert commentary: Multiple studies analyzing TCGA muscle-invasive bladder cancer cases point to the existence of five major expression-based molecular subtypes of the disease, with these subtypes having therapeutic implications.     

lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

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Pan-cancer integrative histology-genomic analysis via multimodal deep learning

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Synthetic lethality between CCNE1 amplification and loss of BRCA1

High-grade serous ovarian cancers (HGSCs) are characterized by a high frequency of TP53 mutations, BRCA1/2 inactivation, homologous recombination dysfunction, and widespread copy number changes. Cyclin E1 (CCNE1) gene amplification has been reported to occur independently of BRCA1/2 mutation, and it is associated with primary treatment failure and reduced patient survival. Insensitivity of CCNE1-amplified tumors to platinum cross-linking agents may be partly because of an intact BRCA1/2 pathway. Both BRCA1/2 dysfunction and CCNE1 amplification are known to promote genomic instability and tumor progression. These events may be mutually exclusive, because either change provides a path to tumor development, with no selective advantage to having both mutations. Using data from a genome-wide shRNA synthetic lethal screen, we show that BRCA1 and members of the ubiquitin pathway are selectively required in cancers that harbor CCNE1 amplification. Furthermore, we show specific sensitivity of CCNE1-amplified tumor cells to the proteasome inhibitor bortezomib. These findings provide an explanation for the observed mutual exclusivity of CCNE1 amplification and BRCA1/2 loss in HGSC and suggest a unique therapeutic approach for treatment-resistant CCNE1-amplified tumors.Epithelial ovarian cancer is complex and histologically diverse but still largely treated as a single disease with limited stratification based on histological or molecular characteristics. High-grade serous ovarian cancer (HGSC) accounts for the majority of epithelial ovarian cancer-related deaths (>60%), and almost no improvement in survival has been observed in the last 20 y (1). Widespread copy number changes are a hallmark of HGSC, including focal amplification of Cyclin E1 (encoded by CCNE1), which is associated with primary treatment failure (2) and reduced survival (3). Amplification of CCNE1 is one of very few well-defined molecular targets in HGSC.Cyclin E1 forms a complex with cyclin-dependent kinase 2 (CDK2) to regulate G1/S transition as well as having kinase-independent functions, including in DNA replication (4). Ovarian cell lines with CCNE1 amplification show a specific dependency for maintenance of CCNE1 expression (5, 6). We have validated CDK2 as a therapeutic target by showing selective sensitivity to suppression either by gene knockdown or using small molecule inhibitors (7), consistent with findings in breast cancer (8).Recent genomic studies have revealed a high frequency of BRCA1/2 (Breast cancer 1/2, early onset) inactivation and homologous recombination (HR) dysfunction in HGSC (9). Alterations of genes in the HR pathway include germ-line and somatic mutations of BRCA1 or BRCA2 (∼20% of patients) and epigenetic silencing of BRCA1 by hypermethylation (∼10%). Other genes inactivated by deletion, mutation, or hypermethylation include ATM, ATR, RAD51C, and PTEN (∼10%), key Fanconi anemia members (∼5%), and amplification or mutation of EMSY (∼8%). Collectively, at least 50% of HGSCs are thought to have HR pathway defects (9).Approximately 30% of HGSC tumors have alterations in the Rb pathway or genes involved in Rb-mediated DNA repair and cell cycle control, including amplification of CCNE1 (∼20%), loss of RB1 (∼10%), or gain of RBBP8 (∼4%) (10). Strikingly, activation of the RB1/CCNE1 pathway is largely exclusive of BRCA1/2 mutation for reasons that are unclear (9, 10). Both BRCA1/2 dysfunction and CCNE1 amplification are known to promote genomic instability and tumor progression (4, 11); therefore, they may be mutually exclusive, because either change provides a path to tumor development, with no selective advantage to having both mutations (10). Insensitivity of CCNE1-amplified tumors to platinum cross-linking agents may be partly because of an intact BRCA1/2 pathway, suggesting that these patients are unlikely to respond to poly-ADP-ribose polymerase (PARP) inhibitors.Here, we show that BRCA1 and members of the ubiquitin pathway are selectively required in cancers that harbor CCNE1 amplifications. Furthermore, we show specific sensitivity of CCNE1-amplified tumor cells to the proteasome inhibitor bortezomib. These findings provide an explanation for the observed mutual exclusivity of CCNE1 amplification and BRCA1/2 loss in HGSCs and suggest a unique therapeutic approach for treatment-resistant CCNE1-amplified tumors.     

泛癌分析长链非编码RNA MIR22HG的表达特征

目的 泛癌分析长链非编码RNA（lncRNA）MIR22HG的表达及其与临床特征的关系。方法 R语言分析癌症基因组图谱（TCGA）中MIR22HG在不同肿瘤组织中的表达及其与临床分期、淋巴结转移、肿瘤突变负荷（TMB）及微卫星不稳定（MSI）的关系;应用TIMER比较MIR22HG表达与免疫浸润的关系;使用cBioPortal分析MIR22HG的突变频率及其与预后的关系;使用GDSC在线数据库分析MIR22HG与化疗药物敏感性的关系。利用GEO数据库肝癌数据集和12对肝癌标本验证MIR22HG在肝癌中的表达及其与索拉非尼治疗反应的关系;分析MIR22HG表达与索拉非尼治疗预后的关系;在肝癌细胞株HCC-LM3中过表达MIR22HG（NC组,MIR22HG过表达组）,在肝癌细胞株MHCC-97H中敲除MIR22HG（NC组,sh-MIR22HG组）,采用CCK-8检测肝癌细胞中MIR22HG对索拉非尼IC50的影响。结果 MIR22HG在大多数肿瘤中低表达（P<0.05）,且多数肿瘤中MIR22HG基因存在缺失突变,其突变与肿瘤不良预后相关（P<0.05）。MIR22HG的表达水平与多种肿瘤的临床分期及淋巴结转移相关（P<0.05）。在多种肿瘤中MIR22HG的表达水平与TBM、MSI、免疫评分、免疫检查点相关基因表达及化疗药的药物敏感性显著相关（P<0.05）。6种常见免疫细胞中,中性粒细胞浸润水平与MIR22HG的表达水平相关性最强,尤其在乳腺癌、直肠癌及肾乳头状细胞癌中明显。多个数据集的分析结果验证MIR22HG在肝癌中低表达,且其低表达与肝癌进展相关（P<0.05）。MIR22HG低表达的患者经索拉非尼治疗后预后较好（HR=2.94, P=0.075）,其低表达能有效预测肝癌患者索拉非尼治疗效果（AUC=0.8095）。过表达MIR22HG能降低肝癌细胞对索拉非尼的敏感性（IC50 NC vs IC50 MIR22HG=7.731 vs 15.61）;而敲除MIR22HG的表达则能增加肝癌细胞对索拉非尼的敏感性（IC50 NC vs IC50sh-MIR22HG=7.986 vs 5.085）。结论 MIR22HG的表达与多种肿瘤的分期、有否淋巴结转移、肿瘤突变负荷、微卫星不稳定、免疫细胞浸润及化疗药物敏感性相关。     

The Impact of Radiotherapy on the Incidence of Secondary Malignancies: A Pan-Cancer Study in the US SEER Cancer Registries

The population of cancer patients with second primary malignancies (SPMs) is rapidly growing. The relationship between radiotherapy and SPMs for some types of tumors is unknown or debated. In this study, we identify 24 types of first primary malignancies (FPMs) between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients in the radiotherapy group were matched to those in the no radiotherapy group with a matching ratio of 1:1. After propensity-score matching (PSM), additional competing risk regression analyses were performed to calculate the efficacy of radiotherapy to SPMs in the PSM-adjusted population. In addition, the Fine and Gray model was utilized in the primary cohorts, and stratified analyses were performed based on surgery. This study includes a total of 2,831,789 eligible patients with tumors diagnosed from 2004 to 2015 in the SEER 18 database, amongst whom 100,194 (3.5%) patients developed SPMs. We observe higher risks of SPMs associated with radiotherapy in several types of tumors in the PSM-adjusted populations (small bowel adenocarcinoma, small cell lung carcinoma, prostate adenocarcinoma, urinary bladder transitional cell carcinoma, invasive ductal breast carcinoma, invasive lobular breast carcinoma, and Hodgkin lymphoma). The results in the PSM-adjusted populations were consistent with outcomes in the multivariable competing risk models. Meanwhile, in subgroup analyses stratified by surgery, some other types of tumor (except for those with positive results in the PSM-adjusted cohorts) with radiotherapy were also associated with a higher prevalence of SPMs in the subgroups of surgical treatment (pancreatic adenocarcinoma, rectal adenocarcinoma, lung adenocarcinoma and follicular thyroid carcinoma in the surgery subgroups). The impact of radiotherapy on the incidence of secondary malignancies is distinct in different types of cancer. These findings merit further investigation and may ultimately impact treatment decision-making for tumor management.