Next Generation Sequencing-based Validation of the Revised International Staging System for Multiple Myeloma: An Analysis of the MMRF CoMMpass Study

IntroductionThe clinical application of the Revised International Staging System (R-ISS) for multiple myeloma may be limited by heterogeneity in clinical interphase fluorescent in situ hybridization (FISH) practices for detecting chromosomal abnormalities (CAs). Next generation sequencing (NGS)-based FISH (Seq-FISH) has demonstrated improved sensitivity and similar specificity relative to clinical FISH, and provides a standardized, single-pass method for identifying high-risk CAs. To date, calculating R-ISS stage using Seq-FISH (R-ISS-NGS) has not been validated.Patients and MethodsWe identified 672 patients with sufficient data to calculate R-ISS-NGS from the Multiple Myeloma Research Foundation (MMRF) CoMMpass Study. R-ISS-NGS was calculated from original ISS stage, lactate dehydrogenase, and CAs detected by Seq-FISH. Endpoints included overall survival and progression-free survival. We conducted multivariate analyses controlling for age and gender in order to compare outcomes across stages I to III of both the original ISS and R-ISS-NGS.ResultsThe median follow-up was 24 months. The R-ISS-NGS resulted in significant redistribution of patients into stage II, relative to the original ISS. With respect to stage I, R-ISS-NGS stages II and III of were associated with worse progression-free survival or overall survival, more so than the staging schema of the ISS, thus validating the use of Seq-FISH in staging.ConclusionUsing CAs detected by Seq-FISH and data from the CoMMpass study, we validated the R-ISS with a large, generalizable cohort. This study validates the substitution of Seq-FISH for clinical FISH, especially in large registry studies. Additionally, use of the validated R-ISS-NGS will strengthen outcomes research generated from the CoMMpass study.     

A prognostic signature based on immune-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is the fourth commonest female malignancy worldwide. CESC progresses in immune-microenvironment mainly composed of infiltrating immune and stromal cells. Here, we performed an integrated analysis incorporating the expression profiles from the Cancer Genome Atlas (TCGA) database and scores of immune and stromal cells calculated by Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm. A two-gene signature (CD1C and CD6 genes) was established to predict the prognosis of CESC. Based on this signature, patients were divided into the high- and low-risk groups, and this signature showed good prognostic performance according to the results of Kaplan-Meier analysis and receiver operating characteristic (ROC) analysis in train set and two validation sets. A nomogram was built for evaluating the clinical applicability of this signature. In addition, based on Tumor Immune Estimation Resource (TIMER) database, 2 hub genes showed negative correlations with tumor purity and positive correlations with infiltrating levels of immune filtrating cells. What’s more, we propose new treatment strategies for the two prognostic subtypes. Low- risk patients were found presenting with a higher level of immune checkpoint molecules and showing higher immunogenicity in immunophenoscore (IPS) analysis, which indicated a better response for immunotherapy. Meanwhile, estimated by Genomics of Drug Sensitivity in Cancer (GDSC) database, the high-risk patients showed sensitive responses to five chemotherapy drugs. Finally, 10 candidate small-molecule drugs for CESC were defined. In summary, the CD1C-CD6 signature can accurately predict the prognosis of CESC.     

Comprehensive analysis of tumor immune infiltration associated with endogenous competitive RNA networks in lung adenocarcinoma

Cancer immunotherapy has achieved unprecedented success in the treatment of cancer. However, different patients have different responses to immunotherapy. More and more studies have shown that tumor immune heterogeneity has an important influence on the prognosis of cancer. Therefore, understanding the clinical impact of tumor immune infiltration and the regulatory mechanism of RNA molecules is crucial for exploring the pathogenesis of lung adenocarcinoma (LUAD) and the development of immunotherapy protocols.The endogenous competitive RNA hypothesis provides new ideas for studying immune heterogeneity. Therefore, by using the method of immune genomics, this article explores the relationship between immune infiltration and prognosis of patients with lung adenocarcinoma, and found that B-cell immune infiltration highly affects the survival of patients. Through differential analysis, differential mRNAs, lncRNAs and miRNAs were extracted, and 318 differentially expressed mRNAs related to B cell immunity were screened by correlation analysis, and prognosis of patients with COX risk regression model was predicted and analyzed. Through multiple database searches, an immune-related ceRNA regulatory network was constructed, containing 3 key mRNAs, 4 miRNAs, and 50 lncRNAs. Three mRNAs and most miRNAs, lncRNAs, are significantly associated with LUAD prognosis. Bioinformatics analysis of the network showed that LINC00337 may up-regulate the expression of PBK and KIF23 through competitive binding of has-mir-373 and has-mir-519d. The competitive binding of has-mir-373 and has-mir-372 can up-regulate the expression of SLC7A11. The interaction between these RNAs may have an important regulatory role in the immune infiltration in lung adenocarcinoma, thereby affecting the patient's prognosis and immunotherapy efficacy.     

2018年系统性红斑狼疮研究新进展

【摘要】 系统性红斑狼疮是一种主要累及中青年女性的复杂自身免疫疾病，临床表现多样，发病机制复杂。对于系统性红斑狼疮的研究一直是国内外自身免疫疾病领域的热点，本文主要综述2018年系统性红斑狼疮的基因组学与临床研究取得的新成果和进展。     

Genomic and phenotypic comparison of two Salmonella Typhimurium strains responsible for consecutive salmonellosis outbreaks in New Zealand

Salmonella enterica serovar Typhimurium DT160 was the predominant cause of notified human salmonellosis cases in New Zealand from 2000 to 2010, before it was superseded by another S. Typhimurium strain, DT56 variant (DT56v). Whole genome sequencing and phenotypic testing were used to compare 109 DT160 isolates with eight DT56v isolates from New Zealand animal and human sources. Phylogenetic analysis provided evidence that DT160 and DT56v strains were distantly related with an estimated date of common ancestor between 1769 and 1821. The strains replicated at different rates but had similar antimicrobial susceptibility profiles. Both strains were resistant to the phage expressed from the chromosome of the other strain, which may have contributed to the emergence of DT56v. DT160 contained the pSLT virulence plasmid, and the sseJ and sseK2 genes that may have contributed to the higher reported prevalence compared to DT56v. A linear pBSSB1-family plasmid was also found in one of the DT56v isolates, but there was no evidence that this plasmid affected bacterial replication or antimicrobial susceptibility. One of the DT56v isolates was also sequenced using long-read technology and found to contain an uncommon chromosome arrangement for a Typhimurium isolate. This study demonstrates how comparative genomics and phenotypic testing can help identify strain-specific elements and factors that may have influenced the emergence and supersession of bacterial strains of public health importance.     

Genomic,pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer

Prostate cancer (CaP) is the most commonly diagnosed malignancy in men in the Western world. In North America, more than 275,000 men are diagnosed annually, whereby approximately 1 in 6 men will be diagnosed with CaP in their lifetime, and 1 in 34 men will die from castration-resistant metastatic disease. Unfortunately, current clinical prognostic factors explain only a proportion of the observed variation in clinical outcome from patient to patient. Furthermore, overtreatment of indolent and low-risk cancers leads to inappropriate morbidity following radiotherapy or surgery. As such, better predictors of individualized prognosis and treatment response are urgently needed to triage patients to customized and intensified CaP treatment. Recent developments in next-generation sequencing have made it possible to identify prognostic and predictive signatures based on genomic profiles. We discuss the genetic basis of CaP progression from localized to systemic disease (e.g., point mutations, copy-number alterations, and structural variants) in relation with unique features of CaP biology, including intraprostatic and interprostatic heterogeneity, multifocality and multiclonality, TMPRSS2:ERG, and other ETS-family gene fusions. Finally, we focus on the use of genomic markers as prognostic factors for local failure and for systemic disease, as novel risk-stratification tools, in triaging patients to existing treatment options, and ultimately the potential of genomics for the identification of molecular targets for therapy of CaP.