National Cancer Institute’s early detection research network:a model organization for biomarker research

For many cancers a primary cause of poor survival is that they are detected at a late stage when therapies are less effective.Although screening methods exist to detect some types of cancer at an early stage,there are currently no effective methods to screen for most types of cancer.Biomarkers have the potential to improve detection of early-stage cancers,risk stratification,and prediction of which pre-cancerous lesions are likely to progress and to make screening tests less invasive.Although thousands of research articles on biomarkers for early detection are published every year,few of these biomarkers have been validated and shown to be clinically useful.This reflects both the inherent difficulty in detecting early-stage cancers and a disconnect between the process of discovering biomarkers and their use in the clinic.To overcome this limitation the US National Cancer Institute created the Early Detection Research Network.It is a highly collaborative program that brings together biomarker discoverers,assay developers,and clinicians.It provides an infrastructure that is essential for developing and validating biomarkers and imaging methods for early cancer detection and has successfully completed several multicenter validation studies.

RIP140 regulates POLK gene expression and the response to alkylating drugs in colon cancer cells

Aim:The transcription factor RIP140(receptor interacting protein of 140 kDa)is involved in intestinal tumorigenesis.It plays a role in the control of microsatellite instability(MSI),through the regulation of MSH2 and MSH6 gene expression.The aim of this study was to explore its effect on the expression of POLK,the gene encoding the specialized translesion synthesis(TLS)DNA polymeraseκknown to perform accurate DNA synthesis at microsatellites.Methods:Different mouse models and engineered human colorectal cancer(CRC)cell lines were used to analyze by RT-qPCR,while Western blotting and luciferase assays were used to elucidate the role of RIP140 on POLK gene expression.Published DNA microarray datasets were reanalyzed.The in vitro sensitivity of CRC cells to methyl methane sulfonate and cisplatin was determined.Results:RIP140 positively regulates,at the transcriptional level,the expression of the POLK gene,and this effect involves,at least partly,the p53 tumor suppressor.In different cohorts of CRC biopsies(with or without MSI),a strong positive correlation was observed between RIP140 and POLK gene expression.In connection with its effect on POLK levels and the TLS function of this polymerase,the cellular response to methyl methane sulfonate was increased in cells lacking the Rip140 gene.Finally,the association of RIP140 expression with better overall survival of CRC patients was observed only when the corresponding tumors exhibited low levels of POLK,thus strengthening the functional link between the two genes in human CRC.Conclusion:The regulation of POLK gene expression by RIP140 could thus contribute to the maintenance of microsatellite stability,and more generally to the control of genome integrity.

Integrated analysis of public datasets for the discovery and validation of survival-associated genes in solid tumors

Identifying genes with prognostic significance that can act as biomarkers in solid tumors can help stratify patients and uncover novel therapy targets.Here,our goal was to expand our previous ranking analysis of survival-associated genes in various solid tumors to include colon cancer specimens with available transcriptomic and clinical data.A Gene Expression Omnibus search was performed to identify available datasets with clinical data and raw gene expression measurements.A combined database was set up and integrated into our Kaplan-Meier plotter,making it possible to identify genes with expression changes linked to altered survival.As a demonstration of the utility of the platform,the most powerful genes linked to overall survival in colon cancer were identified using uni-and multivariate Cox regression analysis.The combined colon cancer database includes 2,137 tumor samples from 17 independent cohorts.The most significant genes associated with relapse-free survival with a false discovery rate below 1%in colon cancer carcinoma were RBPMS(hazard rate[HR]=2.52),TIMP1(HR=2.44),and COL4A2(HR=2.36).The three strongest genes associated with shorter survival in stage II colon cancer include CSF1R(HR=2.86),FLNA(HR=2.88),and TPBG(HR=2.65).In summary,a new integrated database for colon cancer is presented.A colon cancer analysis subsystem was integrated into our Kaplan-Meier plotter that can be used to mine the entire database(https://www.kmplot.com).The portal has the potential to be employed for the identification and prioritization of promising biomarkers and therapeutic target candidates in multiple solid tumors including,among others,breast,lung,ovarian,gastric,pancreatic,and colon cancers.