Biomarkers of Cancer: Biocomputional analysis of data from population-based biobanks and health registries

About 35 000 Norwegians are diagnosed with cancer annually and cancer is the leading cause of death overall in Norway. Breast and prostate cancer are the most common types of cancer in women and men respectively, followed by colorectal and lung cancer in both gender. Tools to detect cancer at an early stage and improve survival is of great importance. The overall aim of this project is to investigate miRNA and other circulating RNAs as early markers and potential screening biomarkers for cancer. A microRNA (miRNA) is a small single-stranded non-coding RNA molecule (containing about 22 nucleotides) that functions in RNA silencing and post-transcriptional regulation of gene expression and are involved in all hallmarks of cancer. The potential of miRNAs as cancer biomarkers is recognized, however little is known about circulating miRNA expression prior to cancer diagnosis. We have produced non-coding RNA sequencing data from pre-diagnostic serum samples from the Janus Serum Bank Cohort. We have included patients with lung cancer (n=404), colorectal cancer (n=488), breast cancer (n=206) and prostate cancer (n=332) with a sample collected within 10 years prior to cancer diagnosis, and a large control group of 673 healthy individuals. In addition we have produced data from patients with testicular, ovarian and gallbladder cancer. The project is initiated and lead by the Cancer Registry of Norway and is performed in close collaboration with the Norwegian Sequencing Centre at Oslo University Hospital, the University of Oslo. We have developed and optimized a RNA sequencing method for samples with low input RNA. The sequencing data is combination with detailed cancer information from the Cancer Registry of Norway and information on environmental exposures from health surveys, in advanced biocomputational analysis. The sequencing depth is 18 mill sequences and we have identified more than 600 unique miRNAs per sample in addition to a number of other non-coding RNAs. Results published on the healthy control group shows that RNA expression levels are significantly affected by age and smoking. For lung cancer the results showed dynamic changes in differentially expressed circulating RNAs specific to histology and stage. The greatest number of differentially expressed RNAs was identified around 7 years before diagnosis for early?stage lung cancer and 1?4 years prior to diagnosis for locally advanced and advanced?stages, regardless of histology. The majority of differentially expressed RNAs were associated with cancer?related pathways. The dynamic RNA signals pinpointed different phases of tumor development over time. Stage?specific RNA profiles may be associated with tumor aggressiveness. Our results improve the molecular understanding of carcinogenesis. They indicate substantial opportunity for screening and improved treatment and will guide further research on early detection of lung cancer. https://www.kreftregisteret.no/en/Research/Projects/Identification-of-early-cancer-biomarkers/

Prosjektet har bidratt til økt kunnskap om dynamikken i miRNA og en rekke andre RNA profiler i prediagnostiske serumprøver avgitt opptil 10 år før en kreftdiagnose. Dette vil bidra til identifisering av tidlige markører for kreft. Prosjektet har bidratt til økt kunnskap om den naturlige variasjonen av RNA profiler hos personer som ikke utvikler kreft, og hvilke faktorer som påvirker uttrykket (alder, røykevaner, prøvekvalitet etc). Videre har prosjektet utviklet en bioinformatisk og biostatistisk pipeline for analyse av komplekse data og ført til økt tverrfaglig og internasjonalt forskningssamaarbeid. Dataene som er produsert i prosjektet har potensiell nytteverdi for kreftpasienter og deres pårørende, helsepersonell som vil ha bruk for verktøy for å stille diagnose på et tidlig tidspunkt og velge behandlingsopplegg for den enkelte pasient og for forskere som studerer kreftbiomarkører.

We propose to build advanced biocomputational analysis capacity to handle large-scale genetics, biomarker and epidemiological data, in collaboration with bioinformatics and biostatistical colleagues at University of Oslo and international collaborators. We will apply this analysis capacity on specific cancer challenges. Cancer is the third-most common cause of premature death worldwide and the second leading cause of death overall in Norway. Screening may lead to early detection of several cancers, however, molecular biomarkers may improve upon detection and distinguish between indolent and aggressive subtypes. miRNAs have a key role in cancer onset and progression due to their regulation of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. The perspective of miRNAs as cancer biomarkers is recognized, however, the translational potential is inadequately proven. Little is known about circulating miRNA expression prior to cancer diagnosis. We propose to profile miRNA expression dynamics in lung and colorectal cancer, in order to determine when, relative to diagnosis, and with what confidence, carcinogenesis can be detected. We will also study whether the associations between miRNA expression levels and these cancers are independent, and not confounded by known risk factors, and whether miRNAs represent intermediate variables in the causal pathway between various exposures and cancer. By combining data from the complete nationwide Cancer Registry of Norway, novel laboratory results from the large population-based Janus Serum Bank, and environmental exposure data from national health surveys, we have a unique possibility to address this lack of knowledge. We will use established miRNA sequencing infrastructure, developed in collaboration with Norwegian sequencing center, funded by the BIOBANK program.