A 10‐year prediagnostic follow‐up study shows that serum RNA signals are highly dynamic in lung carcinogenesis

Abstract

The majority of lung cancer (LC) patients are diagnosed at a late stage, and survival is poor. Circulating RNA molecules are known to have a role in cancer; however, their involvement before diagnosis remains an open question. In this study, we investigated circulating RNA dynamics in prediagnostic LC samples, focusing on smokers, to identify if and when diseaserelated signals can be detected in serum. We sequenced small RNAs in 542 serum LC samples donated up to 10 years before diagnosis and 519 matched cancer-free controls coming from 905 individuals in the Janus Serum Bank. This sample size provided sufficient statistical power to independently analyze time to diagnosis, stage, and histology. The results showed dynamic changes in differentially expressed circulating RNAs specific to LC histology and stage. The greatest number of differentially expressed RNAs was identified around 7 years before diagnosis for earlystage LC and 1-4 years prior to diagnosis for locally advanced and advanced-stage LC, regardless of LC histology. Furthermore, NSCLC and SCLC histologies have distinct prediagnostic signals. 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 LC. However, the dynamic nature of the RNA signals also suggests challenges for prediagnostic biomarker discovery.

Serum RNA Profiling in the 10-Years Period Prior to Diagnosis of Testicular Germ Cell Tumor

“…Although previous studies have identified TGCT specific RNA profiles in patients ( 28 – 30 ), this has not been described for the pre-diagnostic period, as seen in our study. In contrast to our findings, highly dynamic pre-diagnostic RNA signals have been observed in lung cancer and breast cancer samples ( 27 , 47 , 48 ). The reason for this contrast may partly be due to the localization of the tumor within the testis.…”

“…Previous studies have shown the feasibility of using long-term archived serum samples for RNA analyses and the variability of the RNA levels (23,31,36). The methods and analyses of the TGCT serum samples were similar to studies by Umu et al (27). The donors have given broad consent for the use of the samples in cancer research.…”

“…Specifically, miR-150-5p and miR-99b-5p were found to be downregulated in CRC patients compared to healthy patients (26). Differential levels of circulating RNA were also observed in pre-diagnostic serum samples in lung cancer patients, with an overall dynamic trend when advancing clinically (27).…”

Data Resource Profile: thousands of circulating RNA profiles of pre-clinical samples from the Janus Serum Bank Cohort

“…We restricted our selection to cases with at least one sample collected within 10 years prior to cancer diagnosis. The dynamics in RNA levels prior to a cancer diagnosis is sparsely described, however studies in Janus showed that most changes in RNA expression occurred close to a lung cancer diagnosis (8), and depend on staging (9). Based on our knowledge from using pre-diagnostic samples we considered 10 years prior to diagnosis as a reasonable timeframe for the study objectives.…”

Competitive learning suggests circulating miRNA profiles for cancers decades prior to diagnosis

“…Also other factors such as smoking influenced the miRNA expression significantly 18 . Furthermore, we previously also provided first and preliminary indications for pre-diagnostic miRNA profiles 19 in serum of individuals, who were later diagnosed with lung cancer 20 .…”