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The 14q32 maternally imprinted locus is a major source of longitudinally stable circulating microRNAs as measured by small RNA sequencing

Valbuena, Gabriel N., Apostolidou, Sophia, Roberts, Rhiannon, Barnes, Julie, Alderton, Wendy, Harper, Lauren, Jacobs, Ian, Menon, Usha, Keun, Hector C.·2019·Scientific Reports
DOI 10.1038/s41598-019-51948-6PMC PMC6823392
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Abstract

Understanding the normal temporal variation of serum molecules is a critical factor for identifying useful candidate biomarkers for the diagnosis and prognosis of chronic disease. Using small RNA sequencing in a longitudinal study of 66 women with no history of cancer, we determined the distribution and dynamics (via intraclass correlation coefficients, ICCs) of the miRNA profile over 3 time points sampled across 2–5 years in the course of the screening trial, UKCTOCS. We were able to define a subset of longitudinally stable miRNAs (ICC >0.75) that were individually discriminating of women who had no cancer over the study period. These miRNAs were dominated by those originating from the C14MC cluster that is subject to maternal imprinting. This assessment was not significantly affected by common confounders such as age, BMI or time to centrifugation nor alternative methods to data normalisation. Our analysis provides important benchmark data supporting the development of miRNA biomarkers for the impact of life-course exposure as well as diagnosis and prognostication of chronic disease.

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Figure 1 Distributions of study set demographic information. (A) age at sampling, (B) time to centrifugation, (C) BMI at recruitment, (D) Regional Centre of collection for our study set, (E) time difference between successive samples, and (F) time from first to last sample.
Figure 1 Distributions of study set demographic information. (A) age at sampling, (B) time to centrifugation, (C) BMI at recruitment, (D) Regional Centre of collection for our study set, (E) time difference between successive samples, and (F) time from first to last sample.CC BY · PubMed Central
Figure 2 Abundance of miRNAs in circulation. (A) The top 20 miRNAs by percentage of total circulating miRNA. (B) Mean microRNA counts per million (cpm) in circulation, ordered by magnitude. (C) Cumulative fraction of total microRNAs for the top 100 microRNAs by abundance. (D) Cumulative distribution of miRNA detection rates at certain cpm thresholds.
Figure 2 Abundance of miRNAs in circulation. (A) The top 20 miRNAs by percentage of total circulating miRNA. (B) Mean microRNA counts per million (cpm) in circulation, ordered by magnitude. (C) Cumulative fraction of total microRNAs for the top 100 microRNAs by abundance. (D) Cumulative distribution of miRNA detection rates at certain cpm thresholds.CC BY · PubMed Central
Figure 3 Confounding effects of age, BMI, regional centre, and time to centrifugation. Variance explained (R2) against p-values corrected for multiple testing for (A) age, (B) BMI at study enrollment, (C) regional centre of collection, and (D) time to centrifugation.
Figure 3 Confounding effects of age, BMI, regional centre, and time to centrifugation. Variance explained (R2) against p-values corrected for multiple testing for (A) age, (B) BMI at study enrollment, (C) regional centre of collection, and (D) time to centrifugation.CC BY · PubMed Central
Figure 4 Intra-class correlation coefficients (ICCs) for consistently detected circulating miRNAs. (A) Distribution of ICCs for consistently detected miRNAs, with a median ICC of 0.36 shown in red. (B) ICCs vs. read counts per million.
Figure 4 Intra-class correlation coefficients (ICCs) for consistently detected circulating miRNAs. (A) Distribution of ICCs for consistently detected miRNAs, with a median ICC of 0.36 shown in red. (B) ICCs vs. read counts per million.CC BY · PubMed Central
Figure 5 Comparison of ICCs calculated using total depth-normalized data compared to trimmed mean of m (TMM)-normalized data. (A) Distributions of ICCs and (B) scatter plot of ICCs for each miRNA of total depth-normalized data (as reads per million, RPM) and TMM- normalized data.
Figure 5 Comparison of ICCs calculated using total depth-normalized data compared to trimmed mean of m (TMM)-normalized data. (A) Distributions of ICCs and (B) scatter plot of ICCs for each miRNA of total depth-normalized data (as reads per million, RPM) and TMM- normalized data.CC BY · PubMed Central
Figure 6 Comparison of ICCs from the longitudinal study carried out by Keller et al. (2017) and our own study. (A) Distributions of ICCs and (B) scatter plot comparing ICCs for 113 miRNAs detected in both studies.
Figure 6 Comparison of ICCs from the longitudinal study carried out by Keller et al. (2017) and our own study. (A) Distributions of ICCs and (B) scatter plot comparing ICCs for 113 miRNAs detected in both studies.CC BY · PubMed Central
Figure 7 A cluster of miRNAs with ICCs above 0.5 can be found on the long arm of chromosome 14.
Figure 7 A cluster of miRNAs with ICCs above 0.5 can be found on the long arm of chromosome 14.CC BY · PubMed Central

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Citations

Cites

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Metadata

Authors
Valbuena, G. N., Apostolidou, S., Roberts, R., Barnes, J., Alderton, W., Harper, L., Jacobs, I., Menon, U., & Keun, H. C.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-10-31
Volume
9
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-019-51948-6
PMC
PMC6823392
Cited by
13
References
5
Language
en
Licence
Funders
  • Cancer Research UK (C19335/A22544, C1479/A2884)
  • RCUK | Medical Research Council (G9901012, G0801228)

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