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The circular RNome of primary breast cancer

Marcel Smid¹, Saskia M Wilting¹, Katharina Uhr¹

¹Erasmus MC Cancer Institute and Cancer Genomics Netherlands, University Medical Center Rotterdam, Department of Medical Oncology, 3015GD Rotterdam, the Netherlands.

Genome Research

|January 30, 2019

Abstract:

Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R < 0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and RERE in an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2 was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2 levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2 is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer.

Insights

Circular RNAs (circRNAs) are newly identified as important in breast cancer. Specific circRNAs impact cell viability and predict treatment response, showing their clinical relevance.

Area of Science:

Oncology
Molecular Biology
Genomics

Background:

Circular RNAs (circRNAs) are a class of RNA molecules with debated functional roles.
Their specific biogenesis and regulation are not fully understood.
Breast cancer research is exploring novel molecular markers for diagnosis and treatment.

Purpose of the Study:

To identify and characterize circRNAs in breast cancer using RNA-sequencing data.
To investigate the specific regulation and biological relevance of circRNAs in breast cancer.
To determine if circRNAs can serve as predictive biomarkers for breast cancer patient outcomes and therapy response.

Main Methods:

Analysis of RNA-sequencing data from 348 primary breast cancers.
Development of a novel method to identify circRNAs independent of unmapped reads or known splice junctions.
siRNA-mediated knockdown experiments and correlation analyses with clinical and biological features.

Main Results:

Identification of 95,843 circRNAs, with 20,441 found recurrently in breast cancers.
Discovery of 668 circRNAs with low or negative correlation to their linear gene counterparts, suggesting specific regulation.
circRNA profiles associated with breast cancer subgroups, tumor microenvironment, and proliferation.
circCNOT2 knockdown reduced breast cancer cell viability; circCNOT2 levels predicted progression-free survival in patients treated with aromatase inhibitors.
circCNOT2 detected in cell-free plasma RNA.

Conclusions:

CircRNAs are abundantly present in breast cancer and exhibit characteristics of specific regulation.
CircRNAs are associated with distinct clinical and biological properties of breast cancer.
circCNOT2 demonstrates potential as a predictive biomarker for AI therapy response and is detectable in plasma, highlighting the clinical relevance of circRNAs in breast cancer.

Read full analysis

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