Breast cancer associated germline structural variants harboring small noncoding RNAs impact post-transcriptional gene regulation

Mahalakshmi Kumaran,Yutaka Yasui,Carol E Cass,Wan Lam,Sambasivarao Damaraju,Roland Hubaux,Preethi Krishnan

doi:10.1038/s41598-018-25801-1

Mahalakshmi Kumaran, Yutaka Yasui + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-25801-1

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Abstract

Copy Number Variants (CNVs) are a class of structural variations of DNA. Germline CNVs are known to confer disease susceptibility, but their role in breast cancer warrants further investigations. We hypothesized that breast cancer associated germline CNVs contribute to disease risk through gene dosage or other post-transcriptional regulatory mechanisms, possibly through tissue specific expression of CNV-embedded small-noncoding RNAs (CNV-sncRNAs). Our objectives are to identify breast cancer associated CNVs using a genome wide association study (GWAS), identify sncRNA genes embedded within CNVs, confirm breast tissue (tumor and normal) expression of the sncRNAs, correlate their expression with germline copy status and identify pathways influenced by the genes regulated by sncRNAs. We used an association study design and accessed germline CNV data generated on Affymetrix Human SNP 6.0 array in 686 (in-house data) and 495 (TCGA data) subjects served as discovery and validation cohorts. We identified 1812 breast cancer associated CNVs harboring miRNAs (n = 38), piRNAs (n = 9865), snoRNAs (n = 71) and tRNAs (n = 12) genes. A subset of CNV-sncRNAs expressed in breast tissue, also showed correlation with germline copy status. We identified targets potentially regulated by miRNAs and snoRNAs. In summary, we demonstrate the potential impact of embedded CNV-sncRNAs on expression and regulation of down-stream targets.

Highlights

Breast cancer (BC) is one of the most common cancers diagnosed among women[1]
Copy Number Variations (CNVs) can influence phenotype in a variety of ways: through gene dosage, partial deletions in genic regions leading to fusion genes, or complete deletions of genes, and lastly, changes that lead to more complex levels of cis or trans regulatory functions[5,6]
We reasoned that studies of germline CNVs harboring small non-coding RNAs such as microRNAs, piwi-interacting RNAs, small nucleolar RNAs and transfer RNAs and their relative levels of expression in breast tissues potentially offers biological insights into the role of CNV-sncRNAs in breast cancer risk

Summary

Introduction

Breast cancer (BC) is one of the most common cancers diagnosed among women[1]. High, moderate and low penetrance single nucleotide variants associated with breast cancer explained only 50% of the heritable risk and much of the remaining genetic susceptibility (so-called missing heritability) remains unexplored[3,4]. Majority of these variants are present in the intronic or intergenic regions and precludes delineation of their role in breast cancer pathogenesis. Dysregulation of all four classes of sncRNAs has been observed in various cancer types, including breast cancer, and its clinical significance has been addressed in some detail (miRNAs and piRNAs)[10,11] or is emerging (snoRNAs and tRNAs)[12,13]

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