High copy number variation of cancer-related microRNA genes and frequent amplification of DICER1 and DROSHA in lung cancer.

Karol Czubak,Marzena Anna Lewandowska,Katarzyna Klonowska,Marek Figlerowicz,Piotr Kozlowski,Krzysztof Roszkowski,Janusz Kowalewski

doi:10.18632/oncotarget.4351

Abstract

A growing body of evidence indicates that miRNAs may be a class of genetic elements that can either drive or suppress oncogenesis. In this study we analyzed the somatic copy number variation of 14 miRNA genes frequently found to be either over- or underexpressed in lung cancer, as well as two miRNA biogenesis genes, DICER1 and DROSHA, in non-small-cell lung cancer (NSCLC). Our analysis showed that most analyzed miRNA genes undergo substantial copy number alteration in lung cancer. The most frequently amplified miRNA genes include the following: miR-30d, miR-21, miR-17 and miR-155. We also showed that both DICER1 and DROSHA are frequently amplified in NSCLC. The copy number variation of DICER1 and DROSHA correlates well with their expression and survival of NSCLC and other cancer patients. The increased expression of DROSHA and DICER1 decreases and increases the survival, respectively. In conclusion, our results show that copy number variation may be an important mechanism of upregulation/downregulation of miRNAs in cancer and suggest an oncogenic role for DROSHA.

Highlights

Cancer initiation and development are associated with the accumulation of numerous genetic alterations in the cancer genome
non-small-cell lung cancer (NSCLC) can be further divided into adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma
Only a small fraction of alterations occurring in cancer genomes are functional (“driver”) mutations; others are “passenger” mutations that occur as a consequence of the general cancer genome destabilization

Summary

Introduction

Cancer initiation and development are associated with the accumulation of numerous genetic alterations in the cancer genome These alterations include both small-size mutations and large-scale genomic alterations consisting of copy number variants (CNVs - deletions, duplications or amplifications), as well as copy-numberneutral genomic rearrangements (inversions or translocations). Interactions between these alterations (in certain situations, in addition to germline mutations) allow cancer to clonally evolve due to deactivation of tumor suppressor genes (loss-of-function mutations) and activation of oncogenes (gain-of-function mutations). An even higher level of variation seems to be attributed to copy number alterations It was shown with the use of SNP-array-based analysis that approximately 50% of the lung cancer genome undergoes recurrent copy number alterations [7]. The role of “passenger” mutations for particular cancers is mostly unknown (it is not necessarily neutral)

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Conclusion