microRNAs exhibit high frequency genomic alterations in human cancer

Abstract

MicroRNAs (miRNAs) are endogenous noncoding RNAs, which negatively regulate gene expression. To determine genomewide miRNA DNA copy number abnormalities in cancer, 283 known human miRNA genes were analyzed by high-resolution arraybased comparative genomic hybridization in 227 human ovarian cancer, breast cancer, and melanoma specimens. A high proportion of genomic loci containing miRNA genes exhibited DNA copy number alterations in ovarian cancer (37.1%), breast cancer (72.8%), and melanoma (85.9%), where copy number alterations observed in >15% tumors were considered significant for each miRNA gene. We identified 41 miRNA genes with gene copy number changes that were shared among the three cancer types (26 with gains and 15 with losses) as well as miRNA genes with copy number changes that were unique to each tumor type. Importantly, we show that miRNA copy changes correlate with miRNA expression. Finally, we identified high frequency copy number abnormalities of Dicer1, Argonaute2, and other miRNAassociated genes in breast and ovarian cancer as well as melanoma. These findings support the notion that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types.genome ͉ noncoding RNA ͉ comparative genomic hybridization

Potentially important microRNA cluster on chromosome 17p13.1 in primary peritoneal carcinoma

“…2,[48][49][50][51] Specifically, there is a growing body of evidence to suggest that both ovarian serous carcinoma and primary peritoneal carcinoma may arise from a precursor lesion in the distal tubal fimbria, [49][50][51] and thus both tumour types may be genetically related. Importantly, our results do not preclude a common site of origin; they probably reflect temporal 19 described DNA copy number alterations at all genomic loci for our selected microRNAs in ovarian serous carcinoma. In the study by Iorio et al, 9 miR181a and miR-195 were downregulated in ovarian serous carcinoma, whereas Nam et al 52 demonstrate differential expression of miR-16.…”

“…Furthermore, DNA copy number alterations at genomic loci for selected microRNAs have been described in ovarian serous carcinoma. 19 …”

Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor

“…This study investigated 186 miRNA genes and observed that 98 of the miRNA genes were harboured in such fragile loci (Calin et al ., 2004). Another pan‐cancer study indicated that the genomic loci harbouring miRNAs genes exhibited high proportion of somatic copy number alterations accounting for about 37.1% in ovarian cancer, 72.8% in breast cancer and 85.9% in melanomas (Zhang et al ., 2006). miRNA genes were also demonstrated to undergo substantial SCNAs in lung cancer, with miR‐30d, miR‐21, miR‐17 and miR‐155 being the most amplified ones (Czubak et al ., 2015).…”

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

“…Deregulation of miRNAs expression in cancer can occur by genetic mechanisms including amplification, deletion and mutation, as well as by epigenetic silencing (Calin et al, 2004;Zhang et al, 2006). Moreover, it has recently been demonstrated that oncogenes and tumor suppressors exert their action also by regulating the expression of specific miRNAs.…”