Adversary of DNA integrity: a long non-coding RNA stimulates driver oncogenic chromosomal rearrangement in human thyroid cells

Abstract

The flurry of publications devoted to the functions of long non-coding RNAs (lncRNAs) published in the last decade leaves no doubt about the exceptional importance of lncRNAs in various areas including tumor biology. Contribution of lncRNAs to the early stages of oncogenesis remains poorly understood. In this study we explored a new role for lncRNAs: stimulation of driver oncogenic mutations that result from specific chromosomal rearrangements. We demonstrated that lncRNA CASTL1 (ENSG00000269945) stimulates the formation of the CCDC6-RET inversion (RET/PTC1) in human thyroid cells subjected to radiation or chemical DNA damage. Facilitation of chromosomal rearrangement requires lncRNA to contain regions complementary to the introns of both CCDC6 and RET genes as deletion of these regions deprives CASTL1 of the ability to stimulate the gene fusion. We found that CASTL1 expression is elevated in tumors with CCDC6-RET fusion which is the most frequent rearrangement in papillary thyroid carcinoma. Our results open a new venue for the studies of early oncogenesis in various tumor types, especially those associated with physical or chemical DNA damage.

lncRNA: A new danger for genome integrity

“…Recently, an unexpected novel contributor to this vulnerability was revealed. In this issue of the International Journal of Cancer, Demin et al 1 describe how a long noncoding RNA (lncRNA) ENSG00000269945 facilitates CCDC6 ‐ RET fusion (inv(10)(q11;q21)), a rearrangement encountered in thyroid and lung cancers and leading to a constitutive activation of the RET oncogenic tyrosine kinase 4 . The lncRNA located on chromosome 14 contains sequences that are homologous to CCD6 and RET intronic regions, thus potentially providing an illegitimate repair template for chromosome 10.…”

“…Many factors affect the genesis of chromosomal aberrations in cells. In this issue of the International Journal of Cancer, Demin et al 1 describe a long noncoding RNA CASTL (chromosomal aberrations stimulating lncRNA) that facilitates CCDC6 ‐ RET fusion (inv(10)(q11;q21)). Expression of CASTL1 is cell‐type specific and can account for the appearance of CCDC6 ‐ RET fusion only in specific cell types.…”

“…It is plausible that lncRNAs, expressed in a particular cell type, might contribute to the appearance of cell‐specific chromosomal rearrangements between different loci via homologous regions. By analyzing previously published transcriptomes, Demin et al 1 demonstrated that CASTL1 was expressed in normal thyroid tissue and in papillary thyroid carcinoma with CCDC6‐RET inversion.…”