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Review
. 2013 Jun 25;108(12):2419-25.
doi: 10.1038/bjc.2013.233. Epub 2013 May 9.

Long noncoding RNAs and the genetics of cancer

S W Cheetham  1 , F Gruhl, J S Mattick, M E Dinger
Affiliations
Review

Long noncoding RNAs and the genetics of cancer

S W Cheetham et al. Br J Cancer. .

Abstract

Cancer is a disease of aberrant gene expression. While the genetic causes of cancer have been intensively studied, it is becoming evident that a large proportion of cancer susceptibility cannot be attributed to variation in protein-coding sequences. This is highlighted by genome-wide association studies in cancer that reveal that more than 80% of cancer-associated SNPs occur in noncoding regions of the genome. In this review, we posit that a significant fraction of the genetic aetiology of cancer is exacted by noncoding regulatory sequences, particularly by long noncoding RNAs (lncRNAs). Recent studies indicate that several cancer risk loci are transcribed into lncRNAs and these transcripts play key roles in tumorigenesis. We discuss the epigenetic and other mechanisms through which lncRNAs function and how they contribute to each stage of cancer progression, understanding of which will be crucial for realising new opportunities in cancer diagnosis and treatment. Long noncoding RNAs play important roles in almost every aspect of cell biology from nuclear organisation and epigenetic regulation to post-transcriptional regulation and splicing, and we link these processes to the hallmarks and genetics of cancer. Finally, we highlight recent progress and future potential in the application of lncRNAs as therapeutic targets and diagnostic markers.

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Figures

Figure 1
Figure 1
Generalised mechanisms and associated examples of lncRNAs involved in cancer progression. Long noncoding RNAs act through a variety of mechanisms such as remodelling of chromatin (A), transcriptional co-activation or -repression (B), protein inhibition (C), as post-transcriptional modifiers (D) or decoy elements (E). Consequently, mis-expression of lncRNAs can lead to changed expression profiles of various target genes involved in different aspects of cell homeostasis.
Figure 2
Figure 2
Heritability and genomic distribution of SNPs in cancer. (A) The heritable component of risk for common cancers. Despite many cancers having sizeable genetic components, the identity of most of these heritable risk factors is currently unknown. Table adapted from SNPedia (Cariaso and Lennon, 2012). (B) Genomic distribution (%) of SNPs in selected cancer types. The majority of cancer-related SNPs are located in noncoding regions of the genome (intergenic or intronic) and only a small number are found in coding regions.
Figure 3
Figure 3
The GWAS ‘hot spot' at the ANRIL locus. Multiple disease-associated SNPs map to the ANRIL locus, including various cancers (blue) and vascular-related conditions (red). These individual polymorphisms may affect ANRIL function differently, resulting in diverse diseases.
See this image and copyright information in PMC

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