Cis-regulatory variation and cancer

Abstract

In the traditional model of human disease genetics, mutations in coding regions of the genome were assumed to underlie disease phenotypes. It is only in the recent past that functional noncoding regions - such as promoters, enhancers and silencers - have been implicated in disease states. At its most basic level, cancer is a disease caused by the misexpression of genes normally responsible for regulating cell proliferation. It is therefore logical that mutations and variants within cis-regulatory elements controlling the expression of proto-oncogenes and tumor suppressor genes would underlie some tumorigenic gene expression changes. As changes in noncoding functional elements are harder to identify than alterations in protein -coding sequences, many of the recent insights into cis-regulatory variants involved in cancer etiology have been uncovered by genome-wide association studies (GWAS), highlighting risk variants in non-genic regions. Here, we highlight examples of cancer-associated variation in promoters, enhancers, and silencers, as well as changes to the overall architecture of a gene's regulatory landscape. These functional characterizations bring us closer to understanding the role of cis-regulatory mutations and cancer risk/progression.