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Cis-Regulatory Variation and Cancer

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Book cover Gene Regulatory Sequences and Human Disease

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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.

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Abbreviations

3C:

Chromosomal conformation capture

bcl-2 :

B cell CLL/lymphoma 2

C/EBPβ:

CCAAT/enhancer-binding protein beta

ChIP:

Chromatin immunoprecipitation

E14.5:

Mouse embryonic day 14.5

EIF3H :

Eukaryotic translation initiation factor 3 subunit H

EMSA:

Electrophoretic mobility shift assay

ERG :

v-ETS erythroblastosis virus E26 oncogene homolog

ES:

Embryonic stem

ETV1 :

ETS variant 1

FGFR2 :

Fibroblast growth factor receptor 2

FISH:

Fluorescence in situ hybridization

FOXE1 :

Forkhead box E1

GFP:

Green fluorescent protein

GWAS:

Genome-wide association studies

Ig:

Immunoglobulin

KCNIP3 :

Kv channel interacting protein 3 calsenilin

LCLs:

Lymphoblastoid cell lines

LD:

Linkage disequilibrium

MSMB :

Microseminoprotein beta

MYC :

Proto-oncogene v-myc myelocytomatosis viral oncogene homolog

RACE:

RNA ligase-mediated rapid amplification of cDNA ends

RUNX2 :

Runt-related transcription factor 2

SMAD7 :

SMAD family member 7

SNP:

Single nucleotide polymorphism

TCF7L2 :

Transcription factor 7-like 2

TMPRSS2 :

Transmembrane protease serine 2

TSS:

Transcriptional start site

USF:

Upstream transcription factor

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Authors and Affiliations

  1. Department of Human Genetics, University of Chicago, 920 E 58th Street, CLSC 319, Chicago, IL, 60637, USA

    Nora F. Wasserman & Marcelo A. Nobrega

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  1. Nora F. Wasserman
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  2. Marcelo A. Nobrega
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Correspondence to Marcelo A. Nobrega .

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  1. Institute for Human Genetics, 513 Parnassus Ave., San Francisco, 94143, USA

    Nadav Ahituv

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Wasserman, N.F., Nobrega, M.A. (2012). Cis-Regulatory Variation and Cancer. In: Ahituv, N. (eds) Gene Regulatory Sequences and Human Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1683-8_10

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