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Cis-Regulatory Variation and Cancer

  • Nora F. Wasserman
  • Marcelo A. NobregaEmail author
Chapter

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.

Keywords

Prostate cancer MSMB Thyroid cancer FOXE1 MYC 8q24 Breast cancer FGFR2 Colorectal cancer SMAD7 EIF3H Immunoglobulin Hematologic cancer TMPRSS2 ETS 

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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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Human GeneticsUniversity of ChicagoChicagoUSA

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