Allelic Variation at the 8q23.3 Colorectal Cancer Risk Locus Functions as a Cis-Acting Regulator of
Common genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at 8q23.3 in 1,964 CRC cases and 2,081 healthy controls. Reporter gene studies showed that the single nucleotide polymorphism rs16888589 acts as an allele-specific transcriptional repressor. Chromosome conformation capture (3C) analysis demonstrated that the genomic region harboring rs16888589 interacts with the promoter of gene for eukaryotic translation initiation factor 3, subunit H (EIF3H). We show that increased expression of EIF3H gene increases CRC growth and invasiveness thereby providing a biological mechanism for the 8q23.3 association. These data provide evidence for a functional basis for the non-coding risk variant rs16888589 at 8q23.3 and provides novel insight into the etiological basis of CRC.
Vyšlo v časopise:
Allelic Variation at the 8q23.3 Colorectal Cancer Risk Locus Functions as a Cis-Acting Regulator of. PLoS Genet 6(9): e32767. doi:10.1371/journal.pgen.1001126
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001126
Souhrn
Common genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at 8q23.3 in 1,964 CRC cases and 2,081 healthy controls. Reporter gene studies showed that the single nucleotide polymorphism rs16888589 acts as an allele-specific transcriptional repressor. Chromosome conformation capture (3C) analysis demonstrated that the genomic region harboring rs16888589 interacts with the promoter of gene for eukaryotic translation initiation factor 3, subunit H (EIF3H). We show that increased expression of EIF3H gene increases CRC growth and invasiveness thereby providing a biological mechanism for the 8q23.3 association. These data provide evidence for a functional basis for the non-coding risk variant rs16888589 at 8q23.3 and provides novel insight into the etiological basis of CRC.
Zdroje
1. LichtensteinP
HolmNV
VerkasaloPK
IliadouA
KaprioJ
2000 Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343 78 85
2. AaltonenL
JohnsL
JarvinenH
MecklinJP
HoulstonR
2007 Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors. Clin Cancer Res 13 356 361
3. ZankeBW
GreenwoodCM
RangrejJ
KustraR
TenesaA
2007 Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 39 989 994
4. TomlinsonI
WebbE
Carvajal-CarmonaL
BroderickP
KempZ
2007 A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39 984 988
5. TomlinsonIP
WebbE
Carvajal-CarmonaL
BroderickP
HowarthK
2008 A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet 40 623 630
6. TenesaA
FarringtonSM
PrendergastJG
PorteousME
WalkerM
2008 Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet 40 631 637
7. BroderickP
Carvajal-CarmonaL
PittmanAM
WebbE
HowarthK
2007 A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet 39 1315 1317
8. JaegerE
WebbE
HowarthK
Carvajal-CarmonaL
RowanA
2008 Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet 40 26 28
9. HoulstonRS
WebbE
BroderickP
PittmanAM
Di BernardoMC
2008 Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet 40 1426 1435
10. PittmanAM
NaranjoS
WebbE
BroderickP
LipsEH
2009 The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression. Genome Res 19 987 993
11. PomerantzMM
AhmadiyehN
JiaL
HermanP
VerziMP
2009 The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat Genet 41 882 884
12. TuupanenS
TurunenM
LehtonenR
HallikasO
VanharantaS
2009 The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nat Genet 41 885 890
13. MiddeldorpA
Jagmohan-ChangurS
van EijkR
TopsC
DevileeP
2009 Enrichment of low penetrance susceptibility loci in a Dutch familial colorectal cancer cohort. Cancer Epidemiol Biomarkers Prev 18 3062 3067
14. ZegginiE
RaynerW
MorrisAP
HattersleyAT
WalkerM
2005 An evaluation of HapMap sample size and tagging SNP performance in large-scale empirical and simulated data sets. Nat Genet 37 1320 1322
15. Gomez-SkarmetaJL
LenhardB
BeckerTS
2006 New technologies, new findings, and new concepts in the study of vertebrate cis-regulatory sequences. Dev Dyn 235 870 885
16. TaylorJ
TyekuchevaS
KingDC
HardisonRC
MillerW
2006 ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements. Genome Res 16 1596 1604
17. PalinK
TaipaleJ
UkkonenE
2006 Locating potential enhancer elements by comparative genomics using the EEL software. Nat Protoc 1 368 374
18. BessaJ
TenaJJ
de la Calle-MustienesE
Fernandez-MinanA
NaranjoS
2009 Zebrafish enhancer detection (ZED) vector: a new tool to facilitate transgenesis and the functional analysis of cis-regulatory regions in zebrafish. Dev Dyn 238 2409 2417
19. YeeSP
RigbyPW
1993 The regulation of myogenin gene expression during the embryonic development of the mouse. Genes Dev 7 1277 1289
20. TuupanenS
NiittymakiI
NousiainenK
VanharantaS
MecklinJP
2008 Allelic imbalance at rs6983267 suggests selection of the risk allele in somatic colorectal tumor evolution. Cancer Res 68 14 17
21. JalavaSE
PorkkaKP
RauhalaHE
IsotaloJ
TammelaTL
2009 TCEB1 promotes invasion of prostate cancer cells. Int J Cancer 124 95 102
22. SavinainenKJ
HeleniusMA
LehtonenHJ
VisakorpiT
2006 Overexpression of EIF3S3 promotes cancer cell growth. Prostate 66 1144 1150
23. ZhangL
Smit-McBrideZ
PanX
RheinhardtJ
HersheyJW
2008 An oncogenic role for the phosphorylated h-subunit of human translation initiation factor eIF3. J Biol Chem 283 24047 24060
24. SaramakiO
WilliN
BrattO
GasserTC
KoivistoP
2001 Amplification of EIF3S3 gene is associated with advanced stage in prostate cancer. Am J Pathol 159 2089 2094
25. CooksonW
LiangL
AbecasisG
MoffattM
LathropM
2009 Mapping complex disease traits with global gene expression. Nat Rev Genet 10 184 194
26. PenegarS
WoodW
LubbeS
ChandlerI
BroderickP
2007 National study of colorectal cancer genetics. Br J Cancer 97 1305 1309
27. EisenT
MatakidouA
HoulstonR
2008 Identification of low penetrance alleles for lung cancer: the GEnetic Lung CAncer Predisposition Study (GELCAPS). BMC Cancer 8 244
28. OginoH
McConnellWB
GraingerRM
2006 Highly efficient transgenesis in Xenopus tropicalis using I-SceI meganuclease. Mech Dev 123 103 113
29. HagegeH
KlousP
BraemC
SplinterE
DekkerJ
2007 Quantitative analysis of chromosome conformation capture assays (3C-qPCR). Nat Protoc 2 1722 1733
30. NupponenNN
VisakorpiT
2000 Molecular cytogenetics of prostate cancer. Microsc Res Tech 51 456 463
31. LipsEH
van EijkR
de GraafEJ
OostingJ
de MirandaNF
2008 Integrating chromosomal aberrations and gene expression profiles to dissect rectal tumorigenesis. BMC Cancer 8 314
32. de BruinEC
van de PasS
LipsEH
van EijkR
van der ZeeMM
2005 Macrodissection versus microdissection of rectal carcinoma: minor influence of stroma cells to tumor cell gene expression profiles. BMC Genomics 6 142
33. TurkheimerFE
HinzR
CunninghamVJ
2003 On the undecidability among kinetic models: from model selection to model averaging. J Cereb Blood Flow Metab 23 490 498
34. ScheetP
StephensM
2006 A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet 78 629 644
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2010 Číslo 9
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Synthesizing and Salvaging NAD: Lessons Learned from
- Optimal Strategy for Competence Differentiation in Bacteria
- Long- and Short-Term Selective Forces on Malaria Parasite Genomes
- Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data