Analysis of the 10q11 Cancer Risk Locus Implicates and in Human Prostate Tumorigenesis

English version České info

Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states.

Vyšlo v časopise: Analysis of the 10q11 Cancer Risk Locus Implicates and in Human Prostate Tumorigenesis. PLoS Genet 6(11): e32767. doi:10.1371/journal.pgen.1001204
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001204

Souhrn

Zdroje

1. EelesRA

Kote-JaraiZ

GilesGG

OlamaAA

GuyM

2008 Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 40 316 321

2. Kote-JaraiZ

EastonDF

StanfordJL

OstranderEA

SchleutkerJ

2008 Multiple novel prostate cancer predisposition loci confirmed by an international study: the PRACTICAL Consortium. Cancer Epidemiol Biomarkers Prev 17 2052 2061

3. ThomasG

JacobsKB

YeagerM

KraftP

WacholderS

2008 Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 40 310 315

4. WatersKM

Le MarchandL

KolonelLN

MonroeKR

StramDO

2009 Generalizability of associations from prostate cancer genome-wide association studies in multiple populations. Cancer Epidemiol Biomarkers Prev 18 1285 1289

5. ZhengSL

SunJ

WiklundF

GaoZ

StattinP

2009 Genetic variants and family history predict prostate cancer similar to prostate-specific antigen. Clin Cancer Res 15 1105 1111

6. ReevesJR

DuludeH

PanchalC

DaigneaultL

RamnaniDM

2006 Prognostic value of prostate secretory protein of 94 amino acids and its binding protein after radical prostatectomy. Clin Cancer Res 12 6018 6022

7. ShukeirN

ArakelianA

KadhimS

GardeS

RabbaniSA

2003 Prostate secretory protein PSP-94 decreases tumor growth and hypercalcemia of malignancy in a syngenic in vivo model of prostate cancer. Cancer Res 63 2072 2078

8. ChangBL

CramerSD

WiklundF

IsaacsSD

StevensVL

2009 Fine mapping association study and functional analysis implicate a SNP in MSMB at 10q11 as a causal variant for prostate cancer risk. Hum Mol Genet 18 1368 1375

9. LouH

YeagerM

LiH

BosquetJG

HayesRB

2009 Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility. Proc Natl Acad Sci U S A 106 7933 7938

10. NiuY

YehS

MiyamotoH

LiG

AltuwaijriS

2008 Tissue prostate-specific antigen facilitates refractory prostate tumor progression via enhancing ARA70-regulated androgen receptor transactivation. Cancer Res 68 7110 7119

11. PengY

LiCX

ChenF

WangZ

LigrM

2008 Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70. Amer J Pathol 172 225 235

12. HuYC

YehS

YehSD

SampsonER

HuangJ

2004 Functional domain and motif analyses of androgen receptor coregulator ARA70 and its differential expression in prostate cancer. J Biol Chem 279 33438 33446

13. CheungVG

ConlinLK

WeberTM

ArcaroM

JenKY

2003 Natural variation in human gene expression assessed in lymphoblastoid cells. Nat Genet 33 422 425

14. SchadtEE

MonksSA

DrakeTA

LusisAJ

CheN

2003 Genetics of gene expression surveyed in maize, mouse and man. Nature 422 297 302

15. MorleyM

MolonyCM

WeberTM

DevlinJL

EwensKG

2004 Genetic analysis of genome-wide variation in human gene expression. Nature 430 743 747

16. JiaZ

XuS

2007 Mapping quantitative trait loci for expression abundance. Genetics 176 611 623

17. MoffattMF

KabeschM

LiangL

DixonAL

StrachanD

2007 Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448 470 473

18. MeyerKB

MaiaAT

O'ReillyM

TeschendorffAE

ChinSF

2008 Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol 6 e108 doi:10.1371/journal.pbio.0060108

19. 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

20. 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

21. BirneyE

StamatoyannopoulosJA

DuttaA

GuigoR

GingerasTR

2007 Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447 799 816

22. GannPH

HennekensCH

StampferMJ

1995 A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. Jama 273 289 294

23. LiP

YuX

GeK

MelamedJ

RoederRG

2002 Heterogeneous expression and functions of androgen receptor co-factors in primary prostate cancer. Amer J Pathol 161 1467 1474

24. VanajaDK

ChevilleJC

IturriaSJ

YoungCY

2003 Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. Cancer Res 63 3877 3882

25. LapointeJ

LiC

HigginsJP

van de RijnM

BairE

2004 Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci U S A 101 811 816

26. BergerR

FebboPG

MajumderPK

ZhaoJJ

MukherjeeS

2004 Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells. Cancer Res 64 8867 8875

27. FreedmanVH

ShinSI

1974 Cellular tumorigenicity in nude mice: correlation with cell growth in semi-solid medium. Cell 3 355 359

28. ShinSI

FreedmanVH

RisserR

PollackR

1975 Tumorigenicity of virus-transformed cells in nude mice is correlated specifically with anchorage independent growth in vitro. Proc Natl Acad Sci U S A 72 4435 4439

29. BouckN

di MayorcaG

1976 Somatic mutation as the basis for malignant transformation of BHK cells by chemical carcinogens. Nature 264 722 727

30. SpandidosDA

SiminovitchL

1977 Transfer of anchorage independence by isolated metaphase chromosomes in hamster cells. Cell 12 675 682

31. ElenbaasB

SpirioL

KoernerF

FlemingMD

ZimonjicDB

2001 Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev 15 50 65

32. CampNJ

FarnhamJM

WongJ

ChristensenGB

ThomasA

2009 Replication of the 10q11 and Xp11 prostate cancer risk variants: results from a Utah pedigree-based study. Cancer Epidemiol Biomarkers Prev 18 1290 1294

33. FitzgeraldLM

KwonEM

KoopmeinersJS

SalinasCA

StanfordJL

2009 Analysis of recently identified prostate cancer susceptibility loci in a population-based study: associations with family history and clinical features. Clin Cancer Res 15 3231 3237

34. HomG

GrahamRR

ModrekB

TaylorKE

OrtmannW

2008 Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 358 900 909

35. EmilssonV

ThorleifssonG

ZhangB

LeonardsonAS

ZinkF

2008 Genetics of gene expression and its effect on disease. Nature 452 423 428

36. DimasAS

DeutschS

StrangerBE

MontgomerySB

BorelC

2009 Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325 1246 1250

37. LigrM

LiY

ZouX

DanielsG

MelamedJ

2010 Tumor suppressor function of androgen receptor coactivator ARA70 alpha in prostate cancer. Am J Pathol 176 1891 900

38. LibioulleC

LouisE

HansoulS

SandorC

FarnirF

2007 Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet 3 e58 doi:10.1371/journal.pgen.0030058

39. CooksonW

LiangL

AbecasisG

MoffattM

LathropM

2009 Mapping complex disease traits with global gene expression. Nat Rev Genet 10 184 194

40. SetlurSR

MertzKD

HoshidaY

DemichelisF

LupienM

2008 Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J Natl Cancer Inst 100 815 825