Common Genetic Variants and Modification of Penetrance of -Associated Breast Cancer
The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10−5 and 39 SNPs had p-values<10−4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66–0.86, ) and for rs311499 was 0.72 (95% CI 0.61–0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18–1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
Vyšlo v časopise:
Common Genetic Variants and Modification of Penetrance of -Associated Breast Cancer. PLoS Genet 6(10): e32767. doi:10.1371/journal.pgen.1001183
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001183
Souhrn
The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10−5 and 39 SNPs had p-values<10−4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66–0.86, ) and for rs311499 was 0.72 (95% CI 0.61–0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18–1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
Zdroje
1. TryggvadottirL
SigvaldasonH
OlafsdottirGH
JonassonJG
JonssonT
2006 Population-based study of changing breast cancer risk in Icelandic BRCA2 mutation carriers, 1920–2000. J Natl Cancer Inst 98 116 122
2. SimchoniS
FriedmanE
KaufmanB
Gershoni-BaruchR
Orr-UrtregerA
2006 Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci U S A 103 3770 3774
3. BeggCB
HaileRW
BorgA
MaloneKE
ConcannonP
2008 Variation of breast cancer risk among BRCA1/2 carriers. JAMA 299 194 201
4. AntoniouA
PharoahPD
NarodS
RischHA
EyfjordJE
2003 Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72 1117 1130
5. RobsonM
OffitK
2007 Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med 357 154 162
6. OffitK
2006 BRCA mutation frequency and penetrance: new data, old debate. J Natl Cancer Inst 98 1675 1677
7. AntoniouAC
PharoahPD
McMullanG
DayNE
StrattonMR
2002 A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86 76 83
8. AntoniouAC
PharoahPD
McMullanG
DayNE
PonderBA
2001 Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genet Epidemiol 21 1 18
9. AntoniouAC
SinilnikovaOM
SimardJ
LeoneM
DumontM
2007 RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet 81 1186 1200
10. CatucciI
VerderioP
PizzamiglioS
ManoukianS
PeisselB
The CASP8 rs3834129 polymorphism and breast cancer risk in BRCA1 mutation carriers. Breast Cancer Res Treat
11. Palanca SuelaS
Esteban CardenosaE
Barragan GonzalezE
de Juan JimenezI
Chirivella GonzalezI
CASP8 D302H polymorphism delays the age of onset of breast cancer in BRCA1 and BRCA2 carriers. Breast Cancer Res Treat 119 87 93
12. NeuhausenSL
BrummelS
DingYC
SingerCF
PfeilerG
2009 Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers. Breast Cancer Res 11 R76
13. AntoniouAC
SpurdleAB
SinilnikovaOM
HealeyS
PooleyKA
2008 Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 82 937 948
14. SegreAV
GroopL
MoothaVK
DalyMJ
AltshulerD
2010 Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet 6 e1001058 doi:10.1371/journal.pgen.1001058
15. D'AndreaAD
Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med 362 1909 1919
16. O'DonovanPJ
LivingstonDM
2010 BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis 31 961 967
17. StadlerZ
ThomP
RobsonME
WeitzelJN
KauffND
2010 Genome-wide Association Studies of Cancer. J Clin Oncol in press
18. AntoniouAC
2010 A genome-wide association study identified a 19p13 locus that modifies the risk of breast cancer in BRCA1 mutation carriers and is associated with estrogen receptor negative and triple negative breast cancer in the general population. Nat Genet under review
19. KirchhoffT
ChenZQ
GoldB
PalP
GaudetMM
2009 The 6q22.33 Locus and Breast Cancer Susceptibility. Cancer Epidemiol Biomarkers Prev
20. AntoniouAC
SinilnikovaOM
McGuffogL
HealeyS
NevanlinnaH
2009 Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet
21. ZollnerS
PritchardJK
2007 Overcoming the winner's curse: estimating penetrance parameters from case-control data. Am J Hum Genet 80 605 615
22. EllisNA
KirchhoffT
MitraN
YeTZ
ChuaiS
2006 Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping. Genet Epidemiol 30 48 61
23. GusevA
LoweJK
StoffelM
DalyMJ
AltshulerD
2009 Whole population, genome-wide mapping of hidden relatedness. Genome Res 19 318 326
24. TurnbullC
AhmedS
MorrisonJ
PernetD
RenwickA
Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet
25. AntoniouAC
CunninghamAP
PetoJ
EvansDG
LallooF
2008 The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions. Br J Cancer 98 1457 1466
26. FoulkesWD
StefanssonIM
ChappuisPO
BeginLR
GoffinJR
2003 Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95 1482 1485
27. WangX
PankratzVS
FredericksenZ
TarrellR
KarausM
Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Hum Mol Genet 19 2886 2897
28. Chenevix-TrenchG
MilneRL
AntoniouAC
CouchFJ
EastonDF
2007 An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res 9 104
29. KornJM
KuruvillaFG
McCarrollSA
WysokerA
NemeshJ
2008 Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet 40 1253 1260
30. AntoniouAC
GoldgarDE
AndrieuN
Chang-ClaudeJ
BrohetR
2005 A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol 29 1 11
31. ToninP
WeberB
OffitK
CouchF
RebbeckTR
1996 Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 2 1179 1183
32. NeuhausenS
GilewskiT
NortonL
TranT
McGuireP
1996 Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet 13 126 128
33. NeuhausenSL
MazoyerS
FriedmanL
StrattonM
OffitK
1996 Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet 58 271 280
34. OlshenAB
GoldB
LohmuellerKE
StruewingJP
SatagopanJ
2008 Analysis of genetic variation in Ashkenazi Jews by high density SNP genotyping. BMC Genet 9 14
35. AminN
van DuijnCM
AulchenkoYS
2007 A genomic background based method for association analysis in related individuals. PLoS ONE 2 e1274 doi:10.1371/journal.pone.0001274
36. LeuteneggerAL
PrumB
GeninE
VernyC
LemainqueA
2003 Estimation of the inbreeding coefficient through use of genomic data. Am J Hum Genet 73 516 523
37. AulchenkoYS
RipkeS
IsaacsA
van DuijnCM
2007 GenABEL: an R library for genome-wide association analysis. Bioinformatics 23 1294 1296
38. LangeK
WeeksD
BoehnkeM
1988 Programs for Pedigree Analysis: MENDEL, FISHER, and dGENE. Genet Epidemiol 5 471 472
39. HuberPJ
1967 The behaviour of maximum maximum likelihood estimates under non-standard conditions. Proceedings of the Fifth Berkeley Symposium in Mathematical Statistics and Probability 1 221 233
40. LinDY
WeiLJ
1989 The robust inference for the cox-proportional hazards model. J Am Stat Assoc 84 1074 1078
41. PurcellS
NealeB
Todd-BrownK
ThomasL
FerreiraMA
2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
42. ChenH
SharpBM
2004 Content-rich biological network constructed by mining PubMed abstracts. BMC Bioinformatics 5 147
43. O'DonovanP
LivingstonDM
2010 BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double strand break repair. Carcinogenesis 6 961 7
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2010 Číslo 10
- 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
- Genome-Wide Identification of Targets and Function of Individual MicroRNAs in Mouse Embryonic Stem Cells
- Common Genetic Variants and Modification of Penetrance of -Associated Breast Cancer
- Allele-Specific Down-Regulation of Expression Induced by Retinoids Contributes to Climate Adaptations
- Simultaneous Disruption of Two DNA Polymerases, Polη and Polζ, in Avian DT40 Cells Unmasks the Role of Polη in Cellular Response to Various DNA Lesions