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A genome-wide "pleiotropy scan" does not identify new susceptibility loci for estrogen receptor negative breast cancer.

Campa D, Barrdahl M, Tsilidis KK, Severi G, Diver WR, Siddiq A, Chanock S, Hoover RN, Ziegler RG, Berg CD, Buys SS, Haiman CA, Henderson BE, Schumacher FR, Le Marchand L, Flesch-Janys D, Lindström S, Hunter DJ, Hankinson SE, Willett WC, Kraft P, Cox DG, Khaw KT, Tjønneland A, Dossus L, Trichopoulos D, Panico S, van Gils CH, Weiderpass E, Barricarte A, Sund M, Gaudet MM, Giles G, Southey M, Baglietto L, Chang-Claude J, Kaaks R, Canzian F - PLoS ONE (2014)

Bottom Line: None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 × 10(-4).None of the variants reached statistical significance in the replication phase.In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach".

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT
Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5 × 10(-8)) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER- cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 × 10(-4). None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach".

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Manhattan Plot of all SNPs analyzed in phase one of the study.
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pone-0085955-g001: Manhattan Plot of all SNPs analyzed in phase one of the study.

Mentions: None of the 3079 selected variants in the BPC3 ER-GWAS was significant at the adjusted threshold. 186 variants were associated with ER− breast cancer risk at a conventional threshold of P<0.05, with P values ranging from 0.049 to 2.3×10−4 (Figure 1). The strongest observed association was a decreased risk of ER− BC with rs8396 (ORhetero :0.84; 95% CI 0.76–0.92 and ORhomo0.71 (CI 95% 0.58–0.85)). We selected the most significant 10 SNPs (shown in table 1) and analyzed them using independent samples to determine whether they were genuinely associated with BC overall and for ER− breast cancer in particular. All the polymorphic variants were in Hardy-Weinberg equilibrium with the exception of rs12150660 in the CPSII and MARIE cohorts and rs13397985 in the CPSII cohort. Therefore, CPSII was not used as a replication set for rs12150660 and rs13397985 and MARIE was not used for rs12150660. In addition, one polymorphic variant rs8396 was not used in the analysis because it had a call rate lower than 95% (88.2%).


A genome-wide "pleiotropy scan" does not identify new susceptibility loci for estrogen receptor negative breast cancer.

Campa D, Barrdahl M, Tsilidis KK, Severi G, Diver WR, Siddiq A, Chanock S, Hoover RN, Ziegler RG, Berg CD, Buys SS, Haiman CA, Henderson BE, Schumacher FR, Le Marchand L, Flesch-Janys D, Lindström S, Hunter DJ, Hankinson SE, Willett WC, Kraft P, Cox DG, Khaw KT, Tjønneland A, Dossus L, Trichopoulos D, Panico S, van Gils CH, Weiderpass E, Barricarte A, Sund M, Gaudet MM, Giles G, Southey M, Baglietto L, Chang-Claude J, Kaaks R, Canzian F - PLoS ONE (2014)

Manhattan Plot of all SNPs analyzed in phase one of the study.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921107&req=5

pone-0085955-g001: Manhattan Plot of all SNPs analyzed in phase one of the study.
Mentions: None of the 3079 selected variants in the BPC3 ER-GWAS was significant at the adjusted threshold. 186 variants were associated with ER− breast cancer risk at a conventional threshold of P<0.05, with P values ranging from 0.049 to 2.3×10−4 (Figure 1). The strongest observed association was a decreased risk of ER− BC with rs8396 (ORhetero :0.84; 95% CI 0.76–0.92 and ORhomo0.71 (CI 95% 0.58–0.85)). We selected the most significant 10 SNPs (shown in table 1) and analyzed them using independent samples to determine whether they were genuinely associated with BC overall and for ER− breast cancer in particular. All the polymorphic variants were in Hardy-Weinberg equilibrium with the exception of rs12150660 in the CPSII and MARIE cohorts and rs13397985 in the CPSII cohort. Therefore, CPSII was not used as a replication set for rs12150660 and rs13397985 and MARIE was not used for rs12150660. In addition, one polymorphic variant rs8396 was not used in the analysis because it had a call rate lower than 95% (88.2%).

Bottom Line: None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 × 10(-4).None of the variants reached statistical significance in the replication phase.In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach".

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT
Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5 × 10(-8)) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER- cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 × 10(-4). None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach".

Show MeSH
Related in: MedlinePlus