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Identification of novel genetic markers of breast cancer survival.

Guo Q, Schmidt MK, Kraft P, Canisius S, Chen C, Khan S, Tyrer J, Bolla MK, Wang Q, Dennis J, Michailidou K, Lush M, Kar S, Beesley J, Dunning AM, Shah M, Czene K, Darabi H, Eriksson M, Lambrechts D, Weltens C, Leunen K, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Blomqvist C, Aittomäki K, Fagerholm R, Muranen TA, Couch FJ, Olson JE, Vachon C, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Broeks A, Hogervorst FB, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Hopper JL, Tsimiklis H, Apicella C, Southey MC, Cox A, Cross SS, Reed MW, Giles GG, Milne RL, McLean C, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Hooning MJ, Hollestelle A, Martens JW, van den Ouweland AM, Marme F, Schneeweiss A, Yang R, Burwinkel B, Figueroa J, Chanock SJ, Lissowska J, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Brenner H, Dieffenbach AK, Arndt V, Holleczek B, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Li J, Brand JS, Humphreys K, Devilee P, Tollenaar RA, Seynaeve C, Radice P, Peterlongo P, Bonanni B, Mariani P, Fasching PA, Beckmann MW, Hein A, Ekici AB, Chenevix-Trench G, Balleine R, kConFab InvestigatorsPhillips KA, Benitez J, Zamora MP, Arias Perez JI, Menéndez P, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Hamann U, Kabisch M, Ulmer HU, Rüdiger T, Margolin S, Kristensen V, Nord S, Evans DG, Abraham JE, Earl HM, Hiller L, Dunn JA, Bowden S, Berg C, Campa D, Diver WR, Gapstur SM, Gaudet MM, Hankinson SE, Hoover RN, Hüsing A, Kaaks R, Machiela MJ, Willett W, Barrdahl M, Canzian F, Chin SF, Caldas C, Hunter DJ, Lindstrom S, García-Closas M, Hall P, Easton DF, Eccles DM, Rahman N, Nevanlinna H, Pharoah PD - J. Natl. Cancer Inst. (2015)

Bottom Line: A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients.Here the results of genotyping suggested that the finding was less robust.Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

View Article: PubMed Central - PubMed

Affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK (QG, JT, AMD, MS, JEA, DFE, PDPP); Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands (MKS, SC, AB, FBH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (PK, SH, DJH, SL); Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA (PK, CCh, DJH, SL); Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (SK, RF, TAM, HN); Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (MKB, QW, JD, KM, ML, SK, DFE, PDPP); Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia (JBee, GCT); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden (KC, HD, ME, JiL, JBr, KH, PH); Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium (DL); Vesalius Research Center, VIB, Leuven, Belgium (DL); Oncology Department, University Hospital Gasthuisberg, Leuven, Belgium (CW, KL); Copenhagen General Population Study, Herlev Hospital, Copenhagen, Denmark (SEB, BGN, SFN); Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Denmark (SEB, BGN, SFN); Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (SEB, BGN); Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Denmark (HF); Division of Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany (JCC, AR, PS, DC, AHü, RK, MB); Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany (DFJ); Department of Oncology

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Quantile-Quantile (Q-Q) plot for the combined GWAS and COGS analyses for estrogen receptor (ER)–negative cases. The y-axis represents the observed -log10P value, and the x-axis represents the expected -log10P value. The red line represents the expected distribution under the  hypothesis of no association. All statistical tests were two-sided.
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Figure 2: Quantile-Quantile (Q-Q) plot for the combined GWAS and COGS analyses for estrogen receptor (ER)–negative cases. The y-axis represents the observed -log10P value, and the x-axis represents the expected -log10P value. The red line represents the expected distribution under the hypothesis of no association. All statistical tests were two-sided.

Mentions: A single imputed SNP, rs2059614, located on chromosome 11, was associated with breast cancer–specific mortality at genome-wide statistical significance in patients with ER-negative disease (HR = 1.90, 95% CI = 1.54 to 2.33, P = 1.3x10-9) (risk allele frequency = 0.06) (Table 1; Figures 1 and 2). The imputation r2 ranged from 0.75 to 0.82 across eight studies with ER-negative cases. The inflation factor λ for analysis based on ER-negative cases was 1.03. No SNP reached nominal genome-wide statistical significance in the analysis of case patients with ER-positive disease (Supplementary Figures 3 and 4, available online), for which the strongest association was for rs7149859 in chromosome 14 (HR = 1.22, 95% CI = 1.13 to 1.33, P = 7.0x10-7). There was very little between study heterogeneity for the overall analysis for rs148760487 (I2 = 0%, P = .59) (Supplementary Figure 5, available online) or the ER-negative analysis for rs2059614 (I2 = 0%, P = .50) (Supplementary Figure 6, available online).


Identification of novel genetic markers of breast cancer survival.

Guo Q, Schmidt MK, Kraft P, Canisius S, Chen C, Khan S, Tyrer J, Bolla MK, Wang Q, Dennis J, Michailidou K, Lush M, Kar S, Beesley J, Dunning AM, Shah M, Czene K, Darabi H, Eriksson M, Lambrechts D, Weltens C, Leunen K, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Blomqvist C, Aittomäki K, Fagerholm R, Muranen TA, Couch FJ, Olson JE, Vachon C, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Broeks A, Hogervorst FB, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Hopper JL, Tsimiklis H, Apicella C, Southey MC, Cox A, Cross SS, Reed MW, Giles GG, Milne RL, McLean C, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Hooning MJ, Hollestelle A, Martens JW, van den Ouweland AM, Marme F, Schneeweiss A, Yang R, Burwinkel B, Figueroa J, Chanock SJ, Lissowska J, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Brenner H, Dieffenbach AK, Arndt V, Holleczek B, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Li J, Brand JS, Humphreys K, Devilee P, Tollenaar RA, Seynaeve C, Radice P, Peterlongo P, Bonanni B, Mariani P, Fasching PA, Beckmann MW, Hein A, Ekici AB, Chenevix-Trench G, Balleine R, kConFab InvestigatorsPhillips KA, Benitez J, Zamora MP, Arias Perez JI, Menéndez P, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Hamann U, Kabisch M, Ulmer HU, Rüdiger T, Margolin S, Kristensen V, Nord S, Evans DG, Abraham JE, Earl HM, Hiller L, Dunn JA, Bowden S, Berg C, Campa D, Diver WR, Gapstur SM, Gaudet MM, Hankinson SE, Hoover RN, Hüsing A, Kaaks R, Machiela MJ, Willett W, Barrdahl M, Canzian F, Chin SF, Caldas C, Hunter DJ, Lindstrom S, García-Closas M, Hall P, Easton DF, Eccles DM, Rahman N, Nevanlinna H, Pharoah PD - J. Natl. Cancer Inst. (2015)

Quantile-Quantile (Q-Q) plot for the combined GWAS and COGS analyses for estrogen receptor (ER)–negative cases. The y-axis represents the observed -log10P value, and the x-axis represents the expected -log10P value. The red line represents the expected distribution under the  hypothesis of no association. All statistical tests were two-sided.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555642&req=5

Figure 2: Quantile-Quantile (Q-Q) plot for the combined GWAS and COGS analyses for estrogen receptor (ER)–negative cases. The y-axis represents the observed -log10P value, and the x-axis represents the expected -log10P value. The red line represents the expected distribution under the hypothesis of no association. All statistical tests were two-sided.
Mentions: A single imputed SNP, rs2059614, located on chromosome 11, was associated with breast cancer–specific mortality at genome-wide statistical significance in patients with ER-negative disease (HR = 1.90, 95% CI = 1.54 to 2.33, P = 1.3x10-9) (risk allele frequency = 0.06) (Table 1; Figures 1 and 2). The imputation r2 ranged from 0.75 to 0.82 across eight studies with ER-negative cases. The inflation factor λ for analysis based on ER-negative cases was 1.03. No SNP reached nominal genome-wide statistical significance in the analysis of case patients with ER-positive disease (Supplementary Figures 3 and 4, available online), for which the strongest association was for rs7149859 in chromosome 14 (HR = 1.22, 95% CI = 1.13 to 1.33, P = 7.0x10-7). There was very little between study heterogeneity for the overall analysis for rs148760487 (I2 = 0%, P = .59) (Supplementary Figure 5, available online) or the ER-negative analysis for rs2059614 (I2 = 0%, P = .50) (Supplementary Figure 6, available online).

Bottom Line: A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients.Here the results of genotyping suggested that the finding was less robust.Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

View Article: PubMed Central - PubMed

Affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK (QG, JT, AMD, MS, JEA, DFE, PDPP); Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands (MKS, SC, AB, FBH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (PK, SH, DJH, SL); Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA (PK, CCh, DJH, SL); Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (SK, RF, TAM, HN); Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (MKB, QW, JD, KM, ML, SK, DFE, PDPP); Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia (JBee, GCT); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden (KC, HD, ME, JiL, JBr, KH, PH); Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium (DL); Vesalius Research Center, VIB, Leuven, Belgium (DL); Oncology Department, University Hospital Gasthuisberg, Leuven, Belgium (CW, KL); Copenhagen General Population Study, Herlev Hospital, Copenhagen, Denmark (SEB, BGN, SFN); Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Denmark (SEB, BGN, SFN); Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (SEB, BGN); Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Denmark (HF); Division of Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany (JCC, AR, PS, DC, AHü, RK, MB); Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany (DFJ); Department of Oncology

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Related in: MedlinePlus