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| IJMEG Copyright © 2010-present. All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711 |
Int J Mol Epidemiol Genet 2010;1(4):332-349.
Original Article
Novel pathway analysis of genomic polymorphism-cancer risk interaction in
the breast cancer prevention trial
Barbara K. Dunn, Mark H. Greene, Jenny M. Kelley, Joseph P. Costantino, Robert J. Clifford, Ying Hu, Gong Tang, Neely
Kazerouni, Philip S. Rosenberg, Daoud M. Meerzaman, Kenneth H. Buetow
NCI Division of Cancer Prevention, Basic Prevention Science Research Group, 6130 Executive Blvd., EPN 2056, Bethesda, MD
20892, USA; NCI Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch
6120 Executive Blvd., EPS 7032, Bethesda, MD 20892, USA; NCI Center for Cancer Research, Laboratory of Population
Genetics, 2115 E. Jefferson St., EJ/6000, Rockville, MD 20892, USA; NSABP Biostatistical Center, University of Pittsburgh
Graduate School of Public Health Department, 316 Parran Hall, 130 DeSoto Street, Pittsburgh, PA 15261, USA; California
Department of Public Health, Genetic Disease Screening Program, USA; NCI Division of Cancer Epidemiology and Genetics,
Biostatistics Branch, 6120 Executive Blvd., EPS 8022, Rockville, MD 20892, USA; NCI Center for Biomedical Informatics and
Information Technology, 2115 E. Jefferson St., EJ/6000, Rockville, MD 20892, USA.
Received July 5, 2010; accepted August 29, 2010; available online September 5, 2010
Abstract: Purpose: Tamoxifen was approved for breast cancer risk reduction in high-risk women based on data from the
National Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Prevention Trial (P-1:BCPT). Poor metabolizing CYP2D6
variants have been the subject of intensive scrutiny regarding their impact on clinical outcomes in women receiving adjuvant
tamoxifen for breast cancer. Our study extends to variants in a wider spectrum of genes involved in tamoxifen metabolism and
applies this analysis to the prevention setting. Methods: In a case-only study nested within P-1:BCPT, we explored whether
polymorphisms in estrogen/tamoxifen-metabolizing genes were associated with the efficacy of preventive tamoxifen. Thirty-
nine candidate polymorphisms in 17 candidate genes were genotyped in 249 P-1:BCPT cases. Results: While
CYP2D6_C1111T, as an individual polymorphism and within a CYP2D6 haplotype, showed borderline significant association
with treatment arm, pathway analysis of the entire network of genes in the tamoxifen pathway showed that the tamoxifen
pathway model was consistent with the pattern of observed genotype variability within the placebo arm (P-arm) dataset.
However, correlation of variations in genes in the tamoxifen intervention arm (T-arm) differed significantly from the predictions of
the tamoxifen pathway model. Strong correlations between allelic variation in the tamoxifen pathway at CYP1A1-CYP3A4,
CYP3A4-CYP2C9, and CYP2C9-SULT1A2, in addition to CYP2D6 and its adjacent genes, were seen in the P-arm but not the T-
arm. In conclusion, beyond reinforcing a role for CYP2D6 in tamoxifen response, our pathway analysis strongly suggests that
specific combinations of allelic variants in other genes make major contributions to the tamoxifen-resistance phenotype.
(IJMEG1007001).
Key words: Breast cancer, tamoxifen resistance, chemoprevention, pathway analysis, breast cancer risk, genomic
polymorphisms
Full Text PDF
Address all correspondence to:
Barbara K. Dunn
EPN 2056, 6130 Executive Blvd.
Bethesda, MD 20892
Tel: 301-402-1209; Fax: 301-480-1342
E-mail: dunnb@mail.nih.gov
Kenneth H. Buetow
2115EJ/6000, 2115 E. Jefferson St.
Rockville, MD 20892
Tel: 301-435-1520; Fax: 301-435-8963
E-mail: buetowke@mail.nih.gov
Original Article
Novel pathway analysis of genomic polymorphism-cancer risk interaction in
the breast cancer prevention trial
Barbara K. Dunn, Mark H. Greene, Jenny M. Kelley, Joseph P. Costantino, Robert J. Clifford, Ying Hu, Gong Tang, Neely
Kazerouni, Philip S. Rosenberg, Daoud M. Meerzaman, Kenneth H. Buetow
NCI Division of Cancer Prevention, Basic Prevention Science Research Group, 6130 Executive Blvd., EPN 2056, Bethesda, MD
20892, USA; NCI Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch
6120 Executive Blvd., EPS 7032, Bethesda, MD 20892, USA; NCI Center for Cancer Research, Laboratory of Population
Genetics, 2115 E. Jefferson St., EJ/6000, Rockville, MD 20892, USA; NSABP Biostatistical Center, University of Pittsburgh
Graduate School of Public Health Department, 316 Parran Hall, 130 DeSoto Street, Pittsburgh, PA 15261, USA; California
Department of Public Health, Genetic Disease Screening Program, USA; NCI Division of Cancer Epidemiology and Genetics,
Biostatistics Branch, 6120 Executive Blvd., EPS 8022, Rockville, MD 20892, USA; NCI Center for Biomedical Informatics and
Information Technology, 2115 E. Jefferson St., EJ/6000, Rockville, MD 20892, USA.
Received July 5, 2010; accepted August 29, 2010; available online September 5, 2010
Abstract: Purpose: Tamoxifen was approved for breast cancer risk reduction in high-risk women based on data from the
National Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Prevention Trial (P-1:BCPT). Poor metabolizing CYP2D6
variants have been the subject of intensive scrutiny regarding their impact on clinical outcomes in women receiving adjuvant
tamoxifen for breast cancer. Our study extends to variants in a wider spectrum of genes involved in tamoxifen metabolism and
applies this analysis to the prevention setting. Methods: In a case-only study nested within P-1:BCPT, we explored whether
polymorphisms in estrogen/tamoxifen-metabolizing genes were associated with the efficacy of preventive tamoxifen. Thirty-
nine candidate polymorphisms in 17 candidate genes were genotyped in 249 P-1:BCPT cases. Results: While
CYP2D6_C1111T, as an individual polymorphism and within a CYP2D6 haplotype, showed borderline significant association
with treatment arm, pathway analysis of the entire network of genes in the tamoxifen pathway showed that the tamoxifen
pathway model was consistent with the pattern of observed genotype variability within the placebo arm (P-arm) dataset.
However, correlation of variations in genes in the tamoxifen intervention arm (T-arm) differed significantly from the predictions of
the tamoxifen pathway model. Strong correlations between allelic variation in the tamoxifen pathway at CYP1A1-CYP3A4,
CYP3A4-CYP2C9, and CYP2C9-SULT1A2, in addition to CYP2D6 and its adjacent genes, were seen in the P-arm but not the T-
arm. In conclusion, beyond reinforcing a role for CYP2D6 in tamoxifen response, our pathway analysis strongly suggests that
specific combinations of allelic variants in other genes make major contributions to the tamoxifen-resistance phenotype.
(IJMEG1007001).
Key words: Breast cancer, tamoxifen resistance, chemoprevention, pathway analysis, breast cancer risk, genomic
polymorphisms
Full Text PDF
Address all correspondence to:
Barbara K. Dunn
EPN 2056, 6130 Executive Blvd.
Bethesda, MD 20892
Tel: 301-402-1209; Fax: 301-480-1342
E-mail: dunnb@mail.nih.gov
Kenneth H. Buetow
2115EJ/6000, 2115 E. Jefferson St.
Rockville, MD 20892
Tel: 301-435-1520; Fax: 301-435-8963
E-mail: buetowke@mail.nih.gov
