A functionally significant SNP in TP53 and breast cancer risk in African-American women

doi:10.1038/s41523-017-0007-9

. 2017 Feb 27:3:5.

doi: 10.1038/s41523-017-0007-9. eCollection 2017.

A functionally significant SNP in TP53 and breast cancer risk in African-American women

Maureen E Murphy¹, Song Liu², Song Yao³, Dezheng Huo⁴, Qin Liu¹, Sonia C Dolfi⁵, Kim M Hirshfield⁵, Chi-Chen Hong³, Qiang Hu², Andrew F Olshan⁶, Temidayo O Ogundiran⁷, Clement Adebamowo⁸, Susan M Domchek⁹, Katherine L Nathanson⁹, Barbara Nemesure¹⁰, Stefan Ambs¹¹, William J Blot^{12

13}, Ye Feng¹⁴, Esther M John^{15

16}, Leslie Bernstein¹⁷, Wei Zheng¹⁸, Jennifer J Hu¹⁹, Regina G Ziegler²⁰, Sarah Nyante²¹, Sue A Ingles¹⁴, Michael F Press²², Sandra L Deming¹⁸, Jorge L Rodriguez-Gil¹⁹, Christopher A Haiman¹⁴, Olufunmilayo I Olopade²³, Kathryn L Lunetta²⁴, Julie R Palmer²⁵, Christine B Ambrosone⁵

Affiliations

¹ Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104 USA.
² Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263 USA.
³ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263 USA.
⁴ Department of Public Health Sciences, University of Chicago, Chicago, , IL 60637 USA.
⁵ Department of Medicine, Rutgers Robert Wood Johnson Medical School/Rutgers Cancer Institute of New Jersey, New Brunswick, , NJ 08903 USA.
⁶ University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, , NC 27514 USA.
⁷ Department of Surgery, College of Medicine, University of Ibadan, Ibadan, Nigeria.
⁸ Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, MD 21201 USA.
⁹ Department of Medicine, Abramson Cancer Center, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, , PA 19104 USA.
¹⁰ Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY 11794 USA.
¹¹ Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD 20892 USA.
¹² International Epidemiology Institute, Rockville, MD 20850 USA.
¹³ Vanderbilt University Medical Center, Nashville, , TN 37232 USA.
¹⁴ Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089 USA.
¹⁵ Cancer Prevention Institute of California, Fremont, CA 94305 USA.
¹⁶ Stanford University School of Medicine and Stanford Cancer Institute, Stanford, CA 94305 USA.
¹⁷ Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010 USA.
¹⁸ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232 USA.
¹⁹ Sylvester Comprehensive Cancer Center and Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136 USA.
²⁰ Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892 USA.
²¹ Department of Epidemiology, Gillings School of Global Public Health and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514 USA.
²² Department of Pathology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089 USA.
²³ Department of Medicine, University of Chicago, Chicago, , IL 60637 USA.
²⁴ Department of Biostatistics, Boston University, Boston, , MA 02215 USA.
²⁵ Slone Epidemiology Center at Boston University, Boston, , MA 02215 USA.

PMID: 28649645
PMCID: PMC5445618
DOI: 10.1038/s41523-017-0007-9

A functionally significant SNP in TP53 and breast cancer risk in African-American women

Maureen E Murphy et al. NPJ Breast Cancer. 2017.

. 2017 Feb 27:3:5.

doi: 10.1038/s41523-017-0007-9. eCollection 2017.

Authors

Affiliations

¹ Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104 USA.
² Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263 USA.
³ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263 USA.
⁴ Department of Public Health Sciences, University of Chicago, Chicago, , IL 60637 USA.
⁵ Department of Medicine, Rutgers Robert Wood Johnson Medical School/Rutgers Cancer Institute of New Jersey, New Brunswick, , NJ 08903 USA.
⁶ University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, , NC 27514 USA.
⁷ Department of Surgery, College of Medicine, University of Ibadan, Ibadan, Nigeria.
⁸ Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, MD 21201 USA.
⁹ Department of Medicine, Abramson Cancer Center, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, , PA 19104 USA.
¹⁰ Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY 11794 USA.
¹¹ Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD 20892 USA.
¹² International Epidemiology Institute, Rockville, MD 20850 USA.
¹³ Vanderbilt University Medical Center, Nashville, , TN 37232 USA.
¹⁴ Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089 USA.
¹⁵ Cancer Prevention Institute of California, Fremont, CA 94305 USA.
¹⁶ Stanford University School of Medicine and Stanford Cancer Institute, Stanford, CA 94305 USA.
¹⁷ Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010 USA.
¹⁸ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232 USA.
¹⁹ Sylvester Comprehensive Cancer Center and Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136 USA.
²⁰ Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892 USA.
²¹ Department of Epidemiology, Gillings School of Global Public Health and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514 USA.
²² Department of Pathology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089 USA.
²³ Department of Medicine, University of Chicago, Chicago, , IL 60637 USA.
²⁴ Department of Biostatistics, Boston University, Boston, , MA 02215 USA.
²⁵ Slone Epidemiology Center at Boston University, Boston, , MA 02215 USA.

PMID: 28649645
PMCID: PMC5445618
DOI: 10.1038/s41523-017-0007-9

Abstract

A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08-2.76; p-value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.

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Figures

**Fig. 1**
Forest plot of meta-analysis of *TP53* rs1800371 with breast cancer risk among pre-menopausal women in the AMBER and ROOT consortia. Study-specific odds ratios (OR) from each of BWHS, WCHS, CBCS, and ROOT is indicated as a *shaded square*, with 95% confidence interval (CI) shown as a *horizontal line*. The meta-OR is indicated as a *diamond*, with the width corresponding to the 95% CI. The analyses were performed for all cases, ER-positive cancer, and ER-negative cancer

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References

1. Grochola LF, Zeron-Medina J, Meriaux S, Bond GL. Single-nucleotide polymorphisms in the p53 signaling pathway. Cold Spring Harb. Perspect. Biol. 2010;2:a001032. doi: 10.1101/cshperspect.a001032. - DOI - PMC - PubMed
1. Pietsch EC, Humbey O, Murphy ME. Polymorphisms in the p53 pathway. Oncogene . 2006;25:1602–1611. doi: 10.1038/sj.onc.1209367. - DOI - PubMed
1. Basu, S., Murphy, M. E. Genetic modifiers of the p53 pathway. Cold Spring Harb. Perspect. Med. Apr 1;6(4), a026302 (2016). - PMC - PubMed
1. Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H, et al. Mdm2 snp309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res. . 2006;66:5104–5110. doi: 10.1158/0008-5472.CAN-06-0180. - DOI - PubMed
1. Singh V, Rastogi N, Mathur N, Singh K, Singh MP. Association of polymorphism in mdm-2 and p53 genes with breast cancer risk in indian women. Ann. Epidemiol. . 2008;18:48–57. doi: 10.1016/j.annepidem.2007.06.006. - DOI - PubMed

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[1] Grochola LF, Zeron-Medina J, Meriaux S, Bond GL. Single-nucleotide polymorphisms in the p53 signaling pathway. Cold Spring Harb. Perspect. Biol. 2010;2:a001032. doi: 10.1101/cshperspect.a001032. - DOI - PMC - PubMed

[2] Grochola LF, Zeron-Medina J, Meriaux S, Bond GL. Single-nucleotide polymorphisms in the p53 signaling pathway. Cold Spring Harb. Perspect. Biol. 2010;2:a001032. doi: 10.1101/cshperspect.a001032. - DOI - PMC - PubMed

[3] Pietsch EC, Humbey O, Murphy ME. Polymorphisms in the p53 pathway. Oncogene . 2006;25:1602–1611. doi: 10.1038/sj.onc.1209367. - DOI - PubMed

[4] Pietsch EC, Humbey O, Murphy ME. Polymorphisms in the p53 pathway. Oncogene . 2006;25:1602–1611. doi: 10.1038/sj.onc.1209367. - DOI - PubMed

[5] Basu, S., Murphy, M. E. Genetic modifiers of the p53 pathway. Cold Spring Harb. Perspect. Med. Apr 1;6(4), a026302 (2016). - PMC - PubMed

[6] Basu, S., Murphy, M. E. Genetic modifiers of the p53 pathway. Cold Spring Harb. Perspect. Med. Apr 1;6(4), a026302 (2016). - PMC - PubMed

[7] Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H, et al. Mdm2 snp309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res. . 2006;66:5104–5110. doi: 10.1158/0008-5472.CAN-06-0180. - DOI - PubMed

[8] Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H, et al. Mdm2 snp309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res. . 2006;66:5104–5110. doi: 10.1158/0008-5472.CAN-06-0180. - DOI - PubMed

[9] Singh V, Rastogi N, Mathur N, Singh K, Singh MP. Association of polymorphism in mdm-2 and p53 genes with breast cancer risk in indian women. Ann. Epidemiol. . 2008;18:48–57. doi: 10.1016/j.annepidem.2007.06.006. - DOI - PubMed

[10] Singh V, Rastogi N, Mathur N, Singh K, Singh MP. Association of polymorphism in mdm-2 and p53 genes with breast cancer risk in indian women. Ann. Epidemiol. . 2008;18:48–57. doi: 10.1016/j.annepidem.2007.06.006. - DOI - PubMed

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A functionally significant SNP in TP53 and breast cancer risk in African-American women

Affiliations

A functionally significant SNP in TP53 and breast cancer risk in African-American women

Authors

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Abstract

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