Large-scale fine mapping of the HNF1B locus and prostate cancer risk

Sonja I. Berndt; Joshua Sampson; Meredith Yeager; Kevin B. Jacobs; Zhaoming Wang; Amy Hutchinson; Charles Chung; Nick Orr; Sholom Wacholder; Nilanjan Chatterjee; Kai Yu; Peter Kraft; Heather Spencer Feigelson; Michael J. Thun; W. Ryan Diver; Demetrius Albanes; Jarmo Virtamo; Stephanie Weinstein; Fredrick R. Schumacher; Geraldine Cancel-tassin; Olivier Cussenot; Antoine Valeri; Gerald L. Andriole; E. David Crawford; Christopher Haiman; Brian Henderson; Laurence Kolonel; Loic Le marchand; Afshan Siddiq; Elio Riboli; Ruth C. Travis; Rudolf Kaaks; William Isaacs; Sarah Isaacs; Kathleen E. Wiley; Henrik Gronberg; Fredrik Wiklund; Pär Stattin; Jianfeng Xu; S. Lilly Zheng; Jielin Sun; Lars J. Vatten; Kristian Hveem; Inger Njølstad; Daniela S. Gerhard; Margaret Tucker; Richard B. Hayes; Robert N. Hoover; Joseph F. Fraumeni; David J. Hunter; Gilles Thomas; Stephen J. Chanock

doi:10.1093/hmg/ddr213

Large-scale fine mapping of the HNF1B locus and prostate cancer risk

Sonja I. Berndt, Joshua Sampson, Meredith Yeager, Kevin B. Jacobs, Zhaoming Wang, Amy Hutchinson, Charles Chung, Nick Orr, Sholom Wacholder, Nilanjan Chatterjee, Kai Yu, Peter Kraft, Heather Spencer Feigelson, Michael J. Thun, W. Ryan Diver, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Fredrick R. Schumacher, Geraldine Cancel-tassinOlivier Cussenot, Antoine Valeri, Gerald L. Andriole, E. David Crawford, Christopher Haiman, Brian Henderson, Laurence Kolonel, Loic Le marchand, Afshan Siddiq, Elio Riboli, Ruth C. Travis, Rudolf Kaaks, William Isaacs, Sarah Isaacs, Kathleen E. Wiley, Henrik Gronberg, Fredrik Wiklund, Pär Stattin, Jianfeng Xu, S. Lilly Zheng, Jielin Sun, Lars J. Vatten, Kristian Hveem, Inger Njølstad, Daniela S. Gerhard, Margaret Tucker, Richard B. Hayes, Robert N. Hoover, Joseph F. Fraumeni, David J. Hunter, Gilles Thomas, Stephen J. Chanock

School of Medicine

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10 ^-8 with the most significant association with rs4430796 (P = 1.62 × 10 ^-24). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r ²= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10 ^-23) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10 ^-8); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10 ^-10), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.

Original language	English (US)
Article number	ddr213
Pages (from-to)	3322-3329
Number of pages	8
Journal	Human molecular genetics
Volume	20
Issue number	16
DOIs	https://doi.org/10.1093/hmg/ddr213
State	Published - Aug 2011

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1093/hmg/ddr213

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Berndt, S. I., Sampson, J., Yeager, M., Jacobs, K. B., Wang, Z., Hutchinson, A., Chung, C., Orr, N., Wacholder, S., Chatterjee, N., Yu, K., Kraft, P., Feigelson, H. S., Thun, M. J., Diver, W. R., Albanes, D., Virtamo, J., Weinstein, S., Schumacher, F. R., ... Chanock, S. J. (2011). Large-scale fine mapping of the HNF1B locus and prostate cancer risk. Human molecular genetics, 20(16), 3322-3329. Article ddr213. https://doi.org/10.1093/hmg/ddr213

Berndt, SI, Sampson, J, Yeager, M, Jacobs, KB, Wang, Z, Hutchinson, A, Chung, C, Orr, N, Wacholder, S, Chatterjee, N, Yu, K, Kraft, P, Feigelson, HS, Thun, MJ, Diver, WR, Albanes, D, Virtamo, J, Weinstein, S, Schumacher, FR, Cancel-tassin, G, Cussenot, O, Valeri, A, Andriole, GL, Crawford, ED, Haiman, C, Henderson, B, Kolonel, L, Le marchand, L, Siddiq, A, Riboli, E, Travis, RC, Kaaks, R, Isaacs, W, Isaacs, S, Wiley, KE, Gronberg, H, Wiklund, F, Stattin, P, Xu, J, Zheng, SL, Sun, J, Vatten, LJ, Hveem, K, Njølstad, I, Gerhard, DS, Tucker, M, Hayes, RB, Hoover, RN, Fraumeni, JF, Hunter, DJ, Thomas, G & Chanock, SJ 2011, 'Large-scale fine mapping of the HNF1B locus and prostate cancer risk', Human molecular genetics, vol. 20, no. 16, ddr213, pp. 3322-3329. https://doi.org/10.1093/hmg/ddr213

@article{779c05d3c3d94b49b7c7fba07794aed8,

title = "Large-scale fine mapping of the HNF1B locus and prostate cancer risk",

abstract = "Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10 -8 with the most significant association with rs4430796 (P = 1.62 × 10 -24). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r 2= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10 -23) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10 -8); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10 -10), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.",

author = "Berndt, {Sonja I.} and Joshua Sampson and Meredith Yeager and Jacobs, {Kevin B.} and Zhaoming Wang and Amy Hutchinson and Charles Chung and Nick Orr and Sholom Wacholder and Nilanjan Chatterjee and Kai Yu and Peter Kraft and Feigelson, {Heather Spencer} and Thun, {Michael J.} and Diver, {W. Ryan} and Demetrius Albanes and Jarmo Virtamo and Stephanie Weinstein and Schumacher, {Fredrick R.} and Geraldine Cancel-tassin and Olivier Cussenot and Antoine Valeri and Andriole, {Gerald L.} and Crawford, {E. David} and Christopher Haiman and Brian Henderson and Laurence Kolonel and {Le marchand}, Loic and Afshan Siddiq and Elio Riboli and Travis, {Ruth C.} and Rudolf Kaaks and William Isaacs and Sarah Isaacs and Wiley, {Kathleen E.} and Henrik Gronberg and Fredrik Wiklund and P{\"a}r Stattin and Jianfeng Xu and Zheng, {S. Lilly} and Jielin Sun and Vatten, {Lars J.} and Kristian Hveem and Inger Nj{\o}lstad and Gerhard, {Daniela S.} and Margaret Tucker and Hayes, {Richard B.} and Hoover, {Robert N.} and Fraumeni, {Joseph F.} and Hunter, {David J.} and Gilles Thomas and Chanock, {Stephen J.}",

note = "Funding Information: This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health and in part by National Cancer Institute, National Institutes of Health (CA129684 to J.X.) and contract number HHSN261200800001E. Funding Information: This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products or organization indicate endorsement by the US Government. The authors thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, NCI, the screening center investigators and staff of the PLCO Cancer Screening Trial, Mr Thomas Riley and staff at Information Management Services, Inc., and Ms Barbara O{\textquoteright}Brien and staff at Westat, Inc. for their contributions to the PLCO. Finally, we are grateful to the study participants for donating their time and making this study possible.",

year = "2011",

month = aug,

doi = "10.1093/hmg/ddr213",

language = "English (US)",

volume = "20",

pages = "3322--3329",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "16",

}

TY - JOUR

T1 - Large-scale fine mapping of the HNF1B locus and prostate cancer risk

AU - Berndt, Sonja I.

AU - Sampson, Joshua

AU - Yeager, Meredith

AU - Jacobs, Kevin B.

AU - Wang, Zhaoming

AU - Hutchinson, Amy

AU - Chung, Charles

AU - Orr, Nick

AU - Wacholder, Sholom

AU - Chatterjee, Nilanjan

AU - Yu, Kai

AU - Kraft, Peter

AU - Feigelson, Heather Spencer

AU - Thun, Michael J.

AU - Diver, W. Ryan

AU - Albanes, Demetrius

AU - Virtamo, Jarmo

AU - Weinstein, Stephanie

AU - Schumacher, Fredrick R.

AU - Cancel-tassin, Geraldine

AU - Cussenot, Olivier

AU - Valeri, Antoine

AU - Andriole, Gerald L.

AU - Crawford, E. David

AU - Haiman, Christopher

AU - Henderson, Brian

AU - Kolonel, Laurence

AU - Le marchand, Loic

AU - Siddiq, Afshan

AU - Riboli, Elio

AU - Travis, Ruth C.

AU - Kaaks, Rudolf

AU - Isaacs, William

AU - Isaacs, Sarah

AU - Wiley, Kathleen E.

AU - Gronberg, Henrik

AU - Wiklund, Fredrik

AU - Stattin, Pär

AU - Xu, Jianfeng

AU - Zheng, S. Lilly

AU - Sun, Jielin

AU - Vatten, Lars J.

AU - Hveem, Kristian

AU - Njølstad, Inger

AU - Gerhard, Daniela S.

AU - Tucker, Margaret

AU - Hayes, Richard B.

AU - Hoover, Robert N.

AU - Fraumeni, Joseph F.

AU - Hunter, David J.

AU - Thomas, Gilles

AU - Chanock, Stephen J.

N1 - Funding Information: This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health and in part by National Cancer Institute, National Institutes of Health (CA129684 to J.X.) and contract number HHSN261200800001E. Funding Information: This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products or organization indicate endorsement by the US Government. The authors thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, NCI, the screening center investigators and staff of the PLCO Cancer Screening Trial, Mr Thomas Riley and staff at Information Management Services, Inc., and Ms Barbara O’Brien and staff at Westat, Inc. for their contributions to the PLCO. Finally, we are grateful to the study participants for donating their time and making this study possible.

PY - 2011/8

Y1 - 2011/8

N2 - Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10 -8 with the most significant association with rs4430796 (P = 1.62 × 10 -24). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r 2= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10 -23) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10 -8); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10 -10), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.

AB - Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10 -8 with the most significant association with rs4430796 (P = 1.62 × 10 -24). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r 2= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10 -23) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10 -8); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10 -10), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.

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ER -

Large-scale fine mapping of the HNF1B locus and prostate cancer risk

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