ALBERT

Description:    Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P  = 9.9 × 10 −8 [odds ratio 4.42 (95 % confidence interval 2.56–7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring ( P  = 6.5 × 10 −6 ). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1229-4 Authors Jianfeng Xu, Data Coordinating Center for the ICPCG, Wake Forest University School of Medicine, Winston-Salem, NC, USA Ethan M. Lange, University of Michigan ICPCG Group, University of Michigan Medical School, Ann Arbor, MI, USA Lingyi Lu, Data Coordinating Center for the ICPCG, Wake Forest University School of Medicine, Winston-Salem, NC, USA Siqun L. Zheng, Data Coordinating Center for the ICPCG, Wake Forest University School of Medicine, Winston-Salem, NC, USA Zhong Wang, Data Coordinating Center for the ICPCG, Wake Forest University School of Medicine, Winston-Salem, NC, USA Stephen N. Thibodeau, Mayo Clinic ICPGC Group, Mayo Clinic, Rochester, MN, USA Lisa A. Cannon-Albright, University of Utah ICPCG Group, University of Utah School of Medicine, Salt Lake City, UT, USA Craig C. Teerlink, University of Utah ICPCG Group, University of Utah School of Medicine, Salt Lake City, UT, USA Nicola J. Camp, University of Utah ICPCG Group, University of Utah School of Medicine, Salt Lake City, UT, USA Anna M. Johnson, University of Michigan ICPCG Group, University of Michigan Medical School, Ann Arbor, MI, USA Kimberly A. Zuhlke, University of Michigan ICPCG Group, University of Michigan Medical School, Ann Arbor, MI, USA Janet L. Stanford, Fred Hutchinson Cancer Research Center (FHCRC) ICPCG Group, Seattle, WA, USA Elaine A. Ostrander, Fred Hutchinson Cancer Research Center (FHCRC) ICPCG Group, Seattle, WA, USA Kathleen E. Wiley, Johns Hopkins University ICPCG Group, Baltimore, MD, USA Sarah D. Isaacs, Johns Hopkins University ICPCG Group, Baltimore, MD, USA Patrick C. Walsh, Johns Hopkins University ICPCG Group, Baltimore, MD, USA Christiane Maier, University of Ulm ICPCG Group, University of Ulm, Ulm, Germany Manuel Luedeke, University of Ulm ICPCG Group, University of Ulm, Ulm, Germany Walther Vogel, University of Ulm ICPCG Group, University of Ulm, Ulm, Germany Johanna Schleutker, University of Tampere ICPCG Group, University of Tampere and Fimlab Laboratories, Tampere, Finland Tiina Wahlfors, University of Tampere ICPCG Group, University of Tampere and Fimlab Laboratories, Tampere, Finland Teuvo Tammela, University of Tampere ICPCG Group, University of Tampere and Fimlab Laboratories, Tampere, Finland Daniel Schaid, Mayo Clinic ICPGC Group, Mayo Clinic, Rochester, MN, USA Shannon K. McDonnell, Mayo Clinic ICPGC Group, Mayo Clinic, Rochester, MN, USA Melissa S. DeRycke, Mayo Clinic ICPGC Group, Mayo Clinic, Rochester, MN, USA Geraldine Cancel-Tassin, CeRePP ICPCG Group, Paris, France Olivier Cussenot, CeRePP ICPCG Group, Paris, France Fredrik Wiklund, Karolinska ICPCG Group, Karolinska Institutet, Stockholm, Sweden Henrik Grönberg, Karolinska ICPCG Group, Karolinska Institutet, Stockholm, Sweden Ros Eeles, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Doug Easton, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Zsofia Kote-Jarai, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Alice S. Whittemore, BC/CA/HI ICPCG Group, Stanford School of Medicine, Stanford, CA, USA Chih-Lin Hsieh, BC/CA/HI ICPCG Group, Stanford School of Medicine, Stanford, CA, USA Graham G. Giles, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK John L. Hopper, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Gianluca Severi, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK William J. Catalona, Northwestern University ICPCG Group, Chicago, IL, USA Diptasri Mandal, Louisiana State University ICPCG Group, New Orleans, LA, USA Elisa Ledet, Louisiana State University ICPCG Group, New Orleans, LA, USA William D. Foulkes, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Nancy Hamel, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Lovise Mahle, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Pal Moller, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Isaac Powell, African American Hereditary Prostate Cancer ICPCG Group, Detroit, MI, USA Joan E. Bailey-Wilson, African American Hereditary Prostate Cancer ICPCG Group, Detroit, MI, USA John D. Carpten, African American Hereditary Prostate Cancer ICPCG Group, Detroit, MI, USA Daniela Seminara, National Cancer Institute, NIH, Bethesda, MD, USA Kathleen A. Cooney, University of Michigan ICPCG Group, University of Michigan Medical School, Ann Arbor, MI, USA William B. Isaacs, Johns Hopkins University ICPCG Group, Baltimore, MD, USA International Consortium for Prostate Cancer Genetics Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717