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Vol. 57, No. 4, 2004
Issue release date: November 2004
Hum Hered 2004;57:172–178
(DOI:10.1159/000081443)

Analysis of Candidate Genes for Prostate Cancer

Burmester J.K.a · Suarez B.K.b · Lin J.H.c · Jin C.H.d · Miller R.D.e · Zhang K.-Q.a · Salzman S.A.a · Reding D.J.f · Catalona W.J.g
aDepartment of Cancer Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisc., bDepartments of Psychiatry and Genetics, Washington University School of Medicine, St. Louis, Mo., cDepartment of Medicine, Harvard Medical School, Boston Mass., dDepartment of Psychiatry and eDivision of Dermatology, Washington University, St. Louis, Mo., fDepartment of Oncology, Marshfield Clinic, Marshfield, Wisc., gDepartment of Urology, Northwestern University Feinberg School of Medicine, Chicago, Ill., USA
email Corresponding Author

Abstract

Considerable evidence demonstrates that genetic factors are important in the development and aggressiveness of prostate cancer. To identify genetic variants that predispose to prostate cancer we tested candidate SNPs from genomic regions that show linkage to prostate cancer susceptibility and/or aggressiveness, as well as genes that show a significant difference in mRNA expression level between tumor and normal tissue. Cases had histologically verified prostate cancer. Controls were at least 65 years old, never registered a PSA above 2.5 ng/ml, always had digital rectal examinations that were not suspicious for cancer, and have no known family history of prostate cancer. Thirty-nine coding SNPs and nine non-coding SNPs were tested in up to 590 cases and 556 controls resulting in over 40,000 SNP genotypes. Significant differences in allele frequencies between cases and controls were observed for ID3 (inhibitor of DNA binding), p = 0.05, HPN (hepsin), p = 0.009, BCAS1 (breast carcinoma amplified sequence 1), p = 0.007, CAV2 (caveolin 2), p = 0.007, EMP3 (epithelial membrane protein 3), p < 0.0001, and MLH1 (mutL homolog 1), p < 0.0001. SNPs in three of these genes (BCAS1, EMP3 and MLH1) remained significant in an age-matched subsample.


 goto top of outline Key Words

  • Prostate cancer
  • Genetics
  • Familial disease
  • Aggressiveness
  • Metastasis
  • Single nucleotide polymorphism

 goto top of outline Abstract

Considerable evidence demonstrates that genetic factors are important in the development and aggressiveness of prostate cancer. To identify genetic variants that predispose to prostate cancer we tested candidate SNPs from genomic regions that show linkage to prostate cancer susceptibility and/or aggressiveness, as well as genes that show a significant difference in mRNA expression level between tumor and normal tissue. Cases had histologically verified prostate cancer. Controls were at least 65 years old, never registered a PSA above 2.5 ng/ml, always had digital rectal examinations that were not suspicious for cancer, and have no known family history of prostate cancer. Thirty-nine coding SNPs and nine non-coding SNPs were tested in up to 590 cases and 556 controls resulting in over 40,000 SNP genotypes. Significant differences in allele frequencies between cases and controls were observed for ID3 (inhibitor of DNA binding), p = 0.05, HPN (hepsin), p = 0.009, BCAS1 (breast carcinoma amplified sequence 1), p = 0.007, CAV2 (caveolin 2), p = 0.007, EMP3 (epithelial membrane protein 3), p < 0.0001, and MLH1 (mutL homolog 1), p < 0.0001. SNPs in three of these genes (BCAS1, EMP3 and MLH1) remained significant in an age-matched subsample.

Copyright © 2004 S. Karger AG, Basel


 goto top of outline References
  1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ: Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26.
  2. Catalona WJ, Antenor JA, Roehl KA, Moul JW: Screening for prostate cancer in high risk populations. J Urol 2002;168:1980–1983.
  3. Keetch DW, Humphrey PA, Smith DS, Stahl D, Catalona WJ: Clinical and pathological features of hereditary prostate cancer. J Urol 1996:155:1841–1843.
  4. Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992;89:3367–3371.
  5. Ostrander EA, Stanford JL: Genetics of prostate cancer: too many loci, too few genes. Am J Hum Genet 2000;67:1367–1375.
  6. Easton DF, Schaid DJ, Whittemore AS, Isaacs WJ; International Consortium for Prostate Cancer Genetics: Where are the prostate cancer genes? – A summary of eight genome wide searches. Prostate 2003;57:261–269.
  7. Suarez BK, Lin J, Burmester JK, Broman KW, Weber JL, Banerjee TK, Goddard KA, Witte JS, Elston RC, Catalona WJ: A genome screen of multiplex sibships with prostate cancer. Am J Hum Genet 2000;66:933–944.
  8. Suarez BK, Lin J, Witte, JS, Conti DV, Resnick MI, Klein EA, Burmester JK, Vaske DA, Banerjee TK, Catalona WJ: Replication linkage study for prostate cancer susceptibility genes. Prostate 2000;45:106–114.
  9. Goddard KA, Witte JS, Suarez BK, Catalona WJ, Olson JM: Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. Am J Hum Genet 2001;68:1197–1206.
  10. Witte JS, Goddard KA, Conti DV, Elston RC, Lin J, Suarez BK, Broman KW, Burmester JK, Weber JL, Catalona WJ: Genomewide scan for prostate cancer-aggressiveness loci. Am J Hum Genet 2000;67:92–99.
  11. Witte JS, Suarez BK, Thiel B, Lin J, Yu A, Banerjee TK, Burmester JK, Casey G, Catalona WJ: Genome-wide scan of brothers: replication and fine mapping of prostate cancer susceptibility and aggressiveness loci. Prostate 2003;57:298–308.
  12. Smith DS, Humphrey PA, Catalona WJ: The early detection of prostate cancer with prostate specific antigen: the Washington University experience. Cancer 1997;80:1852–1856.
  13. Smith JR, Freije D, Carpten JD, Gronberg H, Xu J, Isaacs SD, Brownstein MJ, Bova GS, Guo H, Bujnovszky P, Nusskern DR, Damber JE, Bergh A, Emanuelsson M, Kallioniemi OP, Walker-Daniels J, Bailey-Wilson JE, Beaty TH, Meyers DA, Walsh PC, Collins FS, Trent JM, Isaacs WB: Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 1996;274:1371–1374.
  14. Gibbs M, Stanford JL, Jarvik GP, Janer M, Badzioch M, Peters MA, Goode EL, Kolb S, Chakrabarti L, Shook M, Basom R, Ostrander EA, Hood L: A genomic scan of families with prostate cancer identifies multiple regions of interest. Am J Hum Genet 2000;67:100–109.
  15. Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ, Carillo AR, Chen Y, Dayananth P, Desrochers M, Dumont M, Farnham JM, Frank D, Frye C, Ghaffari S, Gupte JS, Hu R, Iliev D, Janecki T, Kort EN, Laity KE, Leavitt A, Leblanc G, McArthur-Morrison J, Pederson A, Penn B, Peterson KT, Reid JE, Richards S, Schroeder M, Smith R, Snyder SC, Swedlund B, Swensen J, Thomas A, Tranchant M, Woodland AM, Labrie F, Skolnick MH, Neuhausen S, Rommens J, Cannon-Albright LA: A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet 2001;27:172–180.
  16. Berry R, Schroeder JJ, French AJ, McDonnell SK, Peterson BJ, Cunningham JM, Thibodeau SN, Schaid DJ: Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am J Hum Genet 2000;67:82–91.
  17. Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y: A high-throughput SNP typing system for genome-wide association studies. J Hum Genet 2001;46:471–477.
  18. Lange K, Weeks D, Boehnke M: Programs for pedigree analysis MENDEL, FISHER and dGENE. Genet Epidemiol 1988;5:471–472.
  19. Boehnke M: Allele frequency estimation from data on relatives. Am J Hum Genet 1991;48:22–25.
  20. Khoury MJ, Beaty TH, Cohen BH: Fundamentals of Genetic Epidemiology. New York, Oxford University Press, 1993.
  21. Lasorella A, Uo T, Iavarone A: Id proteins at the cross-road of development and cancer. Oncogene 2001;20:8326–8333.
  22. Magee JA, Araki T, Patil S, Ehrig T, True L, Humphrey PA, Catalona WJ, Watson MA, Milbrandt J: Expression profiling reveals hepsin overexpression in prostate cancer. Cancer Res 2001;61:5692–5696.
  23. Beardsley DI, Kowbel D, Lataxes TA, Mannino JM, Xin H, Kim WJ, Collins C, Brown KD: Characterization of the novel amplified in breast cancer-1 (NABC1) gene product. Exp Cell Res 2003;290:402–413.
  24. Tang Z, Scherer PE, Okamoto T, Song K, Chu C, Kohtz DS, Nishimoto I, Lodish HF, Lisanti MP: Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle. J Biol Chem 1996;271:2255–2261.
  25. Tahir SA, Yang G, Ebara S, Timme TL, Satoh T, Li L, Goltsov A, Ittmann M, Morrisett JD, Thompson TC: Secreted caveolin-1 stimulates cell survival/clonal growth and contributes to metastasis in androgen-insensitive prostate cancer. Cancer Res 2001;61:3882–3885.
  26. Wilson HL, Wilson SA, Surprenant A, North RA: Epithelial membrane proteins induce membrane blebbing and interact with the P2X7 receptor C terminus. J Biol Chem 2002;277:34017–34023.
  27. Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine, WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Hamilton SR, Peterson GM, Watson P, Lynch HT, Peltomäki P, Mecklin JP, de la Chapelle A, Kinzler KW, Vogelstein B: Mutation of mutL homolog in hereditary colon cancer. Science 1994;263:1625–1629.
  28. Lu ML, Schneider, MC, Zheng Y, Zhang X, Richie JP: Caveolin-1 interacts with androgen receptor. A positive modulator of androgen receptor mediated transactivation. J Biol Chem 2001;276:13442–13451.
  29. Peltomäki P: Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet 2001;10:735–740.
  30. Leach FS: Microsatellite instability and prostate cancer: clinical and pathological implications. Curr Opin Urol 2002;12:407–411.

 goto top of outline Author Contacts

James K. Burmester, PhD
Department of Cancer Genetics
Marshfield Clinic Research Foundation
1000 North Oak Avenue – 2R6, Marshfield, WI 54449 (USA)
Tel. +1 715 389 4368, Fax +1 715 389 5757, E-Mail burmester.jim@mcrf.mfldclin.edu


 goto top of outline Article Information

Received: February 6, 2004
Accepted after revision: April 29, 2004
Number of Print Pages : 7
Number of Figures : 1, Number of Tables : 2, Number of References : 30


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 57, No. 4, Year 2004 (Cover Date: Released November 2004)

Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.ch/hhe


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Considerable evidence demonstrates that genetic factors are important in the development and aggressiveness of prostate cancer. To identify genetic variants that predispose to prostate cancer we tested candidate SNPs from genomic regions that show linkage to prostate cancer susceptibility and/or aggressiveness, as well as genes that show a significant difference in mRNA expression level between tumor and normal tissue. Cases had histologically verified prostate cancer. Controls were at least 65 years old, never registered a PSA above 2.5 ng/ml, always had digital rectal examinations that were not suspicious for cancer, and have no known family history of prostate cancer. Thirty-nine coding SNPs and nine non-coding SNPs were tested in up to 590 cases and 556 controls resulting in over 40,000 SNP genotypes. Significant differences in allele frequencies between cases and controls were observed for ID3 (inhibitor of DNA binding), p = 0.05, HPN (hepsin), p = 0.009, BCAS1 (breast carcinoma amplified sequence 1), p = 0.007, CAV2 (caveolin 2), p = 0.007, EMP3 (epithelial membrane protein 3), p < 0.0001, and MLH1 (mutL homolog 1), p < 0.0001. SNPs in three of these genes (BCAS1, EMP3 and MLH1) remained significant in an age-matched subsample.



 goto top of outline Author Contacts

James K. Burmester, PhD
Department of Cancer Genetics
Marshfield Clinic Research Foundation
1000 North Oak Avenue – 2R6, Marshfield, WI 54449 (USA)
Tel. +1 715 389 4368, Fax +1 715 389 5757, E-Mail burmester.jim@mcrf.mfldclin.edu


 goto top of outline Article Information

Received: February 6, 2004
Accepted after revision: April 29, 2004
Number of Print Pages : 7
Number of Figures : 1, Number of Tables : 2, Number of References : 30


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 57, No. 4, Year 2004 (Cover Date: Released November 2004)

Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.ch/hhe


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ: Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26.
  2. Catalona WJ, Antenor JA, Roehl KA, Moul JW: Screening for prostate cancer in high risk populations. J Urol 2002;168:1980–1983.
  3. Keetch DW, Humphrey PA, Smith DS, Stahl D, Catalona WJ: Clinical and pathological features of hereditary prostate cancer. J Urol 1996:155:1841–1843.
  4. Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992;89:3367–3371.
  5. Ostrander EA, Stanford JL: Genetics of prostate cancer: too many loci, too few genes. Am J Hum Genet 2000;67:1367–1375.
  6. Easton DF, Schaid DJ, Whittemore AS, Isaacs WJ; International Consortium for Prostate Cancer Genetics: Where are the prostate cancer genes? – A summary of eight genome wide searches. Prostate 2003;57:261–269.
  7. Suarez BK, Lin J, Burmester JK, Broman KW, Weber JL, Banerjee TK, Goddard KA, Witte JS, Elston RC, Catalona WJ: A genome screen of multiplex sibships with prostate cancer. Am J Hum Genet 2000;66:933–944.
  8. Suarez BK, Lin J, Witte, JS, Conti DV, Resnick MI, Klein EA, Burmester JK, Vaske DA, Banerjee TK, Catalona WJ: Replication linkage study for prostate cancer susceptibility genes. Prostate 2000;45:106–114.
  9. Goddard KA, Witte JS, Suarez BK, Catalona WJ, Olson JM: Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. Am J Hum Genet 2001;68:1197–1206.
  10. Witte JS, Goddard KA, Conti DV, Elston RC, Lin J, Suarez BK, Broman KW, Burmester JK, Weber JL, Catalona WJ: Genomewide scan for prostate cancer-aggressiveness loci. Am J Hum Genet 2000;67:92–99.
  11. Witte JS, Suarez BK, Thiel B, Lin J, Yu A, Banerjee TK, Burmester JK, Casey G, Catalona WJ: Genome-wide scan of brothers: replication and fine mapping of prostate cancer susceptibility and aggressiveness loci. Prostate 2003;57:298–308.
  12. Smith DS, Humphrey PA, Catalona WJ: The early detection of prostate cancer with prostate specific antigen: the Washington University experience. Cancer 1997;80:1852–1856.
  13. Smith JR, Freije D, Carpten JD, Gronberg H, Xu J, Isaacs SD, Brownstein MJ, Bova GS, Guo H, Bujnovszky P, Nusskern DR, Damber JE, Bergh A, Emanuelsson M, Kallioniemi OP, Walker-Daniels J, Bailey-Wilson JE, Beaty TH, Meyers DA, Walsh PC, Collins FS, Trent JM, Isaacs WB: Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 1996;274:1371–1374.
  14. Gibbs M, Stanford JL, Jarvik GP, Janer M, Badzioch M, Peters MA, Goode EL, Kolb S, Chakrabarti L, Shook M, Basom R, Ostrander EA, Hood L: A genomic scan of families with prostate cancer identifies multiple regions of interest. Am J Hum Genet 2000;67:100–109.
  15. Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ, Carillo AR, Chen Y, Dayananth P, Desrochers M, Dumont M, Farnham JM, Frank D, Frye C, Ghaffari S, Gupte JS, Hu R, Iliev D, Janecki T, Kort EN, Laity KE, Leavitt A, Leblanc G, McArthur-Morrison J, Pederson A, Penn B, Peterson KT, Reid JE, Richards S, Schroeder M, Smith R, Snyder SC, Swedlund B, Swensen J, Thomas A, Tranchant M, Woodland AM, Labrie F, Skolnick MH, Neuhausen S, Rommens J, Cannon-Albright LA: A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet 2001;27:172–180.
  16. Berry R, Schroeder JJ, French AJ, McDonnell SK, Peterson BJ, Cunningham JM, Thibodeau SN, Schaid DJ: Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am J Hum Genet 2000;67:82–91.
  17. Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y: A high-throughput SNP typing system for genome-wide association studies. J Hum Genet 2001;46:471–477.
  18. Lange K, Weeks D, Boehnke M: Programs for pedigree analysis MENDEL, FISHER and dGENE. Genet Epidemiol 1988;5:471–472.
  19. Boehnke M: Allele frequency estimation from data on relatives. Am J Hum Genet 1991;48:22–25.
  20. Khoury MJ, Beaty TH, Cohen BH: Fundamentals of Genetic Epidemiology. New York, Oxford University Press, 1993.
  21. Lasorella A, Uo T, Iavarone A: Id proteins at the cross-road of development and cancer. Oncogene 2001;20:8326–8333.
  22. Magee JA, Araki T, Patil S, Ehrig T, True L, Humphrey PA, Catalona WJ, Watson MA, Milbrandt J: Expression profiling reveals hepsin overexpression in prostate cancer. Cancer Res 2001;61:5692–5696.
  23. Beardsley DI, Kowbel D, Lataxes TA, Mannino JM, Xin H, Kim WJ, Collins C, Brown KD: Characterization of the novel amplified in breast cancer-1 (NABC1) gene product. Exp Cell Res 2003;290:402–413.
  24. Tang Z, Scherer PE, Okamoto T, Song K, Chu C, Kohtz DS, Nishimoto I, Lodish HF, Lisanti MP: Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle. J Biol Chem 1996;271:2255–2261.
  25. Tahir SA, Yang G, Ebara S, Timme TL, Satoh T, Li L, Goltsov A, Ittmann M, Morrisett JD, Thompson TC: Secreted caveolin-1 stimulates cell survival/clonal growth and contributes to metastasis in androgen-insensitive prostate cancer. Cancer Res 2001;61:3882–3885.
  26. Wilson HL, Wilson SA, Surprenant A, North RA: Epithelial membrane proteins induce membrane blebbing and interact with the P2X7 receptor C terminus. J Biol Chem 2002;277:34017–34023.
  27. Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine, WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Hamilton SR, Peterson GM, Watson P, Lynch HT, Peltomäki P, Mecklin JP, de la Chapelle A, Kinzler KW, Vogelstein B: Mutation of mutL homolog in hereditary colon cancer. Science 1994;263:1625–1629.
  28. Lu ML, Schneider, MC, Zheng Y, Zhang X, Richie JP: Caveolin-1 interacts with androgen receptor. A positive modulator of androgen receptor mediated transactivation. J Biol Chem 2001;276:13442–13451.
  29. Peltomäki P: Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet 2001;10:735–740.
  30. Leach FS: Microsatellite instability and prostate cancer: clinical and pathological implications. Curr Opin Urol 2002;12:407–411.