Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer

J. Xu, S. L. Zheng, J. D. Carpten, N. N. Nupponen, C. M. Robbins, J. Mestre, T. Y. Moses, D. A. Faith, B. D. Kelly, S. D. Isaacs, K. E. Wiley, C. M. Ewing, P. Bujnovszky, B. L. Chang, J. Bailey-Wilson, E. R. Bleecker, Patrick Walsh, J. M. Trent, D. A. Meyers, William B Isaacs

Research output: Contribution to journalArticle

Abstract

To investigate the relationship between HPC2/ELAC2 and prostate cancer risk, we performed the following analyses: (1) a linkage study of six markers in and around the HPC2/ELAC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer (HPC); (2) a mutation-screening analysis of all coding exons of the gene in 93 probands with HPC; (3) family-based and population-based association study of common HPC2/ELAC2 missense variants in 159 probands with HPC, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample, nor in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC. In association analyses, family-based tests did not reveal excess transmission of the Leu217 and/or Thr541 alleles to affected offspring, and population-based tests failed to reveal any statistically significant difference in the allele frequencies of the two polymorphisms between patients with prostate cancer and control subjects. The results of this study lead us to reject the three alternative hypotheses of (1) a highly penetrant, major prostate cancer-susceptibility gene at 17p11, (2) the allelic variants Leu217 or Thr541 of HPC2/ELAC2 as high-penetrance mutations, and (3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, we did observe a trend of higher Leu217 homozygous carrier rates in patients than in control subjects. Considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies of prostate cancer and on the power to detect linkage and association in our study sample, our results cannot rule out the possibility of a highly penetrant prostate cancer gene at this locus that only segregates in a small number of pedigrees. Nor can we rule out a prostate cancer-modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to more fully evaluate the role of this gene in prostate cancer risk.

Original languageEnglish (US)
Pages (from-to)901-911
Number of pages11
JournalAmerican Journal of Human Genetics
Volume68
Issue number4
DOIs
StatePublished - 2001

Fingerprint

Prostatic Neoplasms
Penetrance
Neoplasm Genes
Pedigree
Exons
Alleles
Modifier Genes
Genes
Mutation
Genetic Heterogeneity
Age of Onset
Gene Frequency
Population
Familial Prostate cancer

ASJC Scopus subject areas

  • Genetics

Cite this

Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer. / Xu, J.; Zheng, S. L.; Carpten, J. D.; Nupponen, N. N.; Robbins, C. M.; Mestre, J.; Moses, T. Y.; Faith, D. A.; Kelly, B. D.; Isaacs, S. D.; Wiley, K. E.; Ewing, C. M.; Bujnovszky, P.; Chang, B. L.; Bailey-Wilson, J.; Bleecker, E. R.; Walsh, Patrick; Trent, J. M.; Meyers, D. A.; Isaacs, William B.

In: American Journal of Human Genetics, Vol. 68, No. 4, 2001, p. 901-911.

Research output: Contribution to journalArticle

Xu, J, Zheng, SL, Carpten, JD, Nupponen, NN, Robbins, CM, Mestre, J, Moses, TY, Faith, DA, Kelly, BD, Isaacs, SD, Wiley, KE, Ewing, CM, Bujnovszky, P, Chang, BL, Bailey-Wilson, J, Bleecker, ER, Walsh, P, Trent, JM, Meyers, DA & Isaacs, WB 2001, 'Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer', American Journal of Human Genetics, vol. 68, no. 4, pp. 901-911. https://doi.org/10.1086/319513
Xu, J. ; Zheng, S. L. ; Carpten, J. D. ; Nupponen, N. N. ; Robbins, C. M. ; Mestre, J. ; Moses, T. Y. ; Faith, D. A. ; Kelly, B. D. ; Isaacs, S. D. ; Wiley, K. E. ; Ewing, C. M. ; Bujnovszky, P. ; Chang, B. L. ; Bailey-Wilson, J. ; Bleecker, E. R. ; Walsh, Patrick ; Trent, J. M. ; Meyers, D. A. ; Isaacs, William B. / Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer. In: American Journal of Human Genetics. 2001 ; Vol. 68, No. 4. pp. 901-911.
@article{34f4b8413b8d4f079897f66cad6872fd,
title = "Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer",
abstract = "To investigate the relationship between HPC2/ELAC2 and prostate cancer risk, we performed the following analyses: (1) a linkage study of six markers in and around the HPC2/ELAC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer (HPC); (2) a mutation-screening analysis of all coding exons of the gene in 93 probands with HPC; (3) family-based and population-based association study of common HPC2/ELAC2 missense variants in 159 probands with HPC, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample, nor in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC. In association analyses, family-based tests did not reveal excess transmission of the Leu217 and/or Thr541 alleles to affected offspring, and population-based tests failed to reveal any statistically significant difference in the allele frequencies of the two polymorphisms between patients with prostate cancer and control subjects. The results of this study lead us to reject the three alternative hypotheses of (1) a highly penetrant, major prostate cancer-susceptibility gene at 17p11, (2) the allelic variants Leu217 or Thr541 of HPC2/ELAC2 as high-penetrance mutations, and (3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, we did observe a trend of higher Leu217 homozygous carrier rates in patients than in control subjects. Considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies of prostate cancer and on the power to detect linkage and association in our study sample, our results cannot rule out the possibility of a highly penetrant prostate cancer gene at this locus that only segregates in a small number of pedigrees. Nor can we rule out a prostate cancer-modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to more fully evaluate the role of this gene in prostate cancer risk.",
author = "J. Xu and Zheng, {S. L.} and Carpten, {J. D.} and Nupponen, {N. N.} and Robbins, {C. M.} and J. Mestre and Moses, {T. Y.} and Faith, {D. A.} and Kelly, {B. D.} and Isaacs, {S. D.} and Wiley, {K. E.} and Ewing, {C. M.} and P. Bujnovszky and Chang, {B. L.} and J. Bailey-Wilson and Bleecker, {E. R.} and Patrick Walsh and Trent, {J. M.} and Meyers, {D. A.} and Isaacs, {William B}",
year = "2001",
doi = "10.1086/319513",
language = "English (US)",
volume = "68",
pages = "901--911",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",

}

TY - JOUR

T1 - Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer

AU - Xu, J.

AU - Zheng, S. L.

AU - Carpten, J. D.

AU - Nupponen, N. N.

AU - Robbins, C. M.

AU - Mestre, J.

AU - Moses, T. Y.

AU - Faith, D. A.

AU - Kelly, B. D.

AU - Isaacs, S. D.

AU - Wiley, K. E.

AU - Ewing, C. M.

AU - Bujnovszky, P.

AU - Chang, B. L.

AU - Bailey-Wilson, J.

AU - Bleecker, E. R.

AU - Walsh, Patrick

AU - Trent, J. M.

AU - Meyers, D. A.

AU - Isaacs, William B

PY - 2001

Y1 - 2001

N2 - To investigate the relationship between HPC2/ELAC2 and prostate cancer risk, we performed the following analyses: (1) a linkage study of six markers in and around the HPC2/ELAC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer (HPC); (2) a mutation-screening analysis of all coding exons of the gene in 93 probands with HPC; (3) family-based and population-based association study of common HPC2/ELAC2 missense variants in 159 probands with HPC, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample, nor in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC. In association analyses, family-based tests did not reveal excess transmission of the Leu217 and/or Thr541 alleles to affected offspring, and population-based tests failed to reveal any statistically significant difference in the allele frequencies of the two polymorphisms between patients with prostate cancer and control subjects. The results of this study lead us to reject the three alternative hypotheses of (1) a highly penetrant, major prostate cancer-susceptibility gene at 17p11, (2) the allelic variants Leu217 or Thr541 of HPC2/ELAC2 as high-penetrance mutations, and (3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, we did observe a trend of higher Leu217 homozygous carrier rates in patients than in control subjects. Considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies of prostate cancer and on the power to detect linkage and association in our study sample, our results cannot rule out the possibility of a highly penetrant prostate cancer gene at this locus that only segregates in a small number of pedigrees. Nor can we rule out a prostate cancer-modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to more fully evaluate the role of this gene in prostate cancer risk.

AB - To investigate the relationship between HPC2/ELAC2 and prostate cancer risk, we performed the following analyses: (1) a linkage study of six markers in and around the HPC2/ELAC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer (HPC); (2) a mutation-screening analysis of all coding exons of the gene in 93 probands with HPC; (3) family-based and population-based association study of common HPC2/ELAC2 missense variants in 159 probands with HPC, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample, nor in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC. In association analyses, family-based tests did not reveal excess transmission of the Leu217 and/or Thr541 alleles to affected offspring, and population-based tests failed to reveal any statistically significant difference in the allele frequencies of the two polymorphisms between patients with prostate cancer and control subjects. The results of this study lead us to reject the three alternative hypotheses of (1) a highly penetrant, major prostate cancer-susceptibility gene at 17p11, (2) the allelic variants Leu217 or Thr541 of HPC2/ELAC2 as high-penetrance mutations, and (3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, we did observe a trend of higher Leu217 homozygous carrier rates in patients than in control subjects. Considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies of prostate cancer and on the power to detect linkage and association in our study sample, our results cannot rule out the possibility of a highly penetrant prostate cancer gene at this locus that only segregates in a small number of pedigrees. Nor can we rule out a prostate cancer-modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to more fully evaluate the role of this gene in prostate cancer risk.

UR - http://www.scopus.com/inward/record.url?scp=0035071956&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035071956&partnerID=8YFLogxK

U2 - 10.1086/319513

DO - 10.1086/319513

M3 - Article

VL - 68

SP - 901

EP - 911

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -