Abstract
It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3′ end cleavage and polyadenylation specificity factor (CPSF73).
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Woolf, C.M. An investigation of the familial aspects of carcinoma of the prostate. Cancer 13, 361–364 (1960).
Schaid, D.J., McDonnell, S.K., Blute, M.L. & Thibodeau, S.N. Evidence for autosomal dominant inheritance of prostate cancer. Am. J. Hum. Genet. 62, 1425–1438 (1998).
Narod, S.A. et al. The impact of family history on early detection of prostate cancer. Nature Med. 1, 99–101 (1995).
Monroe, K.R. et al. Evidence of an X-linked or recessive genetic component to prostate cancer risk. Nature Med. 1, 827–829 (1995).
Berry, R. et al. Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am. J. Hum. Genet. 67, 82–91 (2000).
Smith, J.R. et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274, 1371–1374 (1996).
Berthon, P. et al. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2–43. Am. J. Hum. Genet. 62, 1416–1424 (1998).
Xu, J. et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nature Genet. 20, 175–179 (1998).
Gibbs, M. et al. Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am. J. Hum. Genet. 64, 776–787 (1999).
Cooney, K.A. et al. Prostate cancer susceptibility locus on chromosome 1q: a confirmatory study. J. Natl. Cancer Inst. 89, 955–959 (1997).
Neuhausen, S.L. et al. Prostate cancer susceptibility locus HPC1 in Utah high-risk pedigrees. Hum. Mol. Genet. 8, 2437–2442 (1999).
Xu, J. & ICPCG Combined analysis of hereditary prostate cancer linkage to 1q24–25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. Am. J. Hum. Genet. 66, 945–957 (2000).
Suarez, B.K. et al. A genome screen of multiplex sibships with prostate cancer. Am. J. Hum. Genet. 66, 933–944 (2000).
Gibbs, M. et al. A genomic scan of families with prostate cancer identifies multiple regions of interest. Am. J. Hum. Genet. 67, 100–109 (2000).
Ostrander, E.A. & Stanford, J.L. Genetics of prostate cancer: too many loci, too few genes. Am. J. Hum. Genet. 67, 1367–1375 (2000).
Chamberlain, N.L., Driver, E.D. & Miesfeld, R.L. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 22, 3181–3186 (1994).
Giovannucci, E. et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc. Natl. Acad. Sci. USA 94, 3320–3323 (1997).
Stanford, J.L. et al. Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res. 57, 1194–1198 (1997).
Makridakis, N. et al. A prevalent missense substitution that modulates activity of prostatic steroid 5α-reductase. Cancer Res. 57, 1020–1022 (1997).
Makridakis, N.M. et al. Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA. Lancet 354, 975–978 (1999).
Jaffe, J.M. et al. Association of SRD5A2 genotype and pathological characteristics of prostate tumors. Cancer Res. 60, 1626–1630 (2000).
Skolnick, M.H. The Utah genealogical data base: a resource for genetic epidemiology. in Banbury Report No. 4: Cancer Incidence in Defined Populations (eds. Cairns, J., Lyon, J.L. & Skolnick, M.H.) 285–297 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1980).
McLellan, T., Jorde, L.B. & Skolnick, M.H. Genetic distances between the Utah Mormons and related populations. Am. J. Hum. Genet. 36, 836–857 (1984).
Jorde, L.B. & Skolnick, M.H. Demographic and genetic application of computerized record linking: the Utah Mormon genealogy. Information Sciences Humaines 56-57, 105–117 (1981).
Thomas, A., Gutin, A., Abkevich, V. & Bansal, A. Multipoint linkage analysis by blocked Gibbs sampling. Stat. Comp. 10, 259–269 (2000).
Tatusov, R.L., Koonin, E.V. & Lipman, D.J. A genomic perspective on protein families. Science 278, 631–637 (1997).
Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).
Dubrovsky, E.B., Dubrovskaya, V.A., Bilderback, A.L. & Berger, E.M. The isolation of two juvenile hormone-inducible genes in Drosophila melanogaster. Dev. Biol. 224, 486–495 (2000).
Walker, J.E., Saraste, M., Runswick, M.J. & Gay, N.J. Distantly related sequences in the α- and β-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1, 945–951 (1982).
Melino, S., Capo, C., Dragani, B., Aceto, A. & Petruzzelli, R. A zinc-binding motif conserved in glyoxalase II, β-lactamase, and arylsulfatases. Trends Biol. Sci. 23, 381–382 (1998).
Nevill-Manning, C.G., Wu, T.D. & Brutlag, D.L. Highly specific protein sequence motifs for genome analysis. Proc. Natl. Acad. Sci. USA 95, 5865–5871 (1998).
Haase, E., Riehl, D., Mack, M. & Brendel, M. Molecular cloning of SNM1, a yeast gene responsible for a specific step in the repair of cross-linked DNA. Mol. Gen. Genet. 218, 64–71 (1989).
Niegemann, E. & Brendel, M. A single amino acid change in SNM1-encoded protein leads to thermoconditional deficiency for DNA cross-link repair in Saccharomyces cerevisiae. Mutat. Res. 315, 275–279 (1994).
Chanfreau, G., Noble, S.M. & Guthrie, C. Essential yeast protein with unexpected similarity to subunits of mammalian cleavage and polyadenylation specificity factor (CPSF). Science 274, 1511–1514 (1996).
Jenny, A., Hauri, H.P. & Keller, W. Characterization of cleavage and polyadenylation specificity factor and cloning of its 100-kilodalton subunit. Mol. Cell. Biol. 14, 8183–8190 (1994).
Jenny, A., Minvielle-Sebastia, L., Preker, P.J. & Keller, W. Sequence similarity between the 73-kilodalton protein of mammalian CPSF and a subunit of yeast polyadenylation factor I. Science 274, 1514–1517 (1996).
Carfi, A. et al. X-ray structure of the ZnII β-lactamase from Bacteroides fragilis in an orthorhombic crystal form. Acta Crystallogr. D. Biol. Crystallogr. 54, 45–57 (1998).
Fabiane, S.M. et al. Crystal structure of the zinc-dependent β-lactamase from Bacillus cereus at 1.9 A resolution: binuclear active site with features of a mononuclear enzyme. Biochemistry 37, 12404–12411 (1998).
Barbeyron, T., Potin, P., Richard, C., Collin, O. & Kloareg, B. Arylsulphatase from Alteromonas carrageenovora. Microbiology 141, 2897–2904 (1995).
Rebbeck, T.R. et al. Association of HPC2/ELAC2 genotypes and prostate cancer. Am. J. Hum. Genet. 67, 1014–1019 (2000).
Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. USA 81, 3443–3446 (1984).
Cottingham, R.W., Jr., Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).
Schaffer, A.A., Gupta, S.K., Shriram, K. & Cottingham, R.W., Jr. Avoiding recomputation in linkage analysis. Hum. Hered. 44, 225–237 (1994).
Ott, J. Linkage probability and its approximate confidence interval under possible heterogeneity. Genet. Epidemiol. Suppl. 1, 251–257 (1986).
Lander, E.S. & Green, P. Construction of multilocus genetic linkage maps in humans. Proc. Natl. Acad. Sci. USA 84, 2363–2367 (1987).
O'Connell, J.R. & Weeks, D.E. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance. Nature Genet. 11, 402–408 (1995).
Tavtigian, S.V. et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nature Genet. 12, 333–337 (1996).
Rust, S., Funke, H. & Assmann, G. Mutagenically separated PCR (MS-PCR): a highly specific one step procedure for easy mutation detection. Nucleic Acids Res. 21, 3623–3629 (1993).
Cochran, W.G. Some methods of strengthening the common chi-squared tests. Biometrics 10, 417–451 (1954).
Armitage, P. Tests for linear trends in proportions and frequencies. Biometrics 11, 375–386 (1955).
Acknowledgements
We thank M. Anderson, M. Boyack, S. Faught, C. Hansen, M. Higbee (deceased), M. Jost, R. Nelson, K. Nguyen, T. Peterson, L. Steele, T. Tran and A. Zeller for technical assistance; F. Bazan for structural modeling; A. Bansal for suggestions with regards to the association studies; K. Heichman, J. Shaw and B. Bleazard for assistance with the yeast knockout; and D. Shattuck for a critical reading of the manuscript. This work was supported by grants CA62154 and CA64477 from the National Institutes of Health, funding from Schering Plough Research Institute, and by Endorecherche. The research was also supported by the Utah Cancer Registry, which is funded by contract no. N01-PC-67000 from the National Cancer Institute with additional support from the Utah Department of Health and the University of Utah.
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Rights and permissions
About this article
Cite this article
Tavtigian, S., Simard, J., Teng, D. et al. A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet 27, 172–180 (2001). https://doi.org/10.1038/84808
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/84808
This article is cited by
-
Research progress on the tsRNA classification, function, and application in gynecological malignant tumors
Cell Death Discovery (2021)
-
Germline BRCA mutation in male carriers—ripe for precision oncology?
Prostate Cancer and Prostatic Diseases (2018)
-
Molecular evolution of the TMS5 gene in rice (Oryza sativa L.)
Genetic Resources and Crop Evolution (2018)
-
Integrated genomic analysis of mitochondrial RNA processing in human cancers
Genome Medicine (2017)
-
Genome-wide association study of myelosuppression in non-small-cell lung cancer patients with platinum-based chemotherapy
The Pharmacogenomics Journal (2016)