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A candidate prostate cancer susceptibility gene at chromosome 17p

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).

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Figure 1: Recombinant, physical and transcript map centered at the human ELAC2 locus on chromosome 17p.
Figure 2: Multiple protein alignment of ELAC1/2 family members.
Figure 3: Analysis of ELAC2 expression in human tissues.
Figure 4: Kindreds 4102 and 4289.
Figure 5: ELAC2 allele definitions and genotype frequencies.

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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.

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Correspondence to Sean V. Tavtigian.

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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

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