Identification and characterization of novel SNPs in CHEK2 in Ashkenazi Jewish men with prostate cancer Journal Article
| Authors: | Tischkowitz, M. D.; Yilmaz, A.; Chen, L. Q.; Karyadi, D. M.; Novak, D.; Kirchhoff, T.; Hamel, N.; Tavtigian, S. V.; Kolb, S.; Bismar, T. A.; Aloyz, R.; Nelson, P. S.; Hood, L.; Narod, S. A.; White, K. A.; Ostrander, E. A.; Isaacs, W. B.; Offit, K.; Cooney, K. A.; Stanford, J. L.; Foulkes, W. D. |
| Article Title: | Identification and characterization of novel SNPs in CHEK2 in Ashkenazi Jewish men with prostate cancer |
| Abstract: | Checkpoint kinase 2 (CHEK2) is a protein involved in arresting cell cycle in response to DNA damage. To investigate whether it plays an important role in the development of prostate cancer (PRCA) in the Ashkenazi Jewish (AJ) population, we sequenced CHEK2 in 75 AJ individuals with prostate, breast, or no cancer (n = 25 each). We identified seven coding SNPs (five are novel) that changed the amino-acid sequence, resulting in R3W, E394F, Y424H, S428F, D438Y, P509S, and P509L. We determined the frequency of each variant in 76 AJ families collected by members of the International Consortium for Prostate Cancer Genetics (ICPCG) where ≥2 men were affected by PRCA. Only one variant, Y424H in exon 11, was identified in more than two families. Exon 11 was then screened in nine additional AJ ICPCG families (a total of 85 families). The Y424H variant occurred in nine affected cases from four different families; however, it did not completely segregate with the disease. We performed bioinformatics analysis, which showed that Y424H is a non-conservative missense substitution that falls at a position that is invariant in vertebrate CHEK2 orthologs. Both SIFT and Align-GVGD predict that Y424H is a loss of function mutation. However, the frequency of Y424H was not significantly different between unselected AJ cases from Montreal/Memorial Sloan Kettering Cancer Centre (MSKCC) and AJ controls from Israel/MSKCC (OR 1.18, 95%CI: 0.34-4.61, p = .99). Moreover, functional assays using Saccharomyces cerevisiae revealed that the Y424H substitution did not alter function of CHEK2 protein. Although we cannot rule out a subtle influence of the CHEK2 variants on PRCA risk, these results suggest that germline CHEK2 mutations have a minor role in, if any, PRCA susceptibility in AJ men. © 2008 Elsevier Ireland Ltd. All rights reserved. |
| Keywords: | controlled study; gene sequence; major clinical study; sequence analysis; single nucleotide polymorphism; exon; missense mutation; mutation; polymorphism, single nucleotide; protein function; gene; cancer susceptibility; genetic predisposition to disease; breast cancer; amino acid substitution; serine; gene frequency; tyrosine; vertebrata; prostate cancer; confidence interval; prostatic neoplasms; amino acid sequence; saccharomyces cerevisiae; protein-serine-threonine kinases; amino acid; checkpoint kinase 2; saccharomycetales; bioinformatics; computer program; genetic screening; glutamic acid; jews; aspartic acid; arginine; histidine; jew; phenylalanine; tryptophan; proline; budding yeast; single-nucleotide polymorphism; orthology; ashkenazi jewish; methyl methanesulfonate; chek2; chek2 gene |
| Journal Title: | Cancer Letters |
| Volume: | 270 |
| Issue: | 1 |
| ISSN: | 0304-3835 |
| Publisher: | Elsevier Ireland Ltd. |
| Date Published: | 2008-10-18 |
| Start Page: | 173 |
| End Page: | 180 |
| Language: | English |
| DOI: | 10.1016/j.canlet.2008.05.006 |
| PUBMED: | 18571837 |
| PROVIDER: | scopus |
| PMCID: | PMC2969172 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 17 November 2011" - "CODEN: CALED" - "Source: Scopus" |
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