TY - JOUR
T1 - Identification and characterization of novel SNPs in CHEK2 in Ashkenazi Jewish men with prostate cancer
AU - Tischkowitz, Marc D.
AU - Yilmaz, Ahmet
AU - Chen, Long Q.
AU - Karyadi, Danielle M.
AU - Novak, David
AU - Kirchhoff, Tomas
AU - Hamel, Nancy
AU - Tavtigian, Sean V.
AU - Kolb, Suzanne
AU - Bismar, Tarek A.
AU - Aloyz, Raquel
AU - Nelson, Peter S.
AU - Hood, Lee
AU - Narod, Steven A.
AU - White, Kirsten A.
AU - Ostrander, Elaine A.
AU - Isaacs, William B.
AU - Offit, Kenneth
AU - Cooney, Kathleen A.
AU - Stanford, Janet L.
AU - Foulkes, William D.
N1 - Funding Information:
We acknowledge support from the National Institutes of Health, on behalf of ICPCG, (grant recipient and grant number in parentheses) (W.B.I., U01CA89600; K.A.C., CA79596; and P.S.N., CA78836), the Koodish Fellowship and the Evan Frankel Foundation (T.K.), the National Human Genome Research Institute and National Institutes of Health (E.A.O.), the US National Cancer Institute (J.L.S., CA080122), the Prostate Cancer Foundation and the Fred Hutchinson Cancer Research Center (J.L.S.), the Department of Defense (D.M.K., W81XWH-04-1-0083), the Canadian Genetic Disease Network (W.D.F., DAMD17-00-1-0033), the Montreal Center for Experimental Therapeutics in Cancer (A.Y.), and the Intramural Program of the National Human Genome Research Institute. We are also grateful for the financial contribution of the Fonds de Recherche en Santé du Québec via their continuing support to the Research Institute of the McGill University Health Center. The authors gratefully acknowledge technical support from Drs. A. Al-Moustafa, S. Elledge, R. Rothstein, B. Bhullar, B. Andreson, and U. Stohaj in performing yeast functional assays.
PY - 2008/10/18
Y1 - 2008/10/18
N2 - 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.
AB - 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.
KW - Ashkenazi Jewish
KW - Budding yeast
KW - CHEK2
KW - Checkpoint kinase 2
KW - Prostate cancer
KW - Single-nucleotide polymorphism
UR - http://www.scopus.com/inward/record.url?scp=50949112322&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=50949112322&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2008.05.006
DO - 10.1016/j.canlet.2008.05.006
M3 - Article
C2 - 18571837
AN - SCOPUS:50949112322
SN - 0304-3835
VL - 270
SP - 173
EP - 180
JO - Cancer Letters
JF - Cancer Letters
IS - 1
ER -