Abstract
Objective: We examined a G-to-A single nucleotide polymorphism of the ATM gene, to determine if it influences hereditary non-polyposis colorectal cancer (HNPCC) age of onset. HNPCC is caused by mutations in mismatch repair genes, especially hMLH1 and hMSH2. ATM germline mutations have been associated with breast and digestive cancers. In a smaller European study, the G-to-A polymorphism was associated with an increased risk of developing an HNPCC-related cancer within HNPCC families.
Materials and methods: We genotyped 109 mismatch repair gene (MMR) mutation carriers from 53 HNPCC families for the ATM polymorphism using PCR and single strand conformational polymorphism (SSCP) analysis. We tested the association between the ATM genotypes and HNPCC age of onset by survival analysis.
Results: The ATM polymorphism did not significantly modify HNPCC age of onset, nor overall risk, in our population.
Conclusions: Although a modifier effect was not seen in our study, future studies that examine the polymorphism in combination with other genetic and environmental factors may elucidate an association. Revealing such associations in MMR mutation carriers may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- HNPCC:
-
hereditary nonpolyposis colorectal cancer
- MMR:
-
mismatch repair
- ATM :
-
ataxia-telangiectasia mutation
- PCR:
-
polymerase chain reaction
- SSCP:
-
single strand conformational polymorphism
- TBE:
-
Tris–borate-EDTA
References
HT Lynch TC Smyrk P Watson et al. (1993) ArticleTitleGenetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review Gastroenterology 104 IssueID5 1535–1549 Occurrence Handle8482467
P Peltomaki HF Vasen (1997) ArticleTitleMutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer Gastroenterology 113 IssueID4 1146–1158 Occurrence Handle9322509
HT Lynch A Chapelle Particlede la (1999) ArticleTitleGenetic susceptibility to non-polyposis colorectal cancer J Med Genet 36 IssueID11 801–818 Occurrence Handle10544223
P Watson HT Lynch (1993) ArticleTitleExtracolonic cancer in hereditary nonpolyposis colorectal cancer Cancer 71 IssueID3 677–685 Occurrence Handle8431847
KK Khanna MF Lavin SP Jackson TD Mulhern (2001) ArticleTitleATM, a central controller of cellular responses to DNA damage Cell Death Differ 8 IssueID11 1052–1065 Occurrence Handle10.1038/sj.cdd.4400874 Occurrence Handle11687884
Y Shiloh (1995) ArticleTitleAtaxia-telangiectasia: closer to unraveling the mystery Eur J Hum Genet 3 IssueID2 116–138 Occurrence Handle7552141
M Swift D Morrell RB Massey CL Chase (1991) ArticleTitleIncidence of cancer in 161 families affected by ataxia-telangiectasia N Engl J Med 325 IssueID26 1831–1836 Occurrence Handle1961222
JM Appleby JB Barber E Levine et al. (1997) ArticleTitleAbsence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapy Br J Cancer 76 IssueID12 1546–1549 Occurrence Handle9413938
P Maillet G Vaudan P Chappuis A Sappino (1999) ArticleTitlePCR-mediated detection of a polymorphism in the ATM gene Mol Cell Probes 13 IssueID1 67–69 Occurrence Handle10.1006/mcpr.1998.0219 Occurrence Handle10024435
N Sandoval M Platzer A Rosenthal et al. (1999) ArticleTitleCharacterization of ATM gene mutations in 66 ataxia-telangiectasia families Hum Mol Genet 8 IssueID1 69–79 Occurrence Handle10.1093/hmg/8.1.69 Occurrence Handle9887333
P Maillet PO Chappuis G Vaudan et al. (2000) ArticleTitleA polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer Int J Cancer 88 IssueID6 928–931 Occurrence Handle10.1002/1097-0215(20001215)88:6<928::AID-IJC14>3.0.CO;2-P Occurrence Handle11093816
S Kong CI Amos R Luthra PM Lynch B Levin ML Frazier (2000) ArticleTitleEffects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer Cancer Res 60 IssueID2 249–252 Occurrence Handle10667569
P Kraft DC Thomas (2000) ArticleTitleBias and efficiency in family-based gene-characterization studies: conditional, prospective, retrospective, and joint likelihoods Am J Hum Genet 66 IssueID3 1119–1131 Occurrence Handle10.1086/302808 Occurrence Handle10712222
Gritz ER, Peterson SK, Vernon SW, et al. (2005) Psychological Impact of Genetic Testing for Hereditary Non-polyposis Colon Cancer. J Clin Oncol (in press)
DY Lin LJ Wei (1989) ArticleTitleThe Robust Inference for the Cox Proportional Hazards Model J Am Stat Assoc 84 IssueID408 1074–1078
HF Vasen JT Wijnen FH Menko et al. (1996) ArticleTitleCancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis Gastroenterology 110 IssueID4 1020–1027 Occurrence Handle8612988
Author information
Authors and Affiliations
Corresponding author
Additional information
*This grant was supported by Grant CA70759 from the National Cancer Institute, by NIH Cancer Center Support Grant CA16672 and also, by a cancer prevention fellowship from the National Cancer Institute, Grant R25 CA57730.
Rights and permissions
About this article
Cite this article
Jones, J.S., Gu, X., Lynch, P.M. et al. ATM Polymorphism and hereditary nonpolyposis colorectal cancer (HNPCC) ageof onset (United States). Cancer Causes Control 16, 749–753 (2005). https://doi.org/10.1007/s10552-005-1540-7
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10552-005-1540-7