TY - JOUR
T1 - Aurora-A/STK15 T+91A a general low penetrance cancer susceptibility gene
T2 - A meta-analysis of multiple cancer types
AU - Ewart-Toland, Amanda
AU - Dai, Qi
AU - Gao, Yu Tang
AU - Nagase, Hiroki
AU - Dunlop, Malcolm G.
AU - Farrington, Susan M.
AU - Barnetson, Rebecca A.
AU - Anton-Culver, Hoda
AU - Peel, David
AU - Ziogas, Argyrios
AU - Lin, Dongxin
AU - Miao, Xiaoping
AU - Sun, Tong
AU - Ostrander, Elaine A.
AU - Stanford, Janet L.
AU - Langlois, Mariela
AU - Chan, June M.
AU - Yuan, Jinwei
AU - Harris, Curtis C.
AU - Bowman, Elise D.
AU - Clayman, Gary L.
AU - Lippman, Scott M.
AU - Lee, J. Jack
AU - Zheng, Wei
AU - Balmain, Allan
N1 - Funding Information:
We thank Drs Bruce Ponder, Paul Pharoah and Doug Easton for thoughtful discussions and sharing of data. The following funding bodies supported this work: the UCSF School of Medicine Research Evaluation and Allocation Committee fund, the Stewart Trust, the UCSF Prostate Spore Grant CA 89520-01, the UCSF Prostate Cancer Center Award, the National Cancer Institute (NCI) P01-5P01CA68233, the Cancer Center Support Grant 5P30 CA16672, the NCI Mouse Models of Human Cancer Consortium Supplement CA84244-03 S1, the National Institutes of Health (NIH) 1 P50 CA89520, the Medical Research Council G0000657-53203, the Cancer Research UK C348/A3758, the Chief Scientist’s Office K/OPR/2/2/D33, the NCI Grant CA56678, the NCI grant CA82664 and the NCI contract N01-CN-05230. A.B. acknowledges the support of the Barbara Bass Bakar endowed chair in this work.
PY - 2005/8
Y1 - 2005/8
N2 - STK15 (Aurora-A) is a serine/threonine kinase involved in mitotic chromosomal segregation. A genetic variant in STK15 T+91A (resulting in the amino acid substitution F31I) is associated with increased aneuploidy in colon tumors and cell transformation in vitro. Since this polymorphism plays a role in mitotic control - a process critical for all cancer types - we conducted association analyses for risk of cancer development of the colon, breast, prostate, skin, lung and esophagus in 10 independent case-control populations. We carried out a meta-analysis of these 10 case-control studies together with 5 additional published studies for a total of 9549 cases of breast, colon, ovarian, prostate, lung, esophageal and non-melanoma skin cancer and 8326 population or hospital-based controls. Meta-analysis of three colorectal cancer studies showed an increased risk in T+91A homozygotes (OR = 1.50; 95% CI of 1.14-1.99). Meta-analysis of four breast cancer studies showed increased risk for T+91A homozygotes (OR = 1.35, 95% CI of 1.12-1.64). The results of the multiple cancer type meta-analysis for all 15 studies combined were significant for cancer risk in both homozygotes and heterozygotes. The T+91A heterozygotes show an OR of 1.10 (95% CI of 1.03-1.18, P-value = 0.006) and the T+91A homozygotes show an OR of 1.40 (95% CI of 1.22-1.59, P-value <0.001) for cancer risk. These results confirm that the STK15 T+91A variant is a low penetrance cancer susceptibility allele affecting multiple cancer types, and provide genetic evidence from large-scale human population studies that genetic stability at the chromosome level is an important determinant of cancer susceptibility. The data also underline the advantages of comparative association studies involving study populations from different ethnic groups for determination of disease risk.
AB - STK15 (Aurora-A) is a serine/threonine kinase involved in mitotic chromosomal segregation. A genetic variant in STK15 T+91A (resulting in the amino acid substitution F31I) is associated with increased aneuploidy in colon tumors and cell transformation in vitro. Since this polymorphism plays a role in mitotic control - a process critical for all cancer types - we conducted association analyses for risk of cancer development of the colon, breast, prostate, skin, lung and esophagus in 10 independent case-control populations. We carried out a meta-analysis of these 10 case-control studies together with 5 additional published studies for a total of 9549 cases of breast, colon, ovarian, prostate, lung, esophageal and non-melanoma skin cancer and 8326 population or hospital-based controls. Meta-analysis of three colorectal cancer studies showed an increased risk in T+91A homozygotes (OR = 1.50; 95% CI of 1.14-1.99). Meta-analysis of four breast cancer studies showed increased risk for T+91A homozygotes (OR = 1.35, 95% CI of 1.12-1.64). The results of the multiple cancer type meta-analysis for all 15 studies combined were significant for cancer risk in both homozygotes and heterozygotes. The T+91A heterozygotes show an OR of 1.10 (95% CI of 1.03-1.18, P-value = 0.006) and the T+91A homozygotes show an OR of 1.40 (95% CI of 1.22-1.59, P-value <0.001) for cancer risk. These results confirm that the STK15 T+91A variant is a low penetrance cancer susceptibility allele affecting multiple cancer types, and provide genetic evidence from large-scale human population studies that genetic stability at the chromosome level is an important determinant of cancer susceptibility. The data also underline the advantages of comparative association studies involving study populations from different ethnic groups for determination of disease risk.
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U2 - 10.1093/carcin/bgi085
DO - 10.1093/carcin/bgi085
M3 - Article
C2 - 15802297
AN - SCOPUS:24944573674
SN - 0143-3334
VL - 26
SP - 1368
EP - 1373
JO - Carcinogenesis
JF - Carcinogenesis
IS - 8
ER -