TY - JOUR
T1 - Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome
AU - Chen, Jinyun
AU - Etzel, Carol J.
AU - Amos, Christopher I.
AU - Zhang, Qing
AU - Viscofsky, Nancy
AU - Lindor, Noralane M.
AU - Lynch, Patrick M.
AU - Frazier, Marsha L.
N1 - Funding Information:
Acknowledgments We thank Haidee Chancoco and Domitila Patenia for their laboratory technical assistance. Grant support: National Cancer Institute Grant CA 70759 (Frazier, ML), National Institutes of Health Cancer Center Support Grant CA 16672 (Mendelsohn, J), the Janis Davis Gordon Memorial Postdoctoral Fellowship, Division of Cancer Prevention, The University of Texas M. D. Anderson Cancer Center (Chen, J).
PY - 2009/11
Y1 - 2009/11
N2 - Purpose: Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model. Experimental design: We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell cycle genes. Results: We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats 19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats 19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset. Conclusions: Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.
AB - Purpose: Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model. Experimental design: We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell cycle genes. Results: We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats 19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats 19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset. Conclusions: Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.
KW - Age of onset
KW - Cell cycle pathway
KW - Lynch syndrome
KW - Polymorphisms
KW - Tree model
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U2 - 10.1007/s10552-009-9416-x
DO - 10.1007/s10552-009-9416-x
M3 - Article
C2 - 19690970
AN - SCOPUS:70350591968
SN - 0957-5243
VL - 20
SP - 1769
EP - 1777
JO - Cancer Causes and Control
JF - Cancer Causes and Control
IS - 9
ER -