title: Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 >or=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 >or=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.
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Unit 1365, 1155 Pressler Boulevard, Houston, TX 77030, USA. janechen@mdanderson.org
authors.forename: Jinyun
authors.initials: J
authors.lastname: Chen
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Etzel
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Nancy
authors.initials: N
authors.lastname: Viscofsky
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lynch
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Frazier
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002453:Cell Cycle / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D055815:Young Adult
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