title: IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer.
abstract: Patients diagnosed with HNPCC harbouring a confirmed germline mutation in DNA mismatch repair (MMR) genes have an 80% lifetime risk of developing an epithelial malignancy. There is, however, considerable variation in the age of disease onset in these patients. Insulin-like growth factor-I (IGFI) has been implicated in colorectal cancer (CRC), and elevated plasma IGFI levels are associated with both sporadic and hereditary CRC risk. In this study, we further investigate the cytosine-adenine (CA) dinucleotide repeat polymorphism located near the promoter region of IGF1 and its relation to early onset CRC risk in 443 Australian and Polish MMR gene mutation carriers using DNA sequencing, Kaplan-Meier survival curves and Cox proportional hazard regression analysis. A significantly smaller number of IGF1 CA repeats was observed in the Polish patient population, which was associated with an earlier age of disease onset compared to the Australian patients. The threshold for the observed modifying effect was again shown to be in patients with 17 or less CA repeats compared to those with 18 or more. Furthermore, when MMR mutation group (i.e., MLH1 or MSH2), gender and family clustering were included in the final Cox model we observed a more robust trend for the role of the IGF1 CA repeat in predicting age of disease onset in HNPCC patients. In addition, this effect was shown to be equal in both MLH1 and MSH2 mutation carrier groups and not restricted to a particular MMR subgroup (p = 0.001). We conclude that the IGF1 CA repeat is an important modifier of disease onset in HNPCC and the first polymorphism to yield consistent results across different populations.
authors.affiliation: Discipline of Medical Genetics, Faculty of Health, University of Newcastle, and Hunter Medical Research Institute, NSW, Australia.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Reeves
authors.forename: Dominique
authors.initials: D
authors.lastname: Rich
authors.forename: Cliff J
authors.initials: CJ
authors.lastname: Meldrum
authors.forename: Kim
authors.initials: K
authors.lastname: Colyvas
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kurzawski
authors.forename: Janina
authors.initials: J
authors.lastname: Suchy
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D017668:Age of Onset; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000401:mortality; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D012737:Sex Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D007334:Insulin-Like Growth Factor I; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein