title: After hMSH2 and hMLH1--what next? Analysis of three-generational, population-based, early-onset colorectal cancer families.
abstract: The aim of our study was to examine the role of genetic factors on early-onset colorectal cancer after excluding the impact of germline mutations in the two major mismatch repair genes. A total of 131 incident probands, under 45 years at diagnosis of a first primary colorectal cancer selected from the Victorian Cancer Registry, and their first-and second-degree relatives, were interviewed. Germline DNA from all 12 probands with a family history meeting the modified Amsterdam Criteria for Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and a random sample of 31 of the remaining probands was screened for mutations in hMSH2 and hMLH1 via manual sequencing. Germline mutations were identified in 6 of the 131 probands (5%), all from the "HNPCC" families. Of the remaining 125 probands, 51 (41%) reported at least one first-or second-degree relative with colorectal cancer with an excess of colorectal cancer in first-degree relatives (SMR = 2.7, 95% CI = 1.7-4.1, p < 0.001). The lifetime risk to age 70 for first-degree relatives was 8.0% (5.0-12.8%), compared to the Victorian population risk of 3.2% (p = 0.01). The best fitting major gene model was a recessively-inherited risk of 98% to age 70 (95% CI = 24-100%) carried by 0.17% of the population and would explain 15% of all colorectal cancer in cases with a diagnosis before age 45. Early-onset colorectal cancer is strongly familial even after excluding families found to be segregating a mutation in either of the 2 major mismatch repair genes. There is evidence for a role of yet to be identified genes associated with a high recessively-inherited risk of colorectal cancer.
authors.affiliation: Centre for Genetic Epidemiology, The University of Melbourne, 723 Swanston Street, Carlton Victoria 3053, Australia. m.jenkins@unimelb.edu.au
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Laura
authors.initials: L
authors.lastname: Baglietto
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Dite
authors.forename: Damien J
authors.initials: DJ
authors.lastname: Jolley
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Jonathan
authors.initials: J
authors.lastname: Whitty
authors.forename: Leeanne J
authors.initials: LJ
authors.lastname: Mead
authors.forename: D James B
authors.initials: DJ
authors.lastname: St  John
authors.forename: Finlay A
authors.initials: FA
authors.lastname: Macrae
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: Deon J
authors.initials: DJ
authors.lastname: Venter
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000367:Age Factors; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D018095:Germ-Line Mutation; D006801:Humans; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012306:Risk
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein