title: DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset.
abstract: The incidence of colorectal cancer (CRC) increases with age and early onset indicates an increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in relation to patient age remains mostly unknown. We have examined the mutation status of five known cancer critical genes in relation to age at diagnosis, and compared the genomic complexity of tumors from young patients without known CRC syndromes with those from elderly patients. Among 181 CRC patients, stratified by microsatellite instability status, DNA sequence changes were identified in KRAS (32%), BRAF (16%), PIK3CA (4%), PTEN (14%) and TP53 (51%). In patients younger than 50 years (n = 45), PIK3CA mutations were not observed and TP53 mutations were more frequent than in the older age groups. The total gene mutation index was lowest in tumors from the youngest patients. In contrast, the genome complexity, assessed as copy number aberrations, was highest in tumors from the youngest patients. A comparable number of tumors from young (<50 years) and old patients (>70 years) was quadruple negative for the four predictive gene markers (KRAS-BRAF-PIK3CA-PTEN); however, 16% of young versus only 1% of the old patients had tumor mutations in PTEN/PIK3CA exclusively. This implies that mutation testing for prediction of EGFR treatment response may be restricted to KRAS and BRAF in elderly (>70 years) patients. Distinct genetic differences found in tumors from young and elderly patients, whom are comparable for known clinical and pathological variables, indicate that young patients have a different genetic risk profile for CRC development than older patients.
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Marianne
authors.initials: M
authors.lastname: Berg
authors.forename: Stine A
authors.initials: SA
authors.lastname: Danielsen
authors.forename: Terje
authors.initials: T
authors.lastname: Ahlquist
authors.forename: Marianne A
authors.initials: MA
authors.lastname: Merok
authors.forename: Trude H
authors.initials: TH
authors.lastname: Ågesen
authors.forename: Morten H
authors.initials: MH
authors.lastname: Vatn
authors.forename: Tom
authors.initials: T
authors.lastname: Mala
authors.forename: Ole H
authors.initials: OH
authors.lastname: Sjo
authors.forename: Arne
authors.initials: A
authors.lastname: Bakka
authors.forename: Ingvild
authors.initials: I
authors.lastname: Moberg
authors.forename: Torunn
authors.initials: T
authors.lastname: Fetveit
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Mathisen
authors.forename: Anders
authors.initials: A
authors.lastname: Husby
authors.forename: Oddvar
authors.initials: O
authors.lastname: Sandvik
authors.forename: Arild
authors.initials: A
authors.lastname: Nesbakken
authors.forename: Espen
authors.initials: E
authors.lastname: Thiis-Evensen
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins