title: KRAS mutations and CDKN2A promoter methylation show an interactive adverse effect on survival and predict recurrence of rectal cancer.
abstract: Colonic and rectal cancers differ in their clinicopathologic features and treatment strategies. Molecular markers such as gene methylation, microsatellite instability and KRAS mutations, are becoming increasingly important in guiding treatment decisions in colorectal cancer. However, their association with clinicopathologic variables and utility in the management of rectal cancer is still poorly understood. We analyzed CDKN2A gene methylation, CpG island methylator phenotype (CIMP), microsatellite instability and KRAS/BRAF mutations in a cohort of 381 rectal cancers with extensive clinical follow-up data. BRAF mutations (2%), CIMP-high (4%) and microsatellite instability-high (2%) were rare, whereas KRAS mutations (39%), CDKN2A methylation (20%) and CIMP-low (25%) were more common. Only CDKN2A methylation and KRAS mutations showed an association with poor overall survival but these did not remain significant when analyzed with other clinicopathologic factors. In contrast, this prognostic effect was strengthened by the joint presence of CDKN2A methylation and KRAS mutations, which independently predicted recurrence of cancer and was associated with poor overall and cancer-specific survival. This study has identified a subgroup of more aggressive rectal cancers that may arise through the KRAS-p16 pathway. It has been previously shown that an interaction of p16 deficiency and oncogenic KRAS promotes carcinogenesis in the mouse and is characterized by loss of oncogene-induced senescence. These findings may provide avenues for the discovery of new treatments in rectal cancer.
authors.affiliation: Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; St Vincent's Clinical School UNSW Medicine, University of NSW, Sydney, NSW, Australia; School of Medicine, University of Western Sydney, Liverpool, NSW, Australia.
authors.forename: Maija R J
authors.initials: MR
authors.lastname: Kohonen-Corish
authors.forename: Jason
authors.initials: J
authors.lastname: Tseung
authors.forename: Charles
authors.initials: C
authors.lastname: Chan
authors.forename: Nicola
authors.initials: N
authors.lastname: Currey
authors.forename: Owen F
authors.initials: OF
authors.lastname: Dent
authors.forename: Stephen
authors.initials: S
authors.lastname: Clarke
authors.forename: Les
authors.initials: L
authors.lastname: Bokey
authors.forename: Pierre H
authors.initials: PH
authors.lastname: Chapuis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012004:Rectal Neoplasms / Q000235:genetics* / Q000401:mortality; D018631:ras Proteins / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: CDKN2A methylation; KRAS mutations; cancer biomarkers; rectal cancer prognosis