{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:17:49Z","timestamp":1788322669558,"version":"build-2803163510"},"reference-count":30,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2013,12,6]],"date-time":"2013-12-06T00:00:00Z","timestamp":1386288000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2014,6,15]]},"abstract":"<jats:p>Colonic and rectal cancers differ in their clinicopathologic features and treatment strategies. Molecular markers such as gene methylation, microsatellite instability and <jats:italic>KRAS<\/jats:italic> 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 <jats:italic>CDKN2A<\/jats:italic> gene methylation, CpG island methylator phenotype (CIMP), microsatellite instability and <jats:italic>KRAS<\/jats:italic>\/<jats:italic>BRAF<\/jats:italic> mutations in a cohort of 381 rectal cancers with extensive clinical follow\u2010up data. <jats:italic>BRAF<\/jats:italic> mutations (2%), CIMP\u2010high (4%) and microsatellite instability\u2010high (2%) were rare, whereas <jats:italic>KRAS<\/jats:italic> mutations (39%), <jats:italic>CDKN2A<\/jats:italic> methylation (20%) and CIMP\u2010low (25%) were more common. Only <jats:italic>CDKN2A<\/jats:italic> methylation and <jats:italic>KRAS<\/jats:italic> 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 <jats:italic>CDKN2A<\/jats:italic> methylation and <jats:italic>KRAS<\/jats:italic> mutations, which independently predicted recurrence of cancer and was associated with poor overall and cancer\u2010specific survival. This study has identified a subgroup of more aggressive rectal cancers that may arise through the KRAS\u2010p16 pathway. It has been previously shown that an interaction of p16 deficiency and oncogenic <jats:italic>KRAS<\/jats:italic> promotes carcinogenesis in the mouse and is characterized by loss of oncogene\u2010induced senescence. These findings may provide avenues for the discovery of new treatments in rectal cancer.<\/jats:p>","DOI":"10.1002\/ijc.28619","type":"journal-article","created":{"date-parts":[[2013,11,21]],"date-time":"2013-11-21T05:50:48Z","timestamp":1385013048000},"page":"2820-2828","source":"Crossref","is-referenced-by-count":45,"title":["<i>KRAS<\/i> mutations and <i>CDKN2A<\/i> promoter methylation show an interactive adverse effect on survival and predict recurrence of rectal cancer"],"prefix":"10.1002","volume":"134","author":[{"given":"Maija R. 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