Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma

Marjun P. Duldulao, Wendy Lee, Rebecca A. Nelson, Wenyan Li, Zhenbin Chen, Joseph Kim, Julio Garcia-Aguilar

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

Background: Mutations in KRAS and TP53 are common in colorectal carcinogenesis and are associated with resistance to therapy. Rectal cancers carrying both mutations are less likely to respond to neoadjuvant chemoradiation therapy (CRT) compared with wild-type tumors. Codon-specific KRAS mutations are associated with variable resistance to targeted therapies, but their association with rectal cancer response to CRT remains unclear. Our objective was to establish a correlation between specific KRAS mutations and rectal cancer response to CRT and to investigate if the correlation was related to a different association between KRAS and TP53 mutations. Methods: A total of 148 stage II-III rectal cancer patients underwent preoperative CRT followed by surgery. DNA was extracted from pretreatment tumor biopsies and paired normal surgical tissues and KRAS and TP53 genotyping was performed. Specific KRAS mutations were then correlated with tumor response and with concurrent TP53 mutation. Results: A total of 60 patients had KRAS mutation, 12 in codon 13 and 48 in other locations. Also, 80 patients had TP53 mutation; 27 had concurrent KRAS/TP53 mutations. Tumors with any KRAS mutation were less likely to have a pCR compared with wild-type KRAS (p = 0.006). Specifically, no tumors with KRAS codon 13 mutations had a pCR (p = 0.03). Tumors with KRAS codon 13 mutations also had a higher incidence of concurrent TP53 mutation compared with tumors with other KRAS mutations (p = 0.02). Conclusions: Mutations in different KRAS codons may have different effects on rectal cancer resistance to CRT. This variable resistance may be related to a different frequency of TP53 mutations in KRAS mutant tumors.

Original languageEnglish
Pages (from-to)2166-2171
Number of pages6
JournalAnnals of Surgical Oncology
Volume20
Issue number7
DOIs
StatePublished - Jul 2013

Bibliographical note

Funding Information:
ACKNOWLEDGMENT The authors thank Nicola Solomon, PhD, for assistance in writing and editing the manuscript. This study was supported by the National Institutes of Health (NIH), National Cancer Institute (NCI) R01 Grant CA090559 (JGA). ClinicalTrials.org Identifier: NCT00335816.

ASJC Scopus subject areas

  • Surgery
  • Oncology

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