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KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy.

ABSTRACT: BACKGROUND AND PURPOSE:KRAS and BRAF are mutated in 35% and 10% of colorectal cancers, respectively. However, data specifically for locally advanced rectal cancers are scarce, and the frequency of KRAS mutations in codons 61 and 146 remains to be established. MATERIALS AND METHODS:DNA was isolated from pre-therapeutic biopsies of 94 patients who were treated within two phase-III clinical trials receiving preoperative chemoradiotherapy. Mutation status of KRAS exons 1-3 and BRAF exon 15 was established using the ABI PRISM Big Dye Sequencing Kit and subsequently correlated with clinical parameters. RESULTS:Overall, KRAS was mutated in 45 patients (48%). Twenty-nine mutations (64%) were located in codon 12, 10 mutations (22%) in codon 13, and 3 mutations (7%) in codons 61 and 146. No V600E BRAF mutation was detected. The presence of KRAS mutations was correlated neither with tumor response or lymph node status after preoperative chemoradiotherapy nor with overall survival or disease-free survival. When KRAS exon 1 mutations were separated based on the amino-acid exchange, we again failed to detect significant correlations (p=0.052). However, G12V mutations appeared to be associated with higher rates of tumor regression than G13D mutations (p=0.012). CONCLUSION:We are the first to report the mutation status of KRAS and BRAF in pre-therapeutic biopsies from locally advanced rectal cancers. The high number of KRAS mutations in codons 61 and 146 emphasizes the importance to expand current mutation analyses, whereas BRAF mutations are not relevant for rectal carcinogenesis. Although the KRAS mutation status was not correlated with response, the subtle difference between G12V and G13D mutations warrants analysis of a larger patient population.

SUBMITTER: Gaedcke J

PROVIDER: S-EPMC7373270 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy.

Gaedcke Jochen J Grade Marian M Jung Klaus K Schirmer Markus M Jo Peter P Obermeyer Christoph C Wolff Hendrik A HA Herrmann Markus K MK Beissbarth Tim T Becker Heinz H Ried Thomas T Ghadimi Michael M

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 20091111 1

<h4>Background and purpose</h4>KRAS and BRAF are mutated in 35% and 10% of colorectal cancers, respectively. However, data specifically for locally advanced rectal cancers are scarce, and the frequency of KRAS mutations in codons 61 and 146 remains to be established.<h4>Materials and methods</h4>DNA was isolated from pre-therapeutic biopsies of 94 patients who were treated within two phase-III clinical trials receiving preoperative chemoradiotherapy. Mutation status of KRAS exons 1-3 and BRAF ex ...[more]

PMID: 19913317

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Project description:The incorporation of chemoradiation prior to resection of the tumour has revolutionized the management of locally advanced rectal cancer. However, a large proportion of these patients are resistant to preoperative treatment schedule. We recently reported that c-Myc gene expression correlates negatively with this resistance in patients with rectal cancer. In this study, we carried out integrated analysis of miRNA and mRNA expression profiling in 45 pre-treatment rectal tumour. Further, expression of miRNAs and c-Myc, and their relationship with clinicopathological factors and patient survival was analysed. As a result, we found that 12 miRNAs were differentially expressed between responder and non-responder rectal cancer patients. Functional classification revealed an association between differentially expressed miRNAs and c-Myc. Subsequent quantitative real-time PCR results showed that both, miRNA-148 and miRNA-375 levels were significantly lower in responder compared to non-responder patients. Notably, the higher level of miRNA-375 was significantly negatively correlated with c-Myc. These results suggest that miRNA-375 and its targeted c-Myc play an important role as predictive biomarker of response to neoadjuvant treatment in patients with locally advanced rectal cancer, but still not suitable for prognosis. Pre-treatment biopsies of 22 patients with LARC were prospectively collected and freshly frozen according to an institutional board-approved protocol. Tumour response was assessed in surgical specimens by pathological examination based on the semi-quantitative tumour regression grading (TRG) system described by Mandard in 1994[36]: TRG1 and TRG2 scores were considered responders, whereas TRG3, TRG4, and TRG5 were classified as non-responders. The inclusion criteria were: histologically proven rectal tumour at a clinical stage UICC II-III (cT3-4/and or N positive), following endorectal ultrasound and/or MRI scan. Patients were excluded if they had the tumour located above 13 cm from the anal verge by rigid rectoscopy, synchronic colonic cancer assessed by colonoscopy, distant metastases by 18FDG PET-CT scan, and suspicion of hereditary colorectal cancer. All patients subsequently received a total dose of 50.4Gy of radiation (28 fractions of 1.8Gy) associated with capecitabine (oral form of 5-FU) with or without oxaliplatine, according to our Hospital Clinical Practice Guidelines. Standardized Surgery was performed, including total mesorectal excision, following an interval of 8-10 weeks after completion of CT/RT.

Dataset Information

KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy.

Publications

KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy.

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