Meat consumption and K-ras mutations in sporadic colon and rectal cancer in The Netherlands Cohort Study

Brink, Mirian; Weijenberg, Matty P.; Goeij, Anton F.P.M. de; Roemen, Guido M.J.M.; Lentjes, Marjolein H.F.M.; Bruïne, Adriaan P. de; Goldbohm, R. Alexandra; Brandt, Piet A. van den

doi:10.1038/sj.bjc.6602491

Cited by 54 publications

(73 citation statements)

References 32 publications

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“…Our key associations (mucinous differentiation, presence of a contiguous polyp, different MSI status and MGMT methylation) were robust to this correction for multiple hypothesis testing. Although some environmental and lifestyle risk factors, such as physical activity, body mass index, tobacco smoke and meat consumption, have been reported to be associated with KRAS-mutated colorectal carcinoma, 31,[46][47][48][49] potential new associations are unlikely to be identified if, as was the case for BRAF-mutated carcinomas until relatively recently, KRAS-mutated carcinomas continue to be included with the bulk of common colorectal carcinoma. Subsequent studies from different population are required to validate our findings.…”

Section: Discussionmentioning

confidence: 99%

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

et al. 2013

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KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O 6 -methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wildtype carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; Po0.001), demonstrated mucinous differentiation (46 vs 31%; P ¼ 0.001) and were associated with different MSI status (Po0.001) and with MGMT methylation (47 vs 21%; P ¼ 0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P ¼ 0.001), mucinous differentiation (46 vs 25%; Po0.001), presence of a contiguous polyp (38 vs 22%; Po0.001), MGMT methylation (47 vs 26%; P ¼ 0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P ¼ 0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P ¼ 0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.

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Section: Discussionmentioning

confidence: 99%

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

et al. 2013

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“…In the present study, we examined the mutational status of the K-ras and Apc genes in AOM-induced tumors. With the exception of one tumor, which showed a GGT-GAT transition mutation in codon 12, none of the samples, including the AJ02-NM 0 cells, revealed mutations within exon 1 of the K-ras oncogene (Vogelstein et al, 1988;Kislitsin et al, 2002;Brink et al, 2003;Corpet and Pierre, 2003). Furthermore, no sequence alterations were identified within the mutational cluster region (MCR) of the Apc gene (Fearnhead et al, 2001).…”

Section: A/j Colon Tumors Display Low-level Msimentioning

confidence: 99%

Carcinogen-induced colon tumors in mice are chromosomally stable and are characterized by low-level microsatellite instability

et al. 2004

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The azoxymethane (AOM)-induced mouse colon tumor model recapitulates many of the histopathological features associated with the multistage progression of human sporadic colorectal cancers (CRCs). To better define the genetic events associated with tumorigenesis in this murine model, we analysed tumors from A/J mice for chromosomal (CIN) and microsatellite (MSI) instabilities, two fundamental pathways of genomic instability that play a critical role in the pathogenesis of human CRCs. Male A/ J mice, 6-week old, were injected with either AOM (n ¼ 5) (10 mg/kg b.w., i.p.) or vehicle (n ¼ 5) (0.9% NaCl solution) once a week for 6 weeks. At 32 weeks after the last dose, comparative genomic hybridization (CGH) was performed on 16 tumors harvested from five animals. Although 25% of the tumors displayed either a gain of chromosome 2 or loss of Y, the majority (75%) showed no genomic imbalances. Further analysis of chromosomal aberrations, using CGH and spectral karyotyping (SKY) was performed in our recently established A/J colon tumor-derived cell line, AJ02-NM 0 . Results showed a pseudotetraploid karyotype with loss of only the Y chromosome in these cultured cells, thereby providing additional evidence for the minimal role of CIN in the primary AOM-induced tumors. Interestingly, the majority (81%) of A/J tumors displayed low-level microsatellite instability (MSI-L) when analysed using mono-and dinucleotide repeat markers, and showed a significant expansion to high-level instability (MSI-H) in the AJ02-NM 0 cells. This finding in cultured cells additionally provides evidence that a mild mutator pathway may contribute to the development of behaviorally benign carcinomas in situ in A/J mice. To better understand the tumorigenic process in the A/J colons, we screened for mutational alterations in key regions of the K-ras and Apc genes. Results showed a very low frequency (6%) of K-ras activating mutations, together with the absence of Apc truncation mutations in primary tumors and AJ02-NM 0 cells. However, these tumors displayed intense nuclear accumulation of b-catenin protein, indicating activation of the Wnt signaling pathway. Based on our molecular and cytogenetic findings, we propose that carcinogen-induced tumors may develop via mechanisms independent of the 'classical' CIN or MSI pathways.

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“…KRAS mutation analysis was carried out by polymerase chain reaction (PCR) amplification of exon 2 and direct sequencing. Primers were modified according to Brink et al (2003). DNA sequencing was carried out using the BigDye Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA, USA) and separation of the products using an automated sequencing system (3130 Genetic Analyzer, Applied Biosystems).…”

Section: Kras Mutational Analysismentioning

confidence: 99%

Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

et al. 2010

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BACKGROUND: Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer. METHODS: Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m À2 at first infusion followed by weekly infusions of 250 mg m À2 combined with FUFOX (oxaliplatin 50 mg m À2 , 5-FU 2000 mg m À2 , and DL-folinic acid 200 mg m À2 d1, 8, 15 and 22 qd36). The primary endpoint was tumour response. RESULTS: Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50 -79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0 -10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9 -11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed. CONCLUSION: Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum -fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.

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Meat consumption and K-ras mutations in sporadic colon and rectal cancer in The Netherlands Cohort Study

Cited by 54 publications

References 32 publications

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

Carcinogen-induced colon tumors in mice are chromosomally stable and are characterized by low-level microsatellite instability

Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

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