Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status

Oliveira, Carla; Westra, Jantine L.; Arango, Diego; Ollikainen, Miina; Domingo, Enric; Ferreira, Ana M.; Velho, Sérgia; Niessen, Renée C.; Lagerstedt, Kristina; Alhopuro, Pia; Laiho, Päivi; Veiga, Isabel; Teixeira, Manuel R.; Ligtenberg, Marjolijn J. L.; Kleibeuker, Jan H.; Sijmons, Rolf H.; Plukker, John Theodorus; Imai, Kohzoh; Lage, Pedro; Hamelin, Richard; Albuquerque, Cristina; Schwartz, Simó; Lindblom, Annika; Peltomäki, Païvi; Yamamoto, Hiroyuki; Aaltonen, Lauri A.; Seruca, Raquel; Hofstra, Robert

doi:10.1093/hmg/ddh238

Cited by 128 publications

(110 citation statements)

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“…Among HNPCCs, while accumulation of RASSF1A methylation and KRAS mutations occurs in 18% (2/11) of HNPCC tumours carrying germline hMSH2 mutations, this accumulation was never (0/9) observed in tumours from patients with hMLH1 germline mutations (Table 1, Figure 2). This result may reflect previous observations showing that tumours from hMLH1 mutation carriers have lower frequency of KRAS mutations in comparison with tumours from hMSH2 mutation carriers (Oliveira et al, 2004). Further, the profile of alterations in the KRAS-BRAF-RASSF1A pathway was distinct in HNPCC carcinomas and MSI SGC (Table 1, Figure 2).…”

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confidence: 86%

“…All tumours were analysed for microsatellite instability according to the international criteria for the determination of microsatellite instability, using various panels of dinucleotide and mononucleotide repeat sequences (Umar et al, 2004). Mutational analysis of BRAF exon 15 and KRAS codons 12 and 13 was performed by PCR/SSCP/Sequencing as described previously (Oliveira et al, , 2004. Associations between the RASSF1A promoter methylation and mutations in KRAS and/or BRAF in the three subsets of MSI carcinomas were assessed by the w 2 test.…”

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confidence: 99%

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Concomitant RASSF1A hypermethylation and KRAS/BRAF mutations occur preferentially in MSI sporadic colorectal cancer

et al. 2005

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Methylation-associated inactivation of RASSF1A has frequently been observed in several human malignancies including sporadic colorectal and gastric cancer. However, nothing is known about the RASSF1A methylation status in the setting of MMR-deficient gastrointestinal tumours. In this study, we analysed systematically alterations in KRAS, BRAF and RASSF1A, in order to define the frequency and the pattern of these genetic/epigenetic alterations in three distinct subsets of MSI gastrointestinal tumours. Further, an association study was performed between RASSF1A methylation and the clinicopathological parameters in order to determine the profile of tumours harbouring this epigenetic event. A total of 56 MSI sporadic gastrointestinal tumours (31 colorectal and 25 gastric) and 20 MSI HNPCC analysed for KRAS/BRAF were analysed for RASSF1A promoter hypermethylation by MSP and DNA sequencing. No significant differences were found between the frequency of RASSF1A methylation in sporadic MSI colorectal and gastric carcinomas and HNPCC carcinomas (P ¼ 0.31). Methylation of RASSF1A was present in 16 of 31 (52%) sporadic MSI colorectal and 11 of 25 (44%) MSI gastric carcinomas, and in six of 20 (30%) HNPCC carcinomas. Nearly 36% of MSI sporadic colorectal carcinomas (CRCs) had RASSF1A methylation and activating mutations at KRAS and/or BRAF. In contrast, only 10 and 8% of HNPCC and sporadic gastric carcinomas, respectively, had concomitant KRAS mutations and RASSF1A methylation. The MSI sporadic gastric and CRCs with RASSF1A methylation were preferentially poorly differentiated (P ¼ 0.03, 0.05, respectively). We show that the profile of alterations RASSF1A, KRAS/BRAF is different among the three groups of MSI gastrointestinal tumours. Further, we demonstrate that MSI sporadic CRCs accumulated significantly more epigenetic/genetic alterations in RASSF1A, KRAS/BRAF than MSI sporadic gastric or HNPCC carcinomas (P ¼ 0.016). These results are likely to have therapeutic implications in the near future, due to the possibilities of using specific kinase inhibitors alone or in association with demethylating agents in MSI tumour types harbouring KRAS or BRAF mutations and RASSF1A methylation. The methylation-associated inactivation of RASSF1A gene, a novel Ras-binding protein identified at 3p21.3, has been observed in several human cancer types and strongly supports its role as a tumour suppressor gene .RASSF1 gene generates several isoforms due to alternative splicing and differential promoter usage. RASSF1A, the longest isoform of RASSF1, apart from reducing tumorigenesis in vivo and in vitro (Dammann et al., 2000;Lerman and Minna, 2000) is able to inhibit cell cycle progression by inhibiting cyclin D1 accumulation (Shivakumar et al., 2002). Moreover, RASSF1A one of the two major isoforms of RASSF1 contain a Ras-binding domain that can associate to active Ras in vitro (Vos et al., 2000), similar to the domain found within Raf-1 allowing the activation of Raf-1 by Ras (Williams et al., 2000).RASSF1A inactivation, through promoter hy...

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confidence: 86%

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confidence: 99%

Concomitant RASSF1A hypermethylation and KRAS/BRAF mutations occur preferentially in MSI sporadic colorectal cancer

et al. 2005

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“…Mutations in other positions, such as codons 61 and 146, have also been reported [51]. However, these alterations account for a minor proportion (1-4%) of KRAS mutations and their clinical relevance in colorectal cancer is unclear [51,53]. KRAS mutations in codons 12 and 13 appear to play a major role in the progression of colorectal cancer [54][55][56], while mutations in codons 12, 13, and 61 are potential biomarkers in lung cancer [57].…”

Section: Kras: a Downstream Target Of Egfr Signalingmentioning

confidence: 99%

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

et al. 2008

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Novel therapeutic agents targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with colorectal carcinoma. However, these therapies are effective only in a subset of patients. Activating mutations in the KRAS gene are found in 30-40% of colorectal tumors and are associated with poor response to anti-EGFR therapies. Thus, KRAS mutation status can predict which patient may or may not benefit from anti-EGFR therapy. Although many diagnostic tools have been developed for KRAS mutation analysis, validated methods and standardized testing procedures are lacking. This poses a challenge for the optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Here we review the molecular basis of EGFR-targeted therapies and the resistance to treatment conferred by KRAS mutations. We also present guideline recommendations and a proposal for a European quality assurance program to help ensure accuracy and proficiency in KRAS mutation testing across the European Union.

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“…Mutations in the proto-oncogene K-Ras are present in 50% of colorectal cancers, 10,11 occurring with similar frequency in both familial and sporadic colorectal cancers. 12 The proto-oncogene B-Raf, a serine/threonine kinase activated by Ras-GTP, is mutated in 10-15% of sporadic colorectal cancers. 1,13,14 The most common B-Raf mutation, accounting for 90% of all B-Raf mutations in human cancers, occurs at codon 600, resulting in an amino acid change from the neutral valine (V) to the negatively charged amino acid glutamic acid (E) and in the constitutive activation of B-Raf.…”

Section: Uiccmentioning

confidence: 99%

Selective inhibition of proliferation in colorectal carcinoma cell lines expressing mutant APC or activated B‐Raf

Zhang

Walker

Kiflemariam

et al. 2009

Intl Journal of Cancer

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Tumor-derived cell lines are indispensable tools for understanding the contribution of activated signaling pathways to the cancer phenotype and for the design and testing of targeted signal therapies. In our study, we characterize 10 colorectal carcinoma cell lines for the presence of mutations in the wnt, Ras/MAPK, PI3K and p53 pathways. The mutational spectrum found in this panel of cell lines is similar to that detected in primary CRC, albeit with higher frequency of mutation in the b-catenin and B-Raf genes. We have monitored activation of the wnt and Ras/MAPK pathways in these cells and analyzed their sensitivity to selective signaling inhibitors. Using b-catenin subcellular distribution as a marker, we show that cells harboring APC mutations have low-level activated wnt signaling, which can be blocked by the extracellular wnt inhibitor DKK-1, suggesting autocrine activation of this pathway; proliferation of these cells is also blocked by DKK-1. In contrast, cells with b-catenin mutations are unresponsive to extracellular wnt inhibition. Constitutive phosphorylation of MAPK is present in the majority of the cell lines and correlates with B-Raf but not K-Ras mutations; correspondingly, the proliferation of cells harboring mutations in B-Raf, but not K-Ras, is exquisitely sensitive inhibition of the MAPK pathway. We find no correlation between PI3K mutation or loss of PTEN expression and increased sensitivity to PI3K inhibitors. Our study discloses clear-cut differences in responsiveness to signaling inhibitors between individual mutations within an activated signaling pathway and suggests likely targets for signal-directed therapy of colorectal carcinomas. ' UICCKey words: colorectal cancer; cell lines; mutations; wnt signaling; signal therapiesThe progression of colorectal cancer from adenomas to carcinomas is characterized by a series of genetic changes, which lead to the activation of oncogenes and to the inactivation of tumor suppressor genes, perturbing the self-renewal, proliferative, adhesive and survival characteristics of the cells. 1,2 Colorectal cancers are characterized by mutations in 4 major pathways: wnt, Ras/MAPK, p53 and DNA repair.The APC gene is a key regulator of the wnt pathway. APC mutations are detected early in the adenoma-carcinoma progression, 3 are the hallmark of Familial Adenomatous Polyposis (FAP) and also occur with high frequency (up to 80%) in sporadic CRC. Mutations of the APC gene cluster in the central region of the protein and result in truncations, which delete most of the b-catenin binding sites, the axin-binding domain and the microtubule-binding regions. These deletions have been associated with activation of the canonical wnt signaling pathway and cytosolic/nuclear accumulation of b-catenin 4 but may also play an important, b-catenin independent, role in the loss of cell polarity observed in many colorectal carcinomas. 5 Underlying the relevance of the wnt pathway in the aetiogenesis of CRC, mutations of other components in the canonical wnt pathway also occur with...

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Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status

Cited by 128 publications

References 50 publications

Concomitant RASSF1A hypermethylation and KRAS/BRAF mutations occur preferentially in MSI sporadic colorectal cancer

Concomitant RASSF1A hypermethylation and KRAS/BRAF mutations occur preferentially in MSI sporadic colorectal cancer

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

Selective inhibition of proliferation in colorectal carcinoma cell lines expressing mutant APC or activated B‐Raf

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