BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?

Velho, Sérgia; Moutinho, Cátia; Cirnes, Luı́s; Albuquerque, Cristina; Hamelin, Richard; Schmitt, Fernando; Carneiro, Fátima; Oliveira, Carla; Seruca, Raquel

doi:10.1186/1471-2407-8-255

Cited by 131 publications

(97 citation statements)

References 24 publications

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“…Similar results have been observed in numerous studies. 7,[9][10][11] However, there seems to be no appreciable difference between the frequency of BRAF mutation seen in proximal hyperplastic polyps and distal hyperplastic polyps. The high level of BRAF mutations in both proximal and distal hyperplastic polyps suggests that although this may be an early event in the development of sporadic unstable cancers, it is not a useful marker for identifying clinically relevant serrated pathway precursors.…”

Section: Discussionmentioning

confidence: 94%

“…2,[7][8][9][10][11] Like microsatellite unstable cancers, these polyps have been shown to exhibit CIMP [7][8][9][10][11] and BRAF mutations; [7][8][9][10][11] however, they do not show high level microsatellite instability. [7][8][9][10] Hyperplastic polyps have also been reported to have MLH1 promoter methylation. [7][8][9] This finding, however, is somewhat puzzling given that these lesions do not show loss of MLH1 protein expression by immunohistochemistry.…”

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confidence: 99%

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Quantitative evaluation of CpG island methylation in hyperplastic polyps

2010

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Microsatellite unstable cancers account for up to 15% of sporadic colon cancers and are predominantly located in the proximal colon. These cancers commonly show MLH1 promoter methylation and the CpG island methylator phenotype (CIMP). A potential precursor of sporadic unstable cancers, the proximal hyperplastic polyp, is also reported to have CIMP and MLH1 methylation. However, this latter finding is not supported by MLH1 protein expression studies. To help resolve this apparent discrepancy, we determined MLH1 promoter methylation and CIMP by quantitative real-time PCR for 29 proximal hyperplastic polyps, 23 distal hyperplastic polyps, and 11 sporadic microsatellite unstable colon cancers. BRAF V600E mutation status was also determined. Positive methylation was defined as the percentage of methylated reference (PMR) 410. Only 1 of 29 proximal hyperplastic polyps showed positive MLH1 methylation (PMR of 13.0). Neither this polyp nor seven other proximal polyps with PMR values between 0 and 10 showed loss of MLH1 protein expression by immunohistochemistry. In contrast, all 11 microsatellite unstable cancers showed high degrees of MLH1 methylation, with PMR values 430. Fourteen of twenty-nine (48%) of the proximal hyperplastic polyps and 1 of 23 (4%) of the distal hyperplastic polyps showed CIMP (Po0.001). Of the unstable cancers, 10 of 11 showed CIMP. The PMR values in the CIMP-positive proximal hyperplastic polyps were significantly lower than those of the unstable cancers for 4 of the 5 CIMP markers (Po0.05). BRAF V600E mutations were seen in 83% of proximal and 74% of distal hyperplastic polyps. Quantitative analysis of MLH1 methylation does not support earlier reports of MLH1 methylation in proximal hyperplastic polyps. However, these lesions do harbor promoter methylation at other CIMP loci, although at a lower level than that seen in unstable cancers. If these polyps are the precursor for sporadic microsatellite unstable cancers, then MLH1 methylation and higher degrees of promoter methylation in general occur at a later stage of carcinogenesis.

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Section: Discussionmentioning

confidence: 94%

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confidence: 99%

Quantitative evaluation of CpG island methylation in hyperplastic polyps

2010

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“…These mutations mimic an active Wnt signaling and are assumed to be initiating at least for traditional colon cancers developing along the adenomacarcinoma sequence (10). KRAS and BRAF mutations, both resulting in a constitutively active Ras-Raf-MEK-MAPK signaling pathway, were described in earliest lesions of tumors following the so-called serrated path (3,11,12). KRAS mutations are furthermore present in some of the abovementioned traditional tumors as well as in tumors combining features of both pathways in a so-called fusion pathway (13).…”

Section: Introductionmentioning

confidence: 99%

Ultrasensitive Detection of Unknown Colon Cancer-Initiating Mutations Using the Example of the Adenomatous Polyposis Coli Gene

Gerecke

Mascher²,

Gottschalk³

et al. 2013

Cancer Prevention Research

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Detection of cancer precursors contributes to cancer prevention, for example, in the case of colorectal cancer. To record more patients early, ultrasensitive methods are required for the purpose of noninvasive precursor detection in body fluids. Our aim was to develop a method for enrichment and detection of known as well as unknown driver mutations in the Adenomatous polyposis coli (APC) gene. By coupled wild-type blocking (WTB) PCR and high-resolution melting (HRM), referred to as WTB-HRM, a minimum detection limit of 0.01% mutant in excess wild-type was achieved according to as little as 1 pg mutated DNA in the assay. The technique was applied to 80 tissue samples from patients with colorectal cancer (n ¼ 17), adenomas (n ¼ 50), serrated lesions (n ¼ 8), and normal mucosa (n ¼ 5). Any kind of known and unknown APC mutations (deletions, insertions, and base exchanges) being situated inside the mutation cluster region was distinguishable from wild-type DNA. Furthermore, by WTB-HRM, nearly twice as many carcinomas and 1.5 times more precursor lesions were identified to be mutated in APC, as compared with direct sequencing. By analyzing 31 associated stool DNA specimens all but one of the APC mutations could be recovered. Transferability of the WTB-HRM method to other genes was proven using the example of KRAS mutation analysis. In summary, WTB-HRM is a new approach for ultrasensitive detection of cancer-initiating mutations. In this sense, it appears especially applicable for noninvasive detection of colon cancer precursors in body fluids with excess wild-type DNA like stool. Cancer Prev Res; 6(9); 898-907. Ó2013 AACR.

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“…113 Mutations of the BRAF gene (most commonly studied mutation is the V600E mutation that occurs in exon 15) is another primary genetic event that happens as often as approximately 5-10% of mCRC cases. Preliminary results from studies presented in American Society of Clinical Oncology 2008 suggested that BRAF mutations can be predictive of poor response to cetuximab and of shorter overall survival.…”

Section: Egfr Inhibitorsmentioning

confidence: 99%

Pharmacogenetics and biomarkers in colorectal cancer

2009

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The prognosis of patients with colorectal cancer (CRC) is affected by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Predicting response and limiting drug-induced toxicity for patients with CRC are also critical. Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets and drug transport molecules are important contributing factors. At present, there is inconsistent and rather low use of pharmacogenetic testing in the clinical setting because of a lack of robust evidence or of resources. Patients' selection and tailored treatments by the introduction of genetic testing will hopefully allow better response prediction and limit drug-induced toxicity leading to improved patient outcomes in the most cost-effective way. Here, we review the main genetic alterations observed in familial and sporadic CRC and their associations with the metabolism, efficacy and toxicities of drugs used in this disease.

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BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?

Cited by 131 publications

References 24 publications

Quantitative evaluation of CpG island methylation in hyperplastic polyps

Quantitative evaluation of CpG island methylation in hyperplastic polyps

Ultrasensitive Detection of Unknown Colon Cancer-Initiating Mutations Using the Example of the Adenomatous Polyposis Coli Gene

Pharmacogenetics and biomarkers in colorectal cancer

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