KRAS Mutation Testing in Colorectal Cancer
Department of Anatomic Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Advances in anatomic pathology
(Impact Factor: 3.23).
08/2009; 16(4):196-203. DOI: 10.1097/PAP.0b013e3181a9d4ed
In the US, colorectal cancer is the third leading cause of cancer-related death. Approximately 20% of patients present with metastatic disease, and an additional 30% to 40% develop metastasis during the course of their disease. Patients with metastatic colon cancer have a 5-year survival rate of only 11%. Although surgery is the mainstay of treatment for early stage colon cancer, adjuvant treatment is usually used in patients advanced stage disease. In particular, epidermal growth factor receptor (EGFR) inhibitor therapies have emerged as effective treatments in a subset of patients with metastatic colorectal carcinoma. Two anti-EGFR biologics, cetuximab and panitumumab, have been approved by the Food and Drug Administrations for the treatment of refractory metastatic colorectal carcinoma. Mounting evidence has shown that these therapies are ineffective in tumors with mutations of codons 12 and 13 of exon 2 of the KRAS gene. Because of this compelling data, the National Comprehensive Cancer Network and the American Society of Clinical Oncology have recommended determination of KRAS mutation status in all patients with metastatic colorectal cancer who are candidates for anti-EGFR therapy. Anatomic pathologists play an integral role in coordinating the testing for KRAS mutations, as this assay is performed on tissue samples selected by the pathologist. Herein, the authors present an up-to-date review of the biologic, clinical, and laboratory aspects of KRAS mutation testing in colorectal cancer.
Available from: Allan Andresson Lima Pereira
- "However, KRAS mutations are thought to be highly concordant during the progression of the disease (Artale et al, 2008; Etienne- Grimaldi et al, 2008; Santini et al, 2008; Cejas et al, 2009). Third, the traditional sequencing (Sanger) method (with B20% allele frequency as lowest threshold for detection) or a mass spectroscopy method (B15% allele frequency) for detection of KRAS mutations was used, both of which have lower sensitivity for mutation analysis than current next-generation sequencing approaches (B5% allele frequency; Jimeno et al, 2009; Plesec and Hunt, 2009). However, the relevance of the additional low-allele frequency mutations revealed by the newer methodology is not clear and awaits for further validation. "
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KRAS mutations have been associated with lung metastases at diagnosis of metastatic colorectal cancer (mCRC), but the impact of this mutation on subsequent development of lung metastasis is unknown. We investigated KRAS mutation as a predictor of lung metastasis development.
We retrospectively evaluated data from patients with mCRC whose tumour was tested for KRAS mutation from 2008 to 2010. The relationships of KRAS mutational status with time-to-lung metastasis (TTLM) and overall survival (OS) were analysed.
Of the 494 patients identified, 202 (41%) had tumours with KRAS mutation. KRAS mutations were associated with a shorter TTLM (median 15.2 vs 22.4 months; hazard ratio=1.40; P=0.002) and a two-fold greater odds of developing lung metastases during the disease course in patients with liver-limited mCRC at diagnosis (72 vs 56%, P=0.007). Overall survival did not differ by KRAS status.
Lung metastasis was more likely to develop during the disease course in patients whose tumour had a KRAS mutation than in those whose tumour did not have a KRAS mutation. This finding may have an impact on decision making for surgical resection of metastatic disease.
British Journal of Cancer 12/2014; 112(3). DOI:10.1038/bjc.2014.619 · 4.84 Impact Factor
Available from: ncbi.nlm.nih.gov
- "This might raise concerns about the sensitivity of the KRAS mutation analysis. We actually used traditional sequencing (Sanger) method with relatively low sensitivity for KRAS mutation analysis . In addition, biopsied specimens of primary tumor showed a trend for higher discordance rate than resected specimens in this study (40.0% vs. 15.8%; "
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We evaluated the association between a KRAS mutational status and various clinicopathologic features including the metastatic pattern in patients with metastatic or recurrent colorectal cancer (MRCRC). The concordance rates of the KRAS status between primary tumor sites and paired metastatic organs were also analyzed.
The KRAS mutational status in codons 12, 13, and 61 from formalin-fixed sections of both primary tumors and related metastases was determined by sequencing analysis. One hundred forty-three Korean patients with MRCRC with available tissues (resection or biopsy) from both primary tumors and related metastatic sites were consecutively enrolled.
The KRAS mutation rate was 52.4% (75/143) when considering both the primary and metastatic sites. When the relationship between the KRAS status and initial metastatic sites at the time of diagnosis of MRCRC was analyzed, lung metastasis was more frequent as the initial metastatic site in patients with the KRAS mutation than in patients without the KRAS mutation (45.3% vs. 22.1%; P = 0.003). However, liver (37.3% vs. 70.6%; P < 0.001) or distant lymph node metastases (6.7% vs. 19.1%; P = 0.025) were less frequent as the initial metastatic organ in patients with the KRAS mutation than in patients without the KRAS mutation. The discordance rate of KRAS mutational status between primary and paired metastatic sites other than the lung was 12.3% (13/106). Compared with primary tumor sites, the KRAS discordance rate was significantly higher in matched lung metastases [32.4% (12/37)] than in other matched metastatic organs (P = 0.005).
Organs initially involved by distant metastasis were different according to the KRAS mutational status in MRCRC patients. The concordance rate (87.7%) of the KRAS mutation status at metastatic sites other than the lung was generally high compared with primary tumor sites; however, lung metastasis had a high rate of KRAS discordance (32.4%).
BMC Cancer 08/2012; 12(1):347. DOI:10.1186/1471-2407-12-347 · 3.36 Impact Factor
Available from: Rola Barhoumi
- "Collectively, these data implicate EGFR as a master signal capable of driving colon tumorigenesis. For these reasons, EGFR is an attractive target for therapeutic intervention; thus, intense efforts have been made to inhibit the activity of EGFR by designing small molecules against the tyrosine kinase domain (erlotinib, gefitinib, and lapatinib) or antibodies against the ligand binding domains (cetuximab and panitumumab) , . "
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ABSTRACT: The epidermal growth factor receptor (EGFR), which regulates cell growth and survival, is integral to colon tumorigenesis. Lipid rafts play a role in regulating EGFR signaling, and docosahexaenoic acid (DHA) is known to perturb membrane domain organization through changes in lipid rafts. Therefore, we investigated the mechanistic link between EGFR function and DHA. Membrane incorporation of DHA into immortalized colonocytes altered the lateral organization of EGFR. DHA additionally increased EGFR phosphorylation but paradoxically suppressed downstream signaling. Assessment of the EGFR-Ras-ERK1/2 signaling cascade identified Ras GTP binding as the locus of the DHA-induced disruption of signal transduction. DHA also antagonized EGFR signaling capacity by increasing receptor internalization and degradation. DHA suppressed cell proliferation in an EGFR-dependent manner, but cell proliferation could be partially rescued by expression of constitutively active Ras. Feeding chronically-inflamed, carcinogen-injected C57BL/6 mice a fish oil containing diet enriched in DHA recapitulated the effects on the EGFR signaling axis observed in cell culture and additionally suppressed tumor formation. We conclude that DHA-induced alteration in both the lateral and subcellular localization of EGFR culminates in the suppression of EGFR downstream signal transduction, which has implications for the molecular basis of colon cancer prevention by DHA.
PLoS ONE 06/2012; 7(6):e39682. DOI:10.1371/journal.pone.0039682 · 3.23 Impact Factor
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