Heterogeneity of KRAS Status May Explain the Subset of Discordant KRAS Status Between Primary and Metastatic Colorectal Cancer

Watanabe, Toshiaki; Kobunai, Takashi; Yamamoto, Yasutake; Matsuda, Keiji; Ishihara, Soichiro; Nozawa, Keijiro; Iinuma, Hisae; Shibuya, Hitoshi; Eshima, Kiyoshi

doi:10.1097/dcr.0b013e31821d37a3

Cited by 72 publications

(61 citation statements)

References 39 publications

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“…Potential reasons to explain this phenomenon are the intratumoral heterogeneity of KRAS alleles within individual primary CRCs (18) and the discordant KRAS status between primary tumor and corresponding metastases (19,20). It has also been reported that the intratumoral heterogeneity within a primary CRC can explain the discordant KRAS status between primary and metastatic CRC tumors (21). In addition, mutational testing requires tumor tissue samples resected by biopsy or surgery, but samples from metastatic tumors are uncommon because of the difficulty of accessing them and low tumor content secondary to treatment effect.…”

Section: Discussionmentioning

confidence: 99%

Regulation of ¹⁸F-FDG Accumulation in Colorectal Cancer Cells with Mutated KRAS

et al. 2014

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KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that 18 F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased 18 F-FDG accumulation. Methods: Using paired isogenic human CRC cell lines that differ only in the mutational status of the KRAS gene, we measured 18 F-FDG accumulation in these cells in vitro and in vivo. We also investigated the roles of proteins that have a function in 18 F-FDG accumulation. Finally, we examined the relationship among mutated KRAS, hypoxia-inducible factor 1α (HIF-1α), and maximum standardized uptake value with 51 clinical CRC samples. Results: In the in vitro experiments, 18 F-FDG accumulation was significantly higher in KRAS-mutant cells than in wild-type controls under normoxic conditions. The expression levels of glucose transporter 1 (GLUT1) and hexokinase type 2 (HK2) were higher in KRAS-mutant cells, and 18 F-FDG accumulation was decreased by knockdown of GLUT1. Hypoxic induction of HIF-1α was higher in KRAS-mutant cells than in wild-type controls; in turn, elevated HIF-1α resulted in higher GLUT1 expression and 18 F-FDG accumulation. In addition, HIF-1α knockdown decreased 18 F-FDG accumulation under hypoxic conditions only in the KRAS-mutant cells. Small-animal PET scans showed in vivo 18 F-FDG accumulation to be significantly higher in xenografts with mutated KRAS than in those with wild-type KRAS. The immunohistochemistry of these xenograft tumors showed that staining of GLUT1 was consistent with that of HIF-1α and pimonidazole. In a retrospective analysis of clinical samples, KRAS mutation exhibited a significantly positive correlation with expressions of GLUT1 and HIF-1α and with maximum standardized uptake value. Conclusion: Mutated KRAS caused higher 18 F-FDG accumulation possibly by upregulation of GLUT1; moreover, HIF-1α additively increased 18 F-FDG accumulation in hypoxic lesions. 18 F-FDG PET might be useful for predicting the KRAS status noninvasively.

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Section: Discussionmentioning

confidence: 99%

Regulation of ¹⁸F-FDG Accumulation in Colorectal Cancer Cells with Mutated KRAS

et al. 2014

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“…This may be due to heterogeneity of the primary tumor. If different parts of the primary tumor are examined, the false-negative rate could be abrogated [92].…”

Section: Krasmentioning

confidence: 99%

Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach

2012

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“…We reported that, as KRAS mutations in some primary tumors are heterogeneous, there are 10% of cases in which KRAS gene status between the primary tumor and metastatic tumors in the same patient are different (30). There were studies reporting a high KRAS gene concordance rate of 95% or more (31 -33) between primary and metastatic tumors.…”

Section: Kras Mutational Status In Japanese Patientsmentioning

confidence: 99%

KRAS Mutational Status in Japanese Patients with Colorectal Cancer: Results from a Nationwide, Multicenter, Cross-sectional Study

Watanabe

Yoshino

Uetake

et al. 2013

Japanese Journal of Clinical Oncology

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Objective: KRAS gene mutations are a useful predictive factor for the efficacy of anti-epidermal growth factor receptor therapeutics. Since there were no large-scale studies among Asian populations, we designed an observational nationwide study in Japan. Methods: Formalin-fixed paraffin-embedded tissue blocks or sections from primary or metastatic lesions were obtained from patients registered between 2009 and 2010 for genomic DNA extraction. KRAS gene was analyzed by direct sequencing or Luminex assay. The primary endpoint was the frequency of KRAS gene mutations and the secondary endpoints were differences in KRAS mutation rates by various stratification factors. Univariate and multivariate analyses were performed to investigate relationships between KRAS mutation rates and patient background factors. Results: We analyzed 5790 eligible samples out of 5887 registered. The overall KRAS mutation rate was 37.6%, with 29.9% in codon 12 and 7.7% in codon 13, and wild type was 62.4%. A significant relationship with the KRAS mutation rate was found for gender, age, the year that the sample was prepared and the site of the primary lesion. Conclusion: The KRAS mutation rate of Japanese colorectal cancer patients was 37.6%. Gender, age, the site of the primary lesion and the year that the sample was prepared were independent risk factors for KRAS mutations.

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Heterogeneity of KRAS Status May Explain the Subset of Discordant KRAS Status Between Primary and Metastatic Colorectal Cancer

Cited by 72 publications

References 39 publications

Regulation of ¹⁸F-FDG Accumulation in Colorectal Cancer Cells with Mutated KRAS

Regulation of ¹⁸F-FDG Accumulation in Colorectal Cancer Cells with Mutated KRAS

Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach

KRAS Mutational Status in Japanese Patients with Colorectal Cancer: Results from a Nationwide, Multicenter, Cross-sectional Study

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Heterogeneity of KRAS Status May Explain the Subset of Discordant KRAS Status Between Primary and Metastatic Colorectal Cancer

Cited by 72 publications

References 39 publications

Regulation of 18F-FDG Accumulation in Colorectal Cancer Cells with Mutated KRAS

Regulation of 18F-FDG Accumulation in Colorectal Cancer Cells with Mutated KRAS

Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach

KRAS Mutational Status in Japanese Patients with Colorectal Cancer: Results from a Nationwide, Multicenter, Cross-sectional Study

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Regulation of ¹⁸F-FDG Accumulation in Colorectal Cancer Cells with Mutated KRAS

Regulation of ¹⁸F-FDG Accumulation in Colorectal Cancer Cells with Mutated KRAS