Let-7 miRNA-binding site polymorphism in the KRAS 3′UTR; colorectal cancer screening population prevalence and influence on clinical outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin +/− cetuximab

Kjersem, Janne B.; Ikdahl, Tone; Guren, Tormod Kyrre; Skovlund, Eva; Sørbye, Halfdan; Hamfjord, Julian; Pfeiffer, Per; Glimelius, Bengt; Kersten, Christian; Solvang, Hiroko Kato; Tveit, Kjell Magne; Kure, Elin H.

doi:10.1186/1471-2407-12-534

Cited by 42 publications

(33 citation statements)

References 40 publications

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“…In our analysis, no such result was found and no significant association between the KRAS and BRAF mutation status and the KRAS-LCS6 genotype for the colorectal carcinoma group was established. This is in line with the results published in a Norwegian study 21 and in Sha 22 . In the group of non-small cell lung cancer, a total of 311 histologically confirmed samples were examined.…”

Section: Discussionsupporting

confidence: 82%

Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population

Uvírová¹,

Šimová²,

Kubova³

et al. 2015

BIOMED PAP

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, Petr Dite a,bAims. A germline SNP (rs61764370) is located in a let-7 complementary site (LCS6) in the 3'UTR of KRAS oncogene, and it was found to alter the binding capability of the mature let-7 microRNA to the KRAS mRNA. The aim of the study was to evaluate the frequency of the KRAS-LCS6 variant allele in different cancer types that included patients with colorectal cancer (CRC), breast cancer (BC), non-small cell lung cancer (NSCLC) and brain tumour patient subgroups from the Czech Republic. The occurrence of this genetic variant was correlated with the presence of selected somatic mutations representing predictive biomarkers in the respective tumours. Methods. DNA of tumour tissues was isolated from 428 colorectal cancer samples, 311 non-small cell lung cancer samples, 195 breast cancer samples and 151 samples with brain tumour. Analysis of SNP (rs61764370) was performed by the PCR+RFLP method and direct sequencing. KRAS, BRAF and EGFR mutation status was assessed using real-time PCR. The status of the HER2 gene was assessed using the FISH method. Results. The KRAS-LCS6 TG genotype has been detected in 16.4% (32/195) of breast cancer cases (in HER2 positive breast cancer 3.3%, in HER2 negative breast cancer 20.1%), in 12.4% (53/428) of CRC cases (KRAS/BRAF wild type CRC in 10.6%, KRAS mutant CRC in 10.1%, BRAF V600E mutant CRC in 18.5%), in 13.2% (41/311) of NSCLC samples, (EGFR mutant NSCLC patients in 8%, EGFR wild type NSCLC in 12.9%), and 17.9% (27/151) of brain tumour cases. The KRAS-LCS6 TG genotype was not significantly different across the studied tumours. In our study, the GG genotype has not been found among the cancer samples. Conclusions. Based on the findings, it is concluded that the occurrence of the KRAS-LCS6 TG genotype was statistically significantly different in association with status of the HER2 gene in breast cancer. Furthermore, significant association between the mutation status of analysed somatic variants in genes of the EGFR signalling pathway (KRAS, BRAF, EGFR) and the KRAS-LCS6 genotype in colorectal cancer and NSCLC has not been established.

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Section: Discussionsupporting

confidence: 82%

Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population

Uvírová¹,

Šimová²,

Kubova³

et al. 2015

BIOMED PAP

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“…While the aforementioned studies were conducted in patients with treatment refractory disease, the Nordic trial was conducted in previously untreated patients with metastatic CRC. In this study, there was no statistically significant effect of the LCS6 variant allele on response rate, PFS or OS in patients treated with FLOX +/− cetuximab [41]. …”

Section: Discussionmentioning

confidence: 99%

Association Study of the let-7 miRNA-Complementary Site Variant in the 3′ Untranslated Region of theKRASGene in Stage III Colon Cancer (NCCTG N0147 Clinical Trial)

Sha

Lee

Alberts

et al. 2014

Clinical Cancer Research

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Purpose A let-7 microRNA-complementary site (LCS6) polymorphism in the 3’UTR of the KRAS gene has been shown to disrupt let-7 binding and upregulate KRAS expression. We evaluated the LCS6 genotype and its association with KRAS mutation status, clinicopathological features, and disease-free survival (DFS) in stage III colon cancer patients enrolled in a phase III clinical trial (NCCTG N0147). Experimental Design The LCS6 genotype was assayed by RT-PCR in DNA extracted from whole blood (n=2834) and compared to paired tumor tissue (n=977). Chi-squared and two-sample t tests were used to compare baseline factors and KRAS mutation status between patients defined by LCS6 variant status. Log-rank tests and multivariate Cox models assessed associations between LCS6 status and DFS, respectively. Results We identified 432 (15.2%) blood samples and 143 (14.6%) tumor samples heterozygous or homozygous for the LCS6 G-allele, and 2402 of 2834 (84.8%) blood samples and 834 of 977(85.4%) tumor samples homozygous for the LCS6 T-allele. Genotype results were highly concordant (99.8%) in cases with paired blood and tumor tissue (n=977). G-allele carriers were significantly more frequent in Caucasians vs other races (chi-squared test, P <0.0001). The LCS6 genotype was not associated with KRAS mutation status, clinicopathological features (all P > 0.2) or DFS (log-rank P=0.49; HR 0.929; 95% CI: 0.76–1.14), even after combining LCS6 genotype with KRAS mutation status. Conclusions In the largest association study investigating the LCS6 polymorphism in colon cancers, the germline LCS6 genotype was not associated with KRAS mutation status or with clinical outcome in patients with stage III tumors.

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“…A polymorphism in the KRAS 3¢ untranslated region LCS6 sequence that affects binding with Let-7 miRNAs has been found to reduce the risk of developing CRC and may be associated with improved survival in early-stage cancers [68]. Whereas some reports suggest that the same LCS6 variant may affect responsiveness to cetuximab in patients with KRAS/BRAF WT CRC [69,70], others question the validity of such findings [71,72]. Different combination therapy regimes (e.g., inclusion of irinotecan or 5-FU/folinic acid and oxaliplatin [Nordic FLOX]) may account for the different outcomes.…”

Section: Micrornasmentioning

confidence: 98%

Incorporating traditional and emerging biomarkers in the clinical management of metastatic colorectal cancer

Karapetis

Maru

Waring

et al. 2015

Expert Review of Molecular Diagnostics

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The role of biomarker assessment in determining the best therapeutic options for patients with metastatic colorectal cancer has become increasingly complex and important. Biomarkers that predict the efficacy and/or toxicity of such treatments can affect medical decision making, leading to decreased harm and/or costs associated with treatment and improvements in therapeutic outcomes for patients. This review discusses traditional and emerging biomarkers of potential clinical utility for patients with metastatic colorectal cancer, current assays and methods used in clinical practice, technologies that have allowed the identification of new biomarkers and key considerations for oncologists and pathologists when determining appropriate biomarker evaluations to be undertaken for their patients.

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Let-7 miRNA-binding site polymorphism in the KRAS 3′UTR; colorectal cancer screening population prevalence and influence on clinical outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin +/− cetuximab

Cited by 42 publications

References 40 publications

Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population

Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population

Association Study of the let-7 miRNA-Complementary Site Variant in the 3′ Untranslated Region of theKRASGene in Stage III Colon Cancer (NCCTG N0147 Clinical Trial)

Incorporating traditional and emerging biomarkers in the clinical management of metastatic colorectal cancer

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