KRAS alleles: the LCS6 3'UTR variant and KRAS coding sequence mutations in the NCI-60 panel.
ABSTRACT The KRAS-variant is a germline single nucleotide polymorphism (SNP) within the 3'UTR of the KRAS gene predicted to disrupt a complementary binding site (LCS6) for the let-7 microRNA (miRNA). The KRAS-variant is associated with increased risk of various cancers, including lung cancer, ovarian cancer and triple-negative breast cancer, and is associated with altered tumor biology in head and neck cancer, colon cancer and melanoma. To better understand the molecular pathways that may be regulated or affected by the presence of the KRAS-variant allele in cancer cells, we examined its prevalence in the NCI-60 panel of cell lines and sought to identify common features of the cell lines that carry the variant allele. This study provides a step forward towards understanding the molecular and pathological significance of the KRAS-variant.
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ABSTRACT: There is a small but growing body of literature regarding the predictive utility of a Let-7 microRNA-binding-site polymorphism in the 3′-untranslated region (UTR) of KRAS (KRAS-LCS6) for colorectal cancer outcome, although the results are conflicting. We performed a review and meta-analysis in an attempt to better clarify this relationship. A PubMed search was conducted to identify all studies reporting on KRAS let-7 microRNA-binding site polymorphism (LCS6; rs61764370) and colorectal cancer outcome. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted or estimated from each manuscript. Log HRs and log CIs were combined across studies using the inverse-variance weight to calculate fixed- and random-effects summary estimates and corresponding 95% CIs for overall and progression-free survival. We did not observe any significant association between overall or progression-free survival, neither when considering all colorectal cancer patients nor for subgroup analyses (metastatic, anti-EGFR [epidermal growth factor receptor] treatment, or KRAS wild type). There was substantial heterogeneity across studies, overall and among subgroups analyzed. We have found no clear evidence to support an association between the KRAS-LCS6 genotype and overall or progression-free survival among colorectal cancer patients, even after conducting subgroup analyses by stage and anti-EGFR treatment status. This information helps to clarify the confusing body of literature regarding the clinical implications of the KRAS-LCS6 genetic variant on colorectal cancer outcomes, indicating that it should not be used at the present time to personalize therapeutic strategies (PROSPERO registration number: CRD42013005325).Cancer Medicine 10/2014; 3(5). DOI:10.1002/cam4.279
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ABSTRACT: Triple Negative Breast Cancer (TNBC) is a very aggressive tumor subtype, which still lacks specific markers for an effective targeted therapy. Despite the common feature of negativity for the three most relevant receptors (ER, PgR and HER2), TNBC is a very heterogeneous disease where different subgroups can be recognized, and both gene and microRNA profiling studies have recently been carried out to dissect the different molecular entities. Moreover, several microRNAs playing a crucial role in triple negative breast cancer biology have been identified, providing the experimental basis for a possible therapeutic application. Indeed, the causal involvement of microRNAs in breast cancer and the possible use of these small noncoding RNA molecules as biomarkers has been extensively studied with promising results. Their application as therapeutic tools might represent an innovative approach, especially for a tumor subgroup still lacking an efficient and specific therapy such as TNBC. In this review, we summarize our knowledge on the most important microRNAs described in TNBC.International Journal of Molecular Sciences 11/2013; 14(11):22202-22220. DOI:10.3390/ijms141122202 · 2.34 Impact Factor
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ABSTRACT: miRNAs, which are small single-stranded RNA molecules composed of 18-23 nts, act as oncogenes or tumor suppressor genes playing important roles in the processes of tumor formation, infiltration and metastasis. Lung cancer currently has the highest morbidity and mortality among all malignant tumors; yet, lack of early specific diagnostic markers and effective treatments hinders its proper management. In lung cancer, about 40-45 abnormal expression patterns of miRNAs have been discovered and are involved in lung cancer development. miRNAs have functions together with oncogenes and tumor suppressor genes of lung cancer. miRNAs-based tests can be used for early clinical diagnosis and prediction of clinical outcomes of lung cancer. Studying the role of miRNAs in lung cancer development and its relationship with diagnostic and prognostic parameters might help to improve the sensitivity of diagnosis and the efficacy of lung cancer treatment.Expert Review of Anti-infective Therapy 02/2014; DOI:10.1586/14737140.2013.870037 · 2.28 Impact Factor