Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial

Sclafani, Francesco; Chau, Ian; Cunningham, David; Peckitt, Clare; Lampis, Andrea; Hahne, Jens C.; Braconi, Chiara; Tabernero, Josep; Glimelius, Bengt; Cervantes, A.; Begum, Ruwaida; Castro, David González de; Wilson, Sanna Hulkki; Eltahir, Zakaria; Wotherspoon, Andrew; Tait, Diana; Brown, Gina; Oates, J.; Valeri, Nicola

doi:10.1093/annonc/mdv285

Cited by 23 publications

(20 citation statements)

References 25 publications

(35 reference statements)

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“…However, the variants in the UTR of the target genes may abolish or attenuate the inhibitory effect of miRNA on mRNA of the target by disrupting the binding or interaction between the miRNA and mRNA (33). KRAS 3'-UTR rs61764370 has been shown to be associated with some cancer phenotypes, such as prognosis in rectal cancer (34), and response to chemotherapy in colorectal cancer (35). Its involvement in some other types of cancer has been ruled out (36).…”

Section: Discussionmentioning

confidence: 99%

A single nucleotide polymorphism in the 3′-untranslated region of the KRAS gene disrupts the interaction with let-7a and enhances the metastatic potential of osteosarcoma cells

Zhang

Hou

et al. 2016

International Journal of Molecular Medicine

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The objective of the present study was to explore the molecular mechanism with which a single nucleotide polymorphism (rs61764370) interferes with the interaction between the 3'-untranslated region (3'-UTR) of Kirsten rat sarcoma viral oncogene homolog (KRAS) and let-7a, and its association with the metastasis of osteosarcoma (OS). In this study, we confirmed that KRAS is a target of let-7a in OS cells, and the introduction of rs61764370 minor allele into KRAS 3'-UTR significantly compromised the microRNA (miRNA)/mRNA interaction using a luciferase reporter system. Additionally, a total of 36 OS tissue samples of three different genotypes (TT,22; TG,10; GG,4) were obtained, and the expression of let-7a and KRAS was determined. We showed that let-7a mRNA expression was similar between each group whereas the mRNA and protein expression of KRAS in the TT genotype group was significantly lower than that in the GT or GG genotype groups. Moreover, we identified a negative regulatory relationship between let-7a and KRAS. Furthermore, we demonstrated that let-7a and KRAS interfered with the viability, invasiveness and migration of OS cells genotyped as TT. In the OS cells genotyped as TG, let-7a exerted minimal effects, and the effect of KRAS siRNA remained. Taken together, the findings of the present study demonstrated that the KRAS 3'-UTR rs61764370 polymorphism interfered with miRNA/mRNA interaction, and showed that the minor allele was associated with an elevated risk of developing metastatic disease in OS.

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Section: Discussionmentioning

confidence: 99%

A single nucleotide polymorphism in the 3′-untranslated region of the KRAS gene disrupts the interaction with let-7a and enhances the metastatic potential of osteosarcoma cells

Zhang

Hou

et al. 2016

International Journal of Molecular Medicine

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“…Given their relative stability in tissues and other biofluids (12,13), miRNAs have been proposed as potential biomarkers for colorectal cancer early detection (14,15), diagnosis (16), and prognosis (17). miRNA upregulation and/or SNPs in miRNA target genes have been postulated as potential determinants of resistance and sensitivity to anti-EGFR mAbs in early and metastatic CRC (18)(19)(20)(21). miR-31-3p expression levels have been examined by RT-PCR in retrospective analyses of the FIRE-3, PICCOLO, NEW-EPOC, and PETACC8 trials (22)(23)(24)(25)(26); in these studies, low miR-31-3p expression was associated with improved outcome and prolonged benefit from anti-EGFR treatment.…”

Section: Introductionmentioning

confidence: 99%

miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial

Anandappa

Lampis

Cunningham

et al. 2019

Clinical Cancer Research

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Purpose: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs. Experimental Design: miR-31-3p was tested by in situ hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and RAS status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination. Results: Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-na€ ve archival tissues (often primary colorectal cancer). Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs.

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“…Few studies focused on the involvement of miR-SNPs in LARC [ 121 , 122 , 123 ]. For instance, the prognostic role of the SNP rs4919510, that is characterized by the guanine to cytosine (G > C) base substitution in the sequence of the mature miRNA-608, has been explored in LARC patients subjected to neodjuvant capecitabine and oxaliplatin (CAPOX) treatment followed by CRT, surgery, or to adjuvant CAPOX ± cetuximab treatment [ 121 ].…”

Section: Single Nucleotide Polymorphisms (Snps) At Mirnas In Larcmentioning

confidence: 99%

Section: Single Nucleotide Polymorphisms (Snps) At Mirnas In Larcmentioning

confidence: 99%

“…The rs61764370 SNP (thymine to guanine (T > G) base substitution) has been identified as potential biomarker of response to neoadjuvant treatment and of a favorable outcome for LARC patients [ 122 ]. This polymorphism, harbored in the complementary site 6 (LCS-6) of the tumor suppressor miRNA let-7, alters the affinity between let-7 and its target oncogene KRAS, and consequently increasing cancer proliferation [ 122 ]. In particular, it has been demonstrated that LARC individuals with LCS-6 TG genotype reached complete response after neoadjuvant treatment and showed a better 5-years PFS and OS when compared to the TT genotype group [ 122 ].…”

Section: Single Nucleotide Polymorphisms (Snps) At Mirnas In Larcmentioning

confidence: 99%

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The Role of Micro-RNAs and Circulating Tumor Markers as Predictors of Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer

Palma

Luglio

Tropeano

et al. 2020

IJMS

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The response to neoadjuvant chemoradiation (nCRT) is a critical step in the management of locally advanced rectal cancer (LARC) patients. Only a minority of LARC patients responds completely to neoadjuvant treatments, thus avoiding invasive radical surgical resection. Moreover, toxic side effects can adversely affect patients’ survival. The difficulty in separating in advances responder from non-responder patients affected by LARC highlights the need for valid biomarkers that guide clinical decision-making. In this context, microRNAs (miRNAs) seem to be promising candidates for predicting LARC prognosis and/or therapy response, particularly due to their stability, facile detection, and disease-specific expression in human tissues, blood, serum, or urine. Although a considerable number of studies involving potential miRNA predictors to nCRT have been conducted over the years, to date, the identification of the perfect miRNA signatures or single miRNA, as well as their use in the clinical practice, is still representing a challenge for the management of LARC patients. In this review, we will first introduce LARC and its difficult management. Then, we will trace the scientific history and the key obstacles for the identification of specific miRNAs that predict responsiveness to nCRT. There is a high potential to identify non-invasive biomarkers that circulate in the human bloodstream and that might indicate the LARC patients who benefit from the watch-and-wait approach. For this, we will critically evaluate recent advances dealing with cell-free nucleic acids including miRNAs and circulating tumor cells as prognostic or predictive biomarkers.

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Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial

Cited by 23 publications

References 25 publications

A single nucleotide polymorphism in the 3′-untranslated region of the KRAS gene disrupts the interaction with let-7a and enhances the metastatic potential of osteosarcoma cells

A single nucleotide polymorphism in the 3′-untranslated region of the KRAS gene disrupts the interaction with let-7a and enhances the metastatic potential of osteosarcoma cells

miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial

The Role of Micro-RNAs and Circulating Tumor Markers as Predictors of Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer

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