Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model

Álamo, Patricia; Gallardo, Alberto; Nicolantonio, Federica Di; Pavón, Miguel Ángel; Casanova, Isolda; Trías, Manuel; López‐Pousa, Antonio; Villaverde, Antonio; Vázquez, Esther; Bardelli, Alberto; Céspedes, María Virtudes; Mangues, Ramón

doi:10.1096/fj.14-262303

Cited by 43 publications

(30 citation statements)

References 50 publications

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“…According to the literature, KRAS mutations at residues G12 and G13 have different risks of tumor progression in lung cancer and CRC [7][8][9]25,26]. The mechanism of different KRAS mutations on tumor progression has not been completely elucidated.…”

Section: Discussionmentioning

confidence: 99%

Mutational analysis of KRAS and its clinical implications in cervical cancer patients

et al. 2018

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Objective: The predictive and prognostic role of KRAS mutations in cervical cancer remains inconclusive. The aim of this study was to explore the clinicopathological and prognostic relevance of KRAS mutations in invasive cervical cancers (ICC). Methods: Reverse transcription polymerase chain reaction (PCR) and Sanger sequencing were employed to detect KRAS mutations in 876 ICC patients. Quantitative real-time PCR was used to detect human papillomavirus (HPV) 16 and HPV 18. Results: Non-synonymous mutations of KRAS were identified in 30 (3.4%) patients. These mutations were more common in non-squamous cell carcinoma than in squamous cell carcinoma (SCC) (8.2% vs. 2.2%, respectively, p<0.001) and were associated with HPV 18 infection (p=0.003). The prevalence of mutations was highest (18.2%) in the uncommon histological subtypes followed by adenocarcinoma (AC, 7.3%) and adenosquamous carcinoma (ASC, 5.8%). During the median follow-up of 55 months, compared to patients with wild-type KRAS, a greater percentage of patients with mutant KRAS relapsed (20.0% vs. 42.9%, respectively, p=0.007). The 3-year relapse-free survival was poorer in patients with mutant KRAS than in patients without KRAS mutations (57.1% vs. 81.9%, respectively, p=0.001). Furthermore, the multivariate analysis showed that the presence of a KRAS mutation was an independent predictor for disease recurrence (hazard ratio [HR]=2.064; 95% confidence interval [CI]=1.125-3.787; p=0.019). Conclusion: KRAS mutations were predominant in non-SCCs of the cervix and were associated with HPV 18 infection. A combination of KRAS mutation detection and HPV genotyping would be useful in identifying patient with poor prognosis for further interventions.

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Section: Discussionmentioning

confidence: 99%

Mutational analysis of KRAS and its clinical implications in cervical cancer patients

et al. 2018

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“…In CRC, KRAS p.G12V was identified in both primary and metastasis samples but the difference was not significant (Neumann et al, 2009). However, a recent clinical study found that the KRAS p.G12V alteration enhances metastases to lymph nodes, an indication of its higher aggressiveness in CRC animal model (Alamo et al, 2015). With regards to precision medicine, this alteration is reported to confer reduced sensitivity against cetuximab or panitumumab (anti-EGFR antibodies) (Di Fiore et al, 2007; Peeters et al, 2013), which is the main treatment for metastatic CRC.…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Somatic Alterations in Dukes’ B and C Colorectal Cancers by Targeted Sequencing

Abdul

Mutalib

Sean³

et al. 2017

Front. Pharmacol.

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Despite global progress in research, improved screening and refined treatment strategies, colorectal cancer (CRC) remains as the third most common malignancy. As each type of cancer is different and exhibits unique alteration patterns, identifying and characterizing gene alterations in CRC that may serve as biomarkers might help to improve diagnosis, prognosis and predict potential response to therapy. With the emergence of next generation sequencing technologies (NGS), it is now possible to extensively and rapidly identify the gene profile of individual tumors. In this study, we aimed to identify actionable somatic alterations in Dukes’ B and C in CRC via NGS. Targeted sequencing of 409 cancer-related genes using the Ion AmpliseqTM Comprehensive Cancer Panel was performed on genomic DNA obtained from paired fresh frozen tissues, cancer and normal, of Dukes’ B (n = 10) and Dukes’ C (n = 9) CRC. The sequencing results were analyzed using Torrent Suite, annotated using ANNOVAR and validated using Sanger sequencing. A total of 141 somatic non-synonymous sequence variations were identified in 86 genes. Among these, 64 variants (45%) were predicted to be deleterious, 38 variants (27%) possibly deleterious while the other 39 variants (28%) have low or neutral protein impact. Seventeen genes have alterations with frequencies of ≥10% in the patient cohort and with 14 overlapped genes in both Dukes’ B and C. The adenomatous polyposis coli gene (APC) was the most frequently altered gene in both groups (n = 6 in Dukes’ B and C). In addition, TP53 was more frequently altered in Dukes’ C (n = 7) compared to Dukes’ B (n = 4). Ten variants in APC, namely p.R283∗, p.N778fs, p.R805∗, p.Y935fs, p.E941fs, p.E1057∗, p.I1401fs, p.Q1378∗, p.E1379∗, and p.A1485fs were predicted to be driver variants. APC remains as the most frequently altered gene in the intermediate stages of CRC. Wnt signaling pathway is the major affected pathway followed by P53, RAS, TGF-β, and PI3K signaling. We reported the alteration profiles in each of the patient which has the potential to affect the clinical decision. We believe that this study will add further to the understanding of CRC molecular landscape.

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“…Tumors injected into the serosal surface of the cecum develop metastasis at relatively low rate, but passage of tumor cells through a xenograft host increases lymph node and lung metastases formation rate to approximately 10% in Kras wild-type cells [94, 95]. Orthotopic injection of murine tumor cells into the rectal mucosa of syngeneic recipient mice produces a liver metastasis rate of only 3.3% 50 days after transplantation [96].…”

Section: Metastatic Modelsmentioning

confidence: 99%

Colorectal cancer models for novel drug discovery

Golovko¹,

Kedrin

Yılmaz

et al. 2015

Expert Opinion on Drug Discovery

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Introduction Despite increased screening rates and advances in targeted therapy, colorectal cancer (CRC) remains the third leading cause of cancer-related mortality. CRC models that recapitulate key features of human disease are essential to the development of novel and effective therapeutics. Classic methods of modeling CRC such as human cell lines and xenograft mice, while useful for many applications, carry significant limitations. Recently developed in vitro and in vivo models overcome some of these deficiencies and thus can be utilized to better model CRC for mechanistic and translational research. Areas Covered The authors review established models of in vitro cell culture and describe advances in organoid culture for studying normal and malignant intestine. They also discuss key features of classic xenograft models and describe other approaches for in vivo CRC research, including patient-derived xenograft, carcinogen-induced, orthotopic transplantation, and transgenic mouse models. We also describe mouse models of metastatic CRC. Expert opinion No single model is optimal for drug discovery in CRC. Genetically engineered models overcome many limitations of xenograft models. Three-dimensional organoids can be efficiently derived from both normal and malignant tissue for large-scale in vitro and in vivo (transplantation) studies, and are thus a significant advance in CRC drug discovery.

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Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model

Cited by 43 publications

References 50 publications

Mutational analysis of KRAS and its clinical implications in cervical cancer patients

Mutational analysis of KRAS and its clinical implications in cervical cancer patients

Molecular Characterization of Somatic Alterations in Dukes’ B and C Colorectal Cancers by Targeted Sequencing

Colorectal cancer models for novel drug discovery

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