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1.
Artículo en Ruso | MEDLINE | ID: mdl-32119223

RESUMEN

The colorectal cancer is considered as the third most common malignant disease in the world. During last decade, the problem of colorectal cancer became especially urgent conditioned not only by increasing of number of metastatic tumors of colon and rectum, but also by implementation of high-tech methods of treatment that significantly improved the results of five-year survival period. Along with success of therapy, understanding of genomics of colorectal cancer and owing to extensive application of next generation sequencing, the opportunity of optimal choice of treatment options was offered. METHODS: The sampling included tumor material of 332 patients diagnosed with colorectal cancer, fixed in formalin and enclosed in paraffin, and treated in oncology dispensaries and centers and in the Kazakh Research Institute of Oncology and Radiology in 2010-2014. After morphological evaluation of the material quality, the molecular genetic analysis was applied to establish mutation of the KRAS gene using polymerase chain reaction in real-time. RESULTS: The study established that KRAS mutation rate in patients with colorectal cancer had no reliable dependency with the region of their residence, since statistical analysis of pair "region of residence - all KRAS mutations" had value of correlation coefficient rp = 0.1 (p = 0.05). CONCLUSIONS: colorectal cancer It was established that there is no reliable dependence of rate of KRAS gene mutation in patients with colorectal cancer in the region of their residence. The high rate of occurrence of mutated type of gene was detected in 3 regions (Kyzyl-Orda, North Kazakhstan and Almaty) within the range of 58.3-76.5% of cases. The wild type of KRAS gene was most frequently detected in patients from the Karaganda region (65.5%), South Kazakhstan (71.4%) and Almaty (60.7%).


Asunto(s)
Neoplasias Colorrectales , Proteínas Proto-Oncogénicas p21(ras) , Neoplasias Colorrectales/genética , Humanos , Kazajstán , Mutación , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas p21(ras)/genética
3.
Cancer Treat Rev ; 85: 101978, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32062493

RESUMEN

Cancers of nearly all lineages harbor alterations that deregulate mitogen-activated protein kinase signaling, a crucial signaling pathway for tumor formation and maintenance. Of these, KRAS mutations are the most frequent gain-of-function alterations found in patients with cancer. In particular they represents the most common molecular alteration detected in non-small cell lung cancer (NSCLC) accounting for up to 25% of all oncogenic mutations. They were identified decades ago and prior efforts to target these proteins have been unsuccessful. KRAS mutation profiles (i.e. frequency of specific codon substitutions) in smokers and never-smokers are distinct and not all KRAS alterations are driver mutations. KRAS has evolved from a mutation with possible predictive value to a therapeutic target with great promise. Here, we will discuss the biology of KRAS in lung cancer and its clinical implications in oncology today and in the foreseeable future.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas p21(ras)/genética , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Predicción , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoterapia/métodos , Neoplasias Pulmonares/mortalidad , Masculino , Mutación , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Análisis de Supervivencia , Resultado del Tratamiento
4.
Cancer Treat Rev ; 84: 101974, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32014824

RESUMEN

Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are among the most common aberrations in cancer, including non-small cell lung cancer (NSCLC). The lack of an ideal small molecule binding pocket in the KRAS protein and its high affinity towards the abundance of cellular guanosine triphosphate (GTP) renders the design of specific small molecule drugs challenging. Despite efforts, KRAS remains a challenging therapeutic target. Among the different known mutations; the KRASG12C (glycine 12 to cysteine) mutation has been considered potentially druggable. Several novel covalent direct inhibitors targeting KRASG12C with similar covalent binding mechanisms are now in clinical trials. Both AMG 510 from Amgen and MRTX849 from Mirati Therapeutics covalently binds to KRASG12C at the cysteine at residue 12, keeping KRASG12C in its inactive GDP-bound state and inhibiting KRAS-dependent signaling. Both inhibitors are being studied as a single agent or as combination with other targets. In addition, two novel KRAS G12C inhibitors JNJ-74699157 and LY3499446 will have entered phase 1 studies by the end of 2019. Given the rapid clinical development of 4 direct covalent KRAS G12C inhibitors within a short period of time, understanding the similarities and differences among these will be important to determine the best treatment option based on tumor specific response (NSCLC versus colorectal carcinoma), potential resistance mechanisms (i.e. anticipated acquired mutation at the cysteine 12 residue) and central nervous system (CNS) activity. Additionally, further investigation evaluating the efficacy and safety of combination therapies with agents such as immune checkpoint inhibitors will be important next steps.


Asunto(s)
Antineoplásicos/uso terapéutico , Terapia Molecular Dirigida , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Humanos , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genética
5.
Anticancer Res ; 40(2): 733-741, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014915

RESUMEN

BACKGROUND/AIM: GPR87 is a member of the cell surface molecular G protein-coupled receptors (GPCR) family and suggested to contribute to the viability of human tumor cells. Its tumor-specific expression and cell surface location make it a potential molecule for targeted therapy. In the present study, we aimed to examine the effect of silencing GPR87 expression and explore the possibility of establishing gene therapy against GPR87-overexpressing lung cancer. MATERIALS AND METHODS: Twenty malignant cell lines were investigated and GPR87-overexpressing H358 and PC9 lung cancer cells were subjected to inhibiting experiments. A short hairpin siRNA targeting the GPR87 gene was transformed into an adenoviral vector (Ad-shGPR87). Real-time RT-PCR and western blot analyses were performed to evaluate gene and protein expression. Tumors derived from human H358 cells were subcutaneously implanted in nude mice for in vivo experiments. RESULTS AND CONCLUSION: About 50% (10/20) malignant cells showed GPR87-overexpression, especially for lung cancer cells (70%, 7/10). Ad-shGPR87 effectively down-regulated the GPR87 expression, and significantly inhibited the cell proliferation in GPR87-overexpressing H358 and PC9 cells. Treatment with Ad-shGPR87 exerted a significant antitumor effect against the GPR87-expressing H358 xenografts. In addition, the gene expression of H3.3, a recently proved activator for GPR87 transcription, was positively correlated with GPR87 gene expression. Furthermore, a significant decrease of KRAS and c-Myc expression was observed in both cell lines after Ad-shGPR87 infection. In conclusion, GPR87 may play a critical role in cancer cell proliferation, and indicate its potential as a novel target for lung cancer treatment.


Asunto(s)
Terapia Genética/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , ARN Interferente Pequeño/administración & dosificación , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Adenoviridae/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Expresión Génica , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , ARN Interferente Pequeño/genética , Receptores del Ácido Lisofosfatídico/biosíntesis , Receptores del Ácido Lisofosfatídico/genética , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Zhonghua Yi Xue Za Zhi ; 100(4): 301-306, 2020 Feb 04.
Artículo en Chino | MEDLINE | ID: mdl-32075360

RESUMEN

Objective: To investigate the clinicopathological characteristics, MSI and K-ras mutation of double primary malignancies (DPM) associated with colorectal cancer (CRC). Methods: From January 2015 to December 2016, the clinicopathological data of CRC patients treated by surgery in the Affiliated Drum Tower Hospital of Nanjing University Medical School were collected, and the clinical data was analyzed. Multiplex real-time fluorescence quantitative PCR and amplification refractory mutation was performed to identify MSI and K-ras gene mutations. Results: Of all patients with CRC, 5.2% (55/1 066) were DPM. There was no significant difference in the male and female ratio, age, colorectal cancer site, T stage, N stage composition ratio between DPM patients with CRC and patients with single CRC (P>0.05). There were significant difference of TNM stage between the two group (P<0.05). The most frequent location of CRC was the colon in both DPM patients with CRC and patients with single CRC[35.5% (359/1 011) and 41.8% (23/55), respectively]. Of 55 DPM patients with CRC, 48 were metachronous DPM patients, 7 were synchronous DPM patients and 41 were colorectal cancer first. In extracolonic organ, digestive system (23/55) was the most commonly occurring system and stomach (11/55) was the most common lesion. DPM patients with CRC had higher incidence of MSI-H than patients with single CRC (P<0.05). There was no significant difference of K-ras gene mutation between DPM patients with CRC and patients with single CRC (P>0.05). MSI-H and K-ras mutation were present in only 2 patients of DPM patients with CRC. Conclusions: The rectum is the most common lesion site in CRC patients. The stomach is the most common extracolonic organ of DPM patients with CRC. DPM patients with CRC has high risk of MSI-H, but no significant difference in the incidence of K-ras mutation.


Asunto(s)
Neoplasias Colorrectales , Genes ras , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Colorrectales/genética , Femenino , Humanos , Masculino , Inestabilidad de Microsatélites , Mutación , Estadificación de Neoplasias
7.
BMC Med Genet ; 21(1): 3, 2020 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-31900123

RESUMEN

BACKGROUND: Liquid biopsies of blood plasma cell free DNA can be used to monitor treatment response and potentially detect mutations that are present in resistant clones in metastatic cancer patients. CASE PRESENTATION: In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that the APC/TP53/KRAS major clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that the APC/TP53/KRAS and other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1 and others) were present in all samples. After the last chemotherapy cycle, CT imaging, CEA and CA19-9 markers validated the cfDNA findings of treatment response. However, 5 weeks later, the tumour had rapidly progressed. CONCLUSION: As FOLFIRI+Bevacizumab has recently also been associated with sustained complete remission in a APC/TP53/KRAS triple-mutated patient, these driver genes should be tested and monitored in a more in-depth manner in future patients. Patients with metastatic disease should be monitored more closely during and after chemotherapy, ideally using cfDNA.


Asunto(s)
Proteína de la Poliposis Adenomatosa del Colon/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/sangre , Proteína p53 Supresora de Tumor/sangre , Proteína de la Poliposis Adenomatosa del Colon/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Ácidos Nucleicos Libres de Células/sangre , ADN Tumoral Circulante/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Biopsia Líquida , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas p21(ras)/genética , Inducción de Remisión , Proteína p53 Supresora de Tumor/genética
9.
Anticancer Res ; 40(1): 427-433, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892597

RESUMEN

BACKGROUND/AIM: The role of anti-PD1/PD-L1 therapy (IO) in NSCLC harboring driver mutations is questionable. This study aimed to examine the efficacy of IO in patients with non-small cell lung cancer (NSCLC) with a KRAS mutation (KRAS+). PATIENTS AND METHODS: We retrospectively identified NSCLC patients harboring KRAS mutation treated with IO in our Institution. We analyzed the results in comparison to non-KRAS patients. RESULTS: Among 328 consecutive KRAS+ NSCLC patients, 43 (13.1%) received IO in our Institution. In parallel 117 non-KRAS NSCLC patients treated with IO were selected for comparison. The baseline characteristics were similar between the two groups. No significant difference was observed between KRAS+ and non-KRAS patients in terms of mPFS (4.6 vs. 3.3 months, p=0.58) or OS (8.1 vs. 13.0 months, p=0.38). CONCLUSION: KRAS mutations seem to be irrelevant for selecting patients for IO that could be therefore considered an effective therapy for NSCLC patients, independently of KRAS status.


Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutación/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Anciano , Antígeno B7-H1/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
10.
Cancer Invest ; 38(2): 85-93, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31939681

RESUMEN

The identification and quantification of actionable mutations are critical for guiding targeted therapy and monitoring drug response in colorectal cancer. Liquid biopsy (LB) based on plasma cell-free DNA analysis has emerged as a noninvasive approach with many clinical advantages over conventional tissue sampling. Here, we developed a LB protocol using ultra-deep massive parallel sequencing and validated its clinical performance for detection and quantification of actionable mutations in three major driver genes (KRAS, NRAS and BRAF). The assay showed a 92% concordance for mutation detection between plasma and paired tissues and great reliability in quantification of variant allele frequency.


Asunto(s)
ADN Tumoral Circulante/genética , Neoplasias Colorrectales/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Biopsia Líquida/métodos , Neoplasias Colorrectales/sangre , GTP Fosfohidrolasas/genética , Humanos , Proteínas de la Membrana/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Reproducibilidad de los Resultados
11.
Cancer Sci ; 111(2): 739-748, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31799787

RESUMEN

There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co-occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next-generation sequencing of 50 cancer-related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.


Asunto(s)
Carcinoma Ductal Pancreático/cirugía , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Secundarias/cirugía , Neoplasias Pancreáticas/cirugía , Proteína Smad4/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Biomarcadores de Tumor , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Análisis Mutacional de ADN , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Estadificación de Neoplasias , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/metabolismo , Neoplasias Primarias Múltiples/cirugía , Neoplasias Primarias Secundarias/metabolismo , Neoplasias Primarias Secundarias/patología , Pancreatectomía , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Análisis de Secuencia de ADN , Proteína Smad4/genética , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/genética
12.
J Photochem Photobiol B ; 202: 111672, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31778952

RESUMEN

In highly proliferating cancer cells oncogenic mutations reprogram the metabolism and increase the production of reactive oxygen species (ROS). Cancer cells prevent ROS accumulation by upregulating antioxidant systems. Here we show that an increase of oxidative stress (ROS and singlet oxygen), generated by photoactivated TMPyP4, results in the upregulation of KRAS and Nrf2, the major regulator of the redox homeostasis. In agreement with a previous observation, the ectopic expression of KRAS G12D or G12 V is found to stimulate Nrf2. This suggests that ROS, KRAS and Nrf2 establish a molecular axis controlling the redox homeostasis in cancer cells. We found that this axis also modulates the function of the NF-kB/Snail/RKIP circuitry, regulating the survival and apoptosis pathways. Our data show that low ROS levels, obtained when Nrf2 is activated by KRAS, results in the upregulation of prosurvival Snail and simultaneous downregulation of proapoptotic RKIP: an expression pattern favouring cell proliferation. By contrast, high ROS levels, obtained when Nrf2 is inhibited by a small molecule (luteolin), favour apoptosis by upregulating proapoptotic RKIP and downregulating prosurvival Snail. The results of this study are useful to design efficient photodynamic therapy (PDT) against cancer. We hypothesize that cancer cells can be sensitized to PDT when the photosensitizer is used in the presence of an inhibitor of Nrf2 (adjuvant). To test this hypothesis, we used luteolin (3',4',5,7-tetrahydroflavone) as Nrf2 inhibitor, since it reduces the expression of Nrf2 and increases intracellular ROS. By means of colony formation and viability assays we found that when Nrf2 is inhibited, PDT shows an increase of efficiency up to 45%.


Asunto(s)
Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Factor 2 Relacionado con NF-E2/genética , Neoplasias/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Proteínas de Unión a Fosfatidiletanolamina/genética , Proteínas de Unión a Fosfatidiletanolamina/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo
13.
Acta Cytol ; 64(1-2): 124-135, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31509835

RESUMEN

Pancreatic cysts are increasingly detected on imaging studies. Accurate determination of the cyst type is important to provide appropriate care for the patients. It is also very clear that not one single modality can provide adequate diagnostic information. A multidisciplinary approach is the key to the diagnosis of pancreatic cysts. In this setting, the role of ancillary testing, which includes biochemical testing (carcinoembryonic antigen and amylase levels in the cyst), molecular testing (e.g., KRAS, GNAS, VHL, and CTNB1), and/or immunohistochemical tests are very important to obtain an accurate diagnosis. This review will discuss helpful ancillary tests in common pancreatic cyst neoplasms and how to approach the diagnosis of pancreatic cysts.


Asunto(s)
Carcinoma Ductal Pancreático/diagnóstico , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/métodos , Quiste Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Antígeno Carcinoembrionario/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Análisis Mutacional de ADN/métodos , Humanos , Inmunohistoquímica/métodos , Mutación , Quiste Pancreático/genética , Quiste Pancreático/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética
14.
Virchows Arch ; 476(1): 57-64, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31705190

RESUMEN

Recent advances in molecular techniques in soft tissue pathology, including the widespread application of next-generation sequencing, have led to significant progress in our understanding of mesenchymal tumors. Recognition of the genetic signatures of these neoplasms not only clarifies the relationship of these entities but also provides a mechanism for more accurate diagnosis. More importantly, insight into the genetic underpinnings of these lesions may offer therapeutic targets for cases not amenable to surgical treatment. This review highlights the clinicopathologic features and novel molecular findings in pericytic, myoid, and myofibroblastic tumors.


Asunto(s)
Fibroma/patología , Neoplasias de los Tejidos Conjuntivo y Blando/patología , Pericitos/patología , Fibroma/genética , Reordenamiento Génico , Humanos , Miofibroma/genética , Miofibroma/patología , Neoplasias de los Tejidos Conjuntivo y Blando/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Proteína con Dedos de Zinc GLI1/genética
15.
J Surg Res ; 246: 325-334, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-30737098

RESUMEN

BACKGROUND: Mutant KRAS tumors are purported to metastasize differently than wild-type KRAS tumors. The biological heterogeneity of tumors from different parts of the colon are also reported to affect metastasis. This study aims to characterize the metastatic profile by evaluating these factors in unison. METHODS: Retrospective analysis of 899 patients with metastatic colorectal cancers treated from January 2010 to December 2014 was conducted. KRAS mutation status and primary tumors location were correlated with single-site metastasis (liver, lung, and peritoneum) and dual-site metastases (liver-peritoneum, liver-lung, and lung-peritoneum). Patients without KRAS analyses were excluded. RESULTS: Right-sided tumors had highest frequency of peritoneal metastasis as compared to left-sided or rectal tumors (34.7% versus 15.8% versus 8.8%, P = 0.00) regardless of KRAS status (32.6% versus 38.5%, P = 0.62). Left-sided tumors with wild-type KRAS had greater proportion of liver metastasis (78.6% versus 53.5%, P = 0.00), whereas those with mutant KRAS had greater proportion of lung metastasis (23.3% versus 8.7%, P = 0.02). Rectal tumors with wild-type KRAS tend to spread to the liver (81.4% versus 48.0%, P = 0.00) and not to the peritoneum (2.3% versus 20.0%, P = 0.01). In dual-site metastases, left-sided tumors with wild-type KRAS had more liver-peritoneal metastases (75.0% versus 29.4%, P = 0.00), whereas mutant KRAS had greater lung-liver metastases (64.7% versus 20.8%, P = 0.01). Rectal tumors had the predilection for lung-liver metastases as compared to right-sided and left-sided tumors (92.3% versus 40.0% versus 39.0%, P = 0.00) regardless of KRAS status (100% versus 75%, P = 0.12). CONCLUSIONS: Our results may streamline surveillance programs based on primary tumor location and KRAS mutational status.


Asunto(s)
Neoplasias Colorrectales/patología , Neoplasias Hepáticas/epidemiología , Neoplasias Pulmonares/epidemiología , Neoplasias Peritoneales/epidemiología , Proteínas Proto-Oncogénicas p21(ras)/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Neoplasias Colorrectales/genética , Femenino , Humanos , Incidencia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/secundario , Estudios Retrospectivos , Adulto Joven
16.
Int J Cancer ; 146(1): 94-102, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31199501

RESUMEN

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year PFS than those with TP53/KRAS/NRAS wild-type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/genética , GTP Fosfohidrolasas/genética , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias del Recto/genética , Proteína p53 Supresora de Tumor/genética , Biomarcadores de Tumor/genética , Análisis Mutacional de ADN/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
17.
Eur J Med Chem ; 185: 111844, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31706640

RESUMEN

Lung cancer is one of the most malignant tumors with the highest morbidity and mortality. Most of them are non-small cell lung cancer (NSCLC). KRASG12C gene mutation is an important driving factor for NSCLC. However, the development of high-affinity inhibitors targeting KRASG12C mutants remains a daunting challenge. Here, we report the design and development of a series of hydrocarbon-stapled peptides containing d-amino acids to mimic the alpha helix of SOS1. D-hydrocarbon-stapled peptides maintain good alpha helix structure and bind to KRASG12C with high affinity. Subsequent anti-proliferation experiments indicated that D-hydrocarbon-stapled peptide 5 inhibited the proliferation of NSCLC H358 cells carrying KRASG12C. However, it showed no significant anti-proliferative effect on KRASG12S-positive A549 cells, suggesting that peptide 5 selectively inhibits KRASG12C-driven tumor cells. D-hydrocarbon-stapled peptide 5 could also cause the cell cycle of H358 cells to arrest in the G2/M phase and induce apoptosis. No significant cell arrest and apoptosis were observed in A549 cells treated by peptide 5. In summary, the introduction of d-amino acids could improve the affinity and cell selectivity of hydrocarbon peptides. We hope that peptides containing D-form amino acids can provide strategies for further optimization of the KRASG12C/SOS1 inhibitor.


Asunto(s)
Aminoácidos/farmacología , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Péptidos/farmacología , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteína SOS1/antagonistas & inhibidores , Células A549 , Aminoácidos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Estructura Molecular , Péptidos/síntesis química , Péptidos/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteína SOS1/metabolismo , Relación Estructura-Actividad
18.
Anal Chim Acta ; 1094: 1-10, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31761034

RESUMEN

Detection of circulating tumor DNA (ctDNA) presents several challenges due to single-nucleotide polymorphisms and large amounts of background DNA. Previously, we reported a sequence-specific DNA extraction procedure utilizing functionalized oligonucleotides called ion-tagged oligonucleotides (ITOs) and disubstituted ion-tagged oligonucleotides (DTOs). ITOs and DTOs are capable of hybridizing to complementary DNA for subsequent capture by a magnetic ionic liquid (MIL) through hydrophobic interactions, π-π stacking, and fluorophilic interactions. However, the performance of the ITOs and DTOs in complex sample matrices has not yet been evaluated. In this study, we compare the amount of KRAS DNA extracted using ITO and DTOs from saline, 2-fold diluted plasma, 10-fold diluted plasma, and 10-fold diluted blood. We demonstrate that ITO/DTO-MIL extraction is capable of selectively preconcentrating DNA from diluted plasma and blood without additional sample preparation steps. In comparison, streptavidin-coated magnetic beads were unable to selectively extract DNA from 10-fold diluted plasma and 10-fold diluted blood without additional sample clean-up steps. Significantly more DNA could be extracted from 2-fold diluted plasma and 10-fold diluted blood matrices using the DTO probes compared to the ITO probes, likely due to stronger interactions between the probe and MIL. The ability of the DTO-MIL method to selectively preconcentrate small concentrations of DNA from complex biological matrices suggests that this method could be beneficial for ctDNA analysis.


Asunto(s)
Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , Líquidos Iónicos/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/aislamiento & purificación , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/aislamiento & purificación , Humanos , Extracción Líquido-Líquido , Fenómenos Magnéticos , Hibridación de Ácido Nucleico , Sondas de Oligonucleótidos/química , Sondas de Oligonucleótidos/genética , Polimorfismo de Nucleótido Simple
19.
J Clin Pathol ; 73(1): 35-41, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31296605

RESUMEN

AIMS: Precision medicine therapy is remodelling the diagnostic landscape of cancer. The success of these new therapies is often based on the presence or absence of a specific mutation in a tumour. The Idylla platform is designed to determine the mutational status of a tumour as quickly and accurately as possible, as a rapid, accurate diagnosis is of the utmost importance for the treatment of patients. This is the first complete prospective study to investigate the robustness of the Idylla platform for EGFR, KRAS and BRAF mutations in non-small cell lung cancer, metastatic colorectal cancer and metastatic melanoma, respectively. METHODS: We compared prospectively the Idylla platform with the results we obtained from parallel high-throughput next-generation sequencing, which is the current gold standard for mutational testing. Furthermore, we evaluated the benefits and disadvantages of the Idylla platform in clinical practice. Additionally, we reviewed all the published Idylla performance articles. RESULTS: There was an overall agreement of 100%, 94% and 94% between the next-generation panel and the Idylla BRAF, KRAS and EGFR mutation test. Two interesting discordant findings among 48 cases were observed and will be discussed together with the advantages and shortcoming of both techniques. CONCLUSION: Our observations demonstrate that the Idylla cartridge for the EGFR, KRAS and BRAF mutations is highly accurate, rapid and has a limited hands-on time compared with next-generation sequencing.


Asunto(s)
Biomarcadores de Tumor/genética , Análisis Mutacional de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Neoplasias/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Melanoma/genética , Melanoma/secundario , Neoplasias/patología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Reproducibilidad de los Resultados , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Flujo de Trabajo
20.
Int J Cancer ; 146(2): 566-576, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31199507

RESUMEN

We investigated the impact of time interval, primary vs. metastatic biopsy site, variant allele fraction (VAF) and histology on concordance of KRAS alterations in tissue vs. circulating tumor DNA (ctDNA), and association of concordance with survival. Blood and tissue were evaluated by next-generation sequencing in 433 patients with diverse cancers. Altogether, 101 patients (23.3%) had KRAS alterations: 56, ctDNA (12.9%); 81, tissue (18.7%); and 36, both (8.3%). The overall blood and tissue concordance rate for KRAS alterations was 85%, but was mainly driven by the large negative/negative subset. Therefore, specificity of one test for the other was high (88.1-94.3%), while sensitivity was not high (44.4-64.3%) and was lower still in patients with >6 vs. ≤2 months between blood and tissue sampling (31.0-40.9% vs. 51.2-84.0%; p = 0.14 time interval-dependent sensitivity of blood for tissue; p = 0.003, tissue for blood). Positive concordance rate for KRAS alterations was 57.1% vs. 27.4% (colorectal vs. noncolorectal cancer; p = 0.01), but site of biopsy (primary vs. metastatic) and VAF (%ctDNA) was not impactful. The presence of KRAS alterations in both tests was independently associated with shorter survival from diagnosis (hazard ratio, 1.72; 95% confidence interval, 1.04-2.86) and from recurrent/metastatic disease (1.70; 1.03-2.81). Positive concordance of KRAS alterations between ctDNA and tissue was negatively affected by a longer time period between blood and tissue sampling and was higher in colorectal cancer than in other malignancies. The presence of KRAS alterations in both tests was an independent prognostic factor for poor survival.


Asunto(s)
ADN Tumoral Circulante/sangre , Neoplasias/mortalidad , Proteínas Proto-Oncogénicas p21(ras)/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Biopsia , Niño , Preescolar , ADN Tumoral Circulante/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neoplasias/sangre , Neoplasias/patología , Pronóstico , Análisis Espacio-Temporal , Análisis de Supervivencia , Factores de Tiempo , Adulto Joven
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