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1.
Int J Mol Sci ; 24(3)2023 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-36768460

RESUMEN

Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li-Fraumeni syndrome (TP53 gene), MUTYH-associated polyposis (MUTYH gene), Peutz-Jeghers syndrome (STK11 gene), Cowden syndrome (PTEN gene), and juvenile polyposis syndrome (BMPR1A and SMAD4 genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1. In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.


Asunto(s)
Poliposis Adenomatosa del Colon , Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Síndromes Neoplásicos Hereditarios , Humanos , Predisposición Genética a la Enfermedad , Poliposis Adenomatosa del Colon/genética , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Pruebas Genéticas , Neoplasias Colorrectales/genética
2.
Int J Mol Sci ; 24(18)2023 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-37762586

RESUMEN

Gastrointestinal cancers (GC) account for 26% of all cancer incidences and 35% of all cancer-related deaths [...].


Asunto(s)
Neoplasias Gastrointestinales , Medicina de Precisión , Humanos , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/terapia
3.
Int J Mol Sci ; 24(22)2023 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-38003273

RESUMEN

Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide. Tissue biopsy is the current gold standard for the diagnosis and molecular profiling of NSCLC. However, this approach presents some limitations due to inadequate tissue sampling, and intra- and intertumour heterogenicity. Liquid biopsy is a noninvasive method to determine cancer-related biomarkers in peripheral blood, and can be repeated at multiple timepoints. One of the most studied approaches to liquid biopsies is represented by circulating tumour cells (CTCs). Several studies have evaluated the prognostic and predictive role of CTCs in advanced NSCLC. Despite the limitations of these studies, the results of the majority of studies seem to be concordant regarding the correlation between high CTC count and poor prognosis in patients with NSCLC. Similarly, the decrease of CTC count during treatment may represent an important predictive marker of sensitivity to therapy in advanced NSCLC. Furthermore, molecular characterization of CTCs can be used to provide information on tumour biology, and on the mechanisms involved in resistance to targeted treatment. This review will discuss the current status of the clinical utility of CTCs in patients with advanced NSCLC, highlighting their potential application to prognosis and to treatment decision making.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Células Neoplásicas Circulantes/patología , Biomarcadores de Tumor/análisis , Biopsia
4.
Int J Mol Sci ; 24(15)2023 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-37569810

RESUMEN

Up to 80% of castration-resistant prostate cancer (CRPC) patients develop bone metastases during the natural history of disease and about 25% harbor mutations in DNA damage repair (DDR) genes. This retrospective observational study evaluated the prevalence of DDR alterations in CRPC patients and their effect on the clinical outcomes associated with bone metastases. The mutational status of CRPC patients was analyzed per FoundationOne® analysis in tissue biopsy or, when it was not possible, in liquid biopsy performed at the onset of metastatic CRPC (mCRPC). The impact of DDR gene mutations on bone-related efficacy endpoints was evaluated at the time of mCRPC diagnoses. In total, 121 mCRPC patients with bone metastases were included: 38 patients had mutations in at least one DDR gene, the remaining 83 ones had a non-mutated DDR status. DDR mutated status was associated with bone metastases volume (p = 0.006), but did not affect SRE (skeletal-related events) incidence and time to SRE onset. Liquid and tissue biopsies were both available for 61 patients with no statistically significant difference in terms of incidence and type of molecular DDR alterations. Mutated DDR status was associated with higher bone metastasic volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed.


Asunto(s)
Neoplasias Óseas , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias Óseas/genética , Neoplasias Óseas/secundario , Mutación , Huesos/patología , Reparación del ADN/genética
5.
BMC Med ; 20(1): 48, 2022 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-35101049

RESUMEN

BACKGROUND: Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel. In this prospective study, we evaluated the prognostic role of CTC gene expression on cabazitaxel-treated patients and its association with plasma androgen receptor (AR) copy number (CN). METHODS: Patients receiving cabazitaxel 20 or 25 mg/sqm for mCRPC were enrolled. Digital PCR was performed to assess plasma AR CN status. CTC enrichment was assessed using the AdnaTest EMT-2/StemCell kit. CTC expression analyses were performed for 17 genes. Data are expressed as hazard ratio (HR) or odds ratio (OR) and 95% CI. RESULTS: Seventy-four patients were fully evaluable. CTC expression of AR-V7 (HR=2.52, 1.24-5.12, p=0.011), AKR1C3 (HR=2.01, 1.06-3.81, p=0.031), AR (HR=2.70, 1.46-5.01, p=0.002), EPCAM (HR=3.75, 2.10-6.71, p< 0.0001), PSMA (HR=2.09, 1.19-3.66, p=0.01), MDK (HR=3.35, 1.83-6.13, p< 0.0001), and HPRT1 (HR=2.46, 1.44-4.18, p=0.0009) was significantly associated with OS. ALDH1 (OR=5.50, 0.97-31.22, p=0.05), AR (OR=8.71, 2.32-32.25, p=0.001), EPCAM (OR=7.26, 1.47-35.73, p=0.015), PSMA (OR=3.86, 1.10-13.50, p=0.035), MDK (OR=6.84, 1.87-24.98, p=0.004), and HPRT1 (OR=7.41, 1.82-30.19, p=0.005) expression was associated with early PD. AR CN status was significantly correlated with AR-V7 (p=0.05), EPCAM (p=0.02), and MDK (p=0.002) expression. In multivariable model, EPCAM and HPRT1 CTC expression, plasma AR CN gain, ECOG PS=2, and liver metastases and PSA were independently associated with poorer OS. In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR-V7 positive than negative patients (6.6 versus 14 months, HR=3.46, 1.47-8.17], p=0.004). CONCLUSIONS: Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis. TRIAL REGISTRATION: Clinicaltrials.gov NCT03381326 . Retrospectively registered on 18 December 2017.


Asunto(s)
Células Neoplásicas Circulantes , Neoplasias de la Próstata Resistentes a la Castración , Biomarcadores de Tumor/metabolismo , Dosificación de Gen , Expresión Génica , Humanos , Masculino , Células Neoplásicas Circulantes/patología , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Taxoides , Resultado del Tratamiento
6.
Int J Mol Sci ; 23(22)2022 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-36430675

RESUMEN

Identifying novel circulating biomarkers predictive of response and informative about the mechanisms of resistance, is the new challenge for breast cancer (BC) management. The integration of omics information will gradually revolutionize the clinical approach. Liquid biopsy is being incorporated into the diagnostic and decision-making process for the treatment of BC, in particular with the analysis of circulating tumor DNA, although with some relevant limitations, including costs. Circulating cell-free DNA (cfDNA) fragmentomics and its integrity index may become a cheaper, noninvasive biomarker that could provide significant additional information for monitoring response to systemic treatments in BC. The purpose of our review is to focus on the available research on cfDNA integrity and its features as a biomarker of diagnosis, prognosis and response to treatments in BC, highlighting new perspectives and critical issues for future applications.


Asunto(s)
Neoplasias de la Mama , Ácidos Nucleicos Libres de Células , ADN Tumoral Circulante , Humanos , Femenino , Ácidos Nucleicos Libres de Células/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Biomarcadores de Tumor/genética , Biopsia Líquida
7.
Int J Mol Sci ; 23(24)2022 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-36555431

RESUMEN

BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations in genes other than BRCA1/2 that could be associated with a high risk of developing OC and permit patients to enter the most appropriate treatment and surveillance program. Next-generation sequencing analysis with a 94-gene panel was performed on germline DNA of 219 OC patients. We identified 34 pathogenic/likely pathogenic variants in BRCA1/2 and 38 in other 21 genes. The patients with pathogenic/likely pathogenic variants in the non-BRCA1/2 genes mainly developed OC alone compared to the other groups that also developed breast cancer or other tumors (p = 0.001). Clinical correlation analysis showed that the low-risk patients were significantly associated with platinum sensitivity (p < 0.001). Regarding PARP inhibitors (PARPi) response, the patients with pathogenic mutations in the non-BRCA1/2 genes had worse PFS and OS. Moreover, a statistically significantly worse PFS was found for every increase of one thousand platelets before PARPi treatment. To conclude, knowledge about molecular alterations in genes beyond BRCA1/2 in OC could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies for OC patients.


Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Humanos , Femenino , Predisposición Genética a la Enfermedad , Proteína BRCA1/genética , Mutación , Neoplasias Ováricas/tratamiento farmacológico , Genes BRCA2 , Mutación de Línea Germinal , Neoplasias de la Mama/genética , Secuenciación de Nucleótidos de Alto Rendimiento
8.
HPB (Oxford) ; 24(2): 244-254, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34366240

RESUMEN

BACKGROUND: Loco-regional treatments have improved the survival of patients with early hepatocellular carcinoma (HCC), but tumor relapse is a frequent event and survival rates remain low. Moreover, conflicting evidences address early HCC patients to surgery or radiofrequency ablation (RFA), with the clinical need to find predictive non-invasive biomarkers able to guide treatment choice and define patients survival. METHODS: Two independent case series of treatment-naïve HCC patients treated with local RFA, and a cohort of 30 HCC patients treated with liver surgery were enrolled. On the basis of literature evidence, we customized a panel of 21 miRNAs correlated with relapse and prognosis after local curative treatment of HCC. RESULTS: Expression levels of let-7c predict tumor relapse after RFA; we also investigated the same panel in a small cohort of HCC patients undergoing surgery, finding no statistically significance in predicting tumor relapse or survival. Moreover, interaction test indicated that let-7c expression levels are predictive for identifying a subset of patients that should be addressed to surgery. CONCLUSION: Results from this study could predict prognosis of early HCC patients, helping to address early HCC patients to surgery or RFA treatment.


Asunto(s)
Carcinoma Hepatocelular , Ablación por Catéter , MicroARN Circulante , Neoplasias Hepáticas , MicroARNs , Ablación por Radiofrecuencia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirugía , Ablación por Catéter/efectos adversos , Ablación por Catéter/métodos , MicroARN Circulante/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , MicroARNs/genética , Recurrencia Local de Neoplasia/patología , Ablación por Radiofrecuencia/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento
9.
Gastric Cancer ; 24(2): 392-401, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33156452

RESUMEN

BACKGROUND: Early Gastric Cancer (EGC) reaches 25% of the gastric cancers surgically treated in some areas of Northeastern Italy and is usually characterized by a good prognosis. However, among EGCs classified according to Kodama's criteria, Pen A subgroup is characterized by extensive submucosal invasion, lymph node metastases and worse prognosis, whereas Pen B subgroup by better prognosis. The aim of the study was to characterize the differences between Pen A, Pen B and locally advanced gastric cancer (T3N0) in order to identify biomarkers involved in aggressiveness and clinical outcome. METHODS: We selected 33 Pen A, 34 Pen B and 20 T3N0 tumors and performed immunohistochemistry of mucins, copy number variation analysis of a gene panel, microsatellite instability (MSI), TP53 mutation and loss of heterozygosity (LOH) analyses. RESULTS: Pen A subgroup was characterized by MUC6 overexpression (p = 0.021). Otherwise, the Pen B subgroup was significantly associated with the amplification of GATA6 gene (p = 0.002). The higher percentage of MSI tumors was observed in T3N0 group (p = 0.002), but no significant differences between EGC types were found. Finally, TP53 gene analysis showed that 32.8% of Pen tumors have a mutation in exons 5-8 and 50.0% presented LOH. Co-occurrence of TP53 mutation and LOH mainly characterized Pen A tumors (p = 0.022). CONCLUSIONS: Our analyses revealed that clinico-pathological parameters, microsatellite status and frequency of TP53 mutations do not seem to distinguish Pen subgroups. Conversely, the amplification of GATA6 was associated with Pen B, as well as the overexpression of MUC6 and the TP53mut/LOH significantly characterized Pen A.


Asunto(s)
Detección Precoz del Cáncer/métodos , Mucinas Gástricas/genética , Invasividad Neoplásica/genética , Neoplasias Gástricas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Humanos , Inmunohistoquímica , Italia , Pérdida de Heterocigocidad , Metástasis Linfática/genética , Masculino , Inestabilidad de Microsatélites , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Mutación , Pronóstico , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/genética
10.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-34207126

RESUMEN

Although immune checkpoint inhibitors have changed the treatment paradigm of a variety of cancers, including non-small-cell lung cancer, not all patients respond to immunotherapy in the same way. Predictive biomarkers for patient selection are thus needed. Tumor mutation burden (TMB), defined as the total number of somatic/acquired mutations per coding area of a tumor genome (Mut/Mb), has emerged as a potential predictive biomarker of response to immune checkpoint inhibitors. We found that the limited use of TMB in clinical practice is due to the difficulty in its detection and compounded by several different biological, methodological and economic issues. The incorporation of both TMB and PD-L1 expression or other biomarkers into multivariable predictive models could result in greater predictive power.


Asunto(s)
Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/genética , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Mutación , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Estudios de Asociación Genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Terapia Molecular Dirigida , Evaluación del Resultado de la Atención al Paciente
11.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-34299099

RESUMEN

The present editorial aims to summarise the six scientific papers that have contributed to this Special Issue, focusing on different aspects of molecular and translational research on colorectal cancer. We believe that the present Special Issue might contribute to the expansion of the current knowledge concerning potential molecular predictive and/or prognostic biomarkers in CRC, as well as new targets for anticancer treatment. This may help in identifying new strategies to improve diagnostic and therapeutic approaches.


Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/terapia , Investigación Biomédica Traslacional , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Humanos
12.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-34360649

RESUMEN

Breast cancer is the most frequent and lethal tumor in women and finding the best therapeutic strategy for each patient is an important challenge. PARP inhibitors (PARPis) are the first, clinically approved drugs designed to exploit synthetic lethality in tumors harboring BRCA1/2 mutations. Recent evidence indicates that PARPis have the potential to be used both in monotherapy and combination strategies in breast cancer treatment. In this review, we show the mechanism of action of PARPis and discuss the latest clinical applications in different breast cancer treatment settings, including the use as neoadjuvant and adjuvant approaches. Furthermore, as a class, PARPis show many similarities but also certain critical differences which can have essential clinical implications. Finally, we report the current knowledge about the resistance mechanisms to PARPis. A systematic PubMed search, using the entry terms "PARP inhibitors" and "breast cancer", was performed to identify all published clinical trials (Phase I-II-III) and ongoing trials (ClinicalTrials.gov), that have been reported and discussed in this review.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Terapia Neoadyuvante/métodos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Animales , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Femenino , Humanos
14.
Int J Mol Sci ; 21(15)2020 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-32752096

RESUMEN

Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.


Asunto(s)
Metilación de ADN/genética , Epigénesis Genética/genética , Neoplasias Gástricas/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estómago/patología , Neoplasias Gástricas/patología
15.
Int J Mol Sci ; 21(10)2020 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-32429465

RESUMEN

Very few data are reported in the literature on the association between elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and prognosis in advanced colorectal cancer. Moreover, there is no information available in relation to the response to antiangiogenic treatment. We analyzed EMAST and vascular endothelial growth factor-B (VEGF-B) microsatellite status, together with standard microsatellite instability (MSI), in relation to prognosis in 141 patients with metastatic colorectal cancer (mCRC) treated with chemotherapy (CT) alone (n = 51) or chemotherapy with bevacizumab (B) (CT + B; n = 90). High MSI (MSI-H) was detected in 3% of patients and was associated with progression-free survival (PFS; p = 0.005) and overall survival (OS; p < 0.0001). A total of 8% of cases showed EMAST instability, which was associated with worse PFS (p = 0.0006) and OS (p < 0.0001) in patients treated with CT + B. A total of 24.2% of patients showed VEGF-B instability associated with poorer outcome in (p = 0.005) in the CT arm. In conclusion, our analysis indicated that EMAST instability is associated with worse prognosis, particularly evident in patients receiving CT + B.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/secundario , Inestabilidad de Microsatélites , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Humanos , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Resultado del Tratamiento , Factor B de Crecimiento Endotelial Vascular/genética
16.
Int J Colorectal Dis ; 34(11): 1999-2002, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31655866

RESUMEN

BACKGROUND: Lynch syndrome (LS) is associated with germline mutations in one of the mismatch repair genes or EPCAM. The majority of the causative alterations are point mutations. Large genomic rearrangements represent only 5-20%. Hypothetically, the allelic imbalance, like the loss of heterozygosity, may be another high penetrance risk factor. CASE PRESENTATION: We describe the case of a patient who developed 5 tumors during her lifetime and with a family history characterized by a high frequency of tumors associated with LS. The proband was tested for mutations and copy number alterations with a panel of hereditary cancer genes and by SNP array. She showed a 187 Kb duplication including EPCAM and the first 7 exons of MSH2, plus two loss of heterozygosity (LOHs) in chromosome 20 and one in chromosome X which include many tumor suppressor genes. CONCLUSION: We found a novel large EPCAM-MSH2 duplication associated with LS and the presence of LOHs in regions containing numerous tumor suppressors, raising the hypothesis that these alterations could contribute to cancer susceptibility. Our results underline the importance to deepen the knowledge of molecular mechanisms in order to determine the role in cancer predisposition of novel genetic alterations.


Asunto(s)
Cromosomas Humanos Par 20/genética , Cromosomas Humanos X/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Molécula de Adhesión Celular Epitelial/genética , Duplicación de Gen , Pérdida de Heterocigocidad/genética , Proteína 2 Homóloga a MutS/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje
17.
Int J Mol Sci ; 20(12)2019 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-31242580

RESUMEN

The present editorial aims to summarize the 17 scientific papers that have contributed to this Special Issue focusing on different aspects of basic and translational research in colorectal cancer.


Asunto(s)
Biomarcadores de Tumor , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/terapia , Investigación , Investigación Biomédica Traslacional , Neoplasias Colorrectales/metabolismo , Humanos
18.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-31509966

RESUMEN

CDH1 gene, encoding E-cadherin, is a tumor suppressor gene frequently altered in gastric cancers (GCs) of both diffuse (DGC) and intestinal (IGC) histotypes, albeit through different mechanisms. The study aimed to characterize CDH1 expression in sporadic IGC and to investigate whether microRNAs (miRs) are involved in its transcriptional control. We evaluated CDH1 expression by quantitative real-time PCR (RT-qPCR) in 33 IGC patients and found a significant downregulation in tumor tissues compared to normal counterparts (p-value = 0.025). Moreover, 14 miRs, predicted to be involved in CDH1 regulation in both a direct and indirect manner, were selected and analyzed by RT-qPCR in an independent case series of 17 IGCs and matched normal tissues. miR-101, miR-26b, and miR-200c emerged as significantly downregulated and were confirmed in the case series of 33 patients (p-value < 0.001). Finally, we evaluated EZH2 expression, a target of both miR-101 and miR-26b, which showed significant upregulation in IGCs (p-value = 0.005). A significant inverse correlation was observed between EZH2 overexpression and CDH1, miR-101, and miR-26b levels (p-value < 0.001). Our results reinforce the link between CDH1 and IGC, highlighting the role of miRs in its transcriptional control and improving our understanding of GC subtypes and biomarkers.


Asunto(s)
Cadherinas/genética , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias Gástricas/genética , Anciano , Cadherinas/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología
19.
Int J Mol Sci ; 19(12)2018 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-30477151

RESUMEN

High inter-patient variability and high spatial heterogeneity are features of colorectal cancer (CRC). This may influence the molecular characterization of tumor tissue, now mandatory for patients with metastatic CRC who are candidates for treatment with an anti-EGFR mAb, as false-negative results can occur, leading to non optimal therapy. Moreover, temporal molecular heterogeneity during treatment is known to influence the response to therapy and prognosis. We present a literature overview of advances made in characterizing molecular heterogeneity in CRC, underlining that the analysis of liquid biopsy could represent an efficient non-invasive tool to overcome the problem. We believe that understanding CRC heterogeneity is fundamental for a more accurate diagnosis, for selecting the best targets to ensure prolonged antitumor response, and for monitoring minimal residual disease and the onset of resistance to therapy, all essential components of successful personalized treatment.


Asunto(s)
Variación Biológica Individual , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/patología , Biomarcadores de Tumor , Heterogeneidad Genética , Humanos , Biopsia Líquida , Técnicas de Diagnóstico Molecular , Metástasis de la Neoplasia , Estadificación de Neoplasias , Medicina de Precisión
20.
Int J Mol Sci ; 19(1)2018 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-29361687

RESUMEN

Targeting angiogenesis in the treatment of colorectal cancer (CRC) is a common strategy, for which potential predictive biomarkers have been studied. miRNAs are small non-coding RNAs involved in several processes including the angiogenic pathway. They are very stable in biological fluids, which turns them into potential circulating biomarkers. In this study, we considered a case series of patients with metastatic (m) CRC treated with a bevacizumab (B)-based treatment, enrolled in the prospective multicentric Italian Trial in Advanced Colorectal Cancer (ITACa). We then analyzed a panel of circulating miRNAs in relation to the patient outcome. In multivariate analysis, circulating basal levels of hsa-miR-20b-5p, hsa-miR-29b-3p and hsa-miR-155-5p resulted in being significantly associated with progression-free survival (PFS) (p = 0.027, p = 0.034 and p = 0.039, respectively) and overall survival (OS) (p = 0.044, p = 0.024 and p = 0.032, respectively). We also observed that an increase in hsa-miR-155-5p at the first clinical evaluation was significantly associated with shorter PFS (HR 3.03 (95% CI 1.06-9.09), p = 0.040) and OS (HR 3.45 (95% CI 1.18-10.00), p = 0.024), with PFS and OS of 9.5 (95% CI 6.8-18.7) and 15.9 (95% CI 8.4-not reached), respectively, in patients with an increase ≥30% of hsa-miR-155-5p and 22.3 (95% CI 10.2-25.5) and 42.9 (24.8-not reached) months, respectively, in patients without such increase. In conclusion, our results highlight the potential usefulness of circulating basal levels of hsa-miR-20b-5p, hsa-miR-29b-3p and hsa-miR-155-5p in predicting the outcome of patients with mCRC treated with B. In addition, the variation of circulating hsa-miR-155-5p could also be indicative of the patient survival.


Asunto(s)
Biomarcadores de Tumor , MicroARN Circulante , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , MicroARNs/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/tratamiento farmacológico , Terapia Combinada , Femenino , Regulación Neoplásica de la Expresión Génica , Genes ras , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento
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