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1.
J Transl Med ; 22(1): 337, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38589873

RESUMEN

BACKGROUND: The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to shed light on the gene regulatory networks linked to PrPC. METHODS: We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients. RESULTS: In silico analyses combined with cell-based assays identified the Wnt-ß-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, ß-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence. CONCLUSIONS: An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Ratones , Animales , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , beta Catenina/metabolismo , Glucocorticoides , Neoplasias del Colon/genética , Neoplasias Colorrectales/genética , Fenotipo , Pronóstico , Vía de Señalización Wnt , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral
2.
BMC Cancer ; 19(1): 232, 2019 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-30871494

RESUMEN

BACKGROUND: Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by a broad range of neoplasms to maintain telomere length, permitting uncontrolled replication during their progression. ALT has been described in different types of sarcoma, but a comprehensive analysis of its clinical significance is still lacking. Therefore, we provide here the first meta-analysis on this topic. METHODS: We searched SCOPUS and PubMed through July 2018 to identify all studies that investigated the prognostic role of ALT in sarcomas. We considered the risk of death (risk ratio, RR) calculated as the number of death vs. total participants during follow-up in ALT+ versus ALT- patients as the primary outcome. The secondary outcome was the hazard ratio (HR), adjusted for the maximum number of covariates available, using ALT- patients as reference. RESULTS: Eight articles comprising a total of 551 patients with sarcomas (226 ALT+ and 325 ALT-) were selected. The ALT+ group showed a higher mitotic count and a higher tumor grade compared with the ALT- group (p < 0.01). Furthermore, we demonstrate a strong impact of ALT on survival. In fact, ALT+ patients showed a statistically significant higher risk of death than ALT- patients, when also considering data from multivariate analyses (RR = 1.50; 95% CI: 1.15-1.96; p = 0.003; HR = 2.02; 95% CI: 1.22-3.38; p = 0.007). CONCLUSIONS: Our results indicate that ALT is associated with an increased risk of death in patients with sarcoma. In these neoplasms, ALT should be taken into account for a precise prognostic stratification and design of potential therapeutic strategies.


Asunto(s)
Sarcoma/patología , Homeostasis del Telómero , Telómero/metabolismo , Humanos , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Medición de Riesgo , Sarcoma/metabolismo , Sarcoma/mortalidad , Análisis de Supervivencia
3.
Gastroenterology ; 152(4): 880-894.e6, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27939373

RESUMEN

BACKGROUND & AIMS: Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in ß-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications. METHODS: We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation. RESULTS: Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with ß-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively. CONCLUSIONS: Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.


Asunto(s)
Adenoma/genética , Carcinoma Hepatocelular/genética , Subunidades beta de Inhibinas/genética , Neoplasias Hepáticas/genética , Proteína con Dedos de Zinc GLI1/genética , Adenoma/química , Adenoma/clasificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/patología , Transformación Celular Neoplásica/genética , Niño , Cromograninas/genética , Receptor gp130 de Citocinas/genética , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Fusión Génica , Proteínas Hedgehog/metabolismo , Hemorragia/etiología , Factor Nuclear 1-alfa del Hepatocito/genética , Humanos , Janus Quinasa 2/genética , Neoplasias Hepáticas/química , Neoplasias Hepáticas/clasificación , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/genética , Proteínas Tirosina Quinasas/genética , Factores de Riesgo , Factor de Transcripción STAT3/genética , Análisis de Secuencia de ARN , Transducción de Señal , Telomerasa/genética , Transcriptoma , Adulto Joven , beta Catenina/genética
4.
J Pathol ; 242(1): 10-15, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28127763

RESUMEN

Germline alterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair (BER) defects remain to be characterized. Here, by analysing a series of colorectal cancers (CRCs) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts in three tumours from a MUTYH-associated polyposis (MAP) patient and in two cases harbouring pathogenic germline MUTYH mutations. In two series of adrenocortical carcinomas (ACCs), we identified four tumours with a similar signature also presenting germline MUTYH mutations. Taken together, these findings demonstrate that MUTYH inactivation results in a particular mutational signature, which may serve as a useful marker of BER-related genomic instability in new cancer types. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Neoplasias Colorrectales/genética , ADN Glicosilasas/genética , Mutación , Animales , ADN Glicosilasas/deficiencia , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Ratones Noqueados , Transcriptoma/genética
5.
Hepatology ; 64(6): 2047-2061, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27177928

RESUMEN

CTNNB1 mutations activating ß-catenin are frequent somatic events in hepatocellular carcinoma (HCC) and adenoma (HCA), particularly associated with a risk of malignant transformation. We aimed to understand the relationship between CTNNB1 mutation types, tumor phenotype, and level of ß-catenin activation in malignant transformation. To this purpose, CTNNB1 mutation spectrum was analyzed in 220 HCAs, 373 HCCs, and 17 borderline HCA/HCC lesions. ß-catenin activation level was assessed in tumors by quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry (IHC), in cellulo by TOP-Flash assay. Overall, ß-catenin activity was higher in malignant mutated tumors, compared to adenomas, and this was related to a different spectrum of CTNNB1 mutations in HCCs and HCAs. In benign tumors, we defined three levels of ß-catenin activation related to specific mutations: (1) S45, K335, and N387 mutations led to weak activation; (2) T41 mutations were related to moderate activity; and (3) highly active mutations included exon 3 deletions and amino acid substitutions within the ß-TRCP binding site (D32-S37). Accordingly, in vitro, K335I and N387K mutants showed a lower activity than S33C. Tumors with highly active mutations demonstrated strong/homogeneous glutamine synthase (GS) staining and were associated with malignancy. In contrast, weak mutants demonstrated heterogeneous pattern of GS staining and were more frequent in HCAs except for the S45 mutants identified similarly in 20% of mutated HCAs and HCCs; however, in most of the HCCs, the weak S45 mutant alleles were duplicated, resulting in a final high ß-catenin activity. CONCLUSION: High ß-catenin activity driven by specific CTNNB1 mutations and S45 allele duplication is associated with malignant transformation. Consequently, HCAs with S45 and all high/moderate mutants should be identified with precise IHC criteria or mutation screening. (Hepatology 2016;64:2047-2061).


Asunto(s)
Adenoma de Células Hepáticas/genética , Carcinoma Hepatocelular/genética , Estudios de Asociación Genética , Neoplasias Hepáticas/genética , Mutación , beta Catenina/genética , Progresión de la Enfermedad , Humanos , Células Tumorales Cultivadas , beta Catenina/fisiología
6.
Nature ; 457(7226): 200-4, 2009 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-19020503

RESUMEN

Inflammatory hepatocellular adenomas are benign liver tumours defined by the presence of inflammatory infiltrates and by the increased expression of inflammatory proteins in tumour hepatocytes. Here we show a marked activation of the interleukin (IL)-6 signalling pathway in this tumour type; sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene, which encodes the signalling co-receptor gp130. Indeed, 60% of inflammatory hepatocellular adenomas harbour small in-frame deletions that target the binding site of gp130 for IL-6, and expression of four different gp130 mutants in hepatocellular cells activates signal transducer and activator of transcription 3 (STAT3) in the absence of ligand. Furthermore, analysis of hepatocellular carcinomas revealed that rare gp130 alterations are always accompanied by beta-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas fully explains activation of the acute inflammatory phase observed in tumourous hepatocytes, and suggests that similar alterations may occur in other inflammatory epithelial tumours with STAT3 activation.


Asunto(s)
Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patología , Receptor gp130 de Citocinas/genética , Receptor gp130 de Citocinas/metabolismo , Eliminación de Secuencia/genética , Línea Celular Tumoral , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inflamación/genética , Inflamación/patología , Interferones/metabolismo , Interleucina-6/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal
7.
Haematologica ; 98(11): 1748-52, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23872306

RESUMEN

STAT3 protein phosphorylation is a frequent event in various hematologic malignancies and solid tumors. Acquired STAT3 mutations have been recently identified in 40% of patients with T-cell large granular lymphocytic leukemia, a rare T-cell disorder. In this study, we investigated the mutational status of STAT3 in a large series of patients with lymphoid and myeloid diseases. STAT3 mutations were identified in 1.6% (4 of 258) of patients with T-cell neoplasms, in 2.5% (2 of 79) of patients with diffuse large B-cell lymphoma but in no other B-cell lymphoma patients (0 of 104) or patients with myeloid malignancies (0 of 96). Functional in vitro assays indicated that the STAT3Y640F mutation leads to a constitutive phosphorylation of the protein. STA21, a STAT3 small molecule inhibitor, inhibited the proliferation of two distinct STAT3 mutated cell lines. Using a mouse bone marrow transplantation assay, we observed that STAT3Y640F expression leads to the development of myeloproliferative neoplasms with expansion of either myeloid cells or megakaryocytes. Together, these data indicate that the STAT3Y640F mutation leads to constitutive activation of STAT3, induces malignant hematopoiesis in vivo, and may represent a novel therapeutic target in some lymphoid malignancies.


Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Modelos Animales de Enfermedad , Neoplasias Hematológicas/genética , Mutación/genética , Trastornos Mieloproliferativos/genética , Factor de Transcripción STAT3/genética , Animales , Neoplasias Hematológicas/diagnóstico , Humanos , Células K562 , Ratones , Ratones Endogámicos C57BL , Trastornos Mieloproliferativos/diagnóstico
8.
J Hepatol ; 56(1): 184-91, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21835143

RESUMEN

BACKGROUND & AIMS: Mosaic G-protein alpha-subunit (GNAS)-activating mutations are responsible for the McCune-Albright (MCA) syndrome. This oncogene that activates the adenylate cyclase is also mutated in various tumor types leading to the accumulation of cyclic-AMP. Identification of a hepatocellular adenoma (HCA) in two MCA patients led us to search for GNAS activation in benign and malignant hepatocellular carcinogenesis. METHODS: GNAS mutations were screened by sequencing 164 HCA, 245 hepatocellular carcinoma (HCC), and 17 fibrolamellar carcinomas. Tumors were characterized by quantitative RT-PCR, gene mutation screening and pathological reviewing. The consequences of wild type and mutant GNAS expression were analyzed in hepatocellular cell lines. RESULTS: A somatic GNAS-activating mutation was identified in 5 benign tumors and in 2 HCC. In benign tumors, GNAS mutations were exclusive from HNF1A, CTNNB1, and IL6ST mutations whereas one HCC demonstrated both CTNNB1 and GNAS mutations. Quantitative RT-PCR showed an activation of the IL-6 and interferon pathways in GNAS-mutated tumor tissues. Accordingly, pathological reviewing identified in GNAS-mutated tumors an inflammatory phenotype characterized by fibrosis and STAT3 activation. We further demonstrated in HCC cell lines that GNAS mutant expression induced inflammatory response and STAT3 activation. CONCLUSIONS: We identified for the first time the association between two rare diseases, MCA syndrome and HCA occurrence, but also that somatic GNAS-activating mutations in sporadic benign and malignant liver tumors are characterized by an inflammatory phenotype. These results showed a cross-talk between cyclic-AMP and JAK/STAT pathways in liver tumors and they reinforce the role of STAT3 activation in liver tumorigenesis.


Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Neoplasias Hepáticas/genética , Mutación , Factor de Transcripción STAT3/metabolismo , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/metabolismo , Adenoma de Células Hepáticas/patología , Adulto , Anciano , Secuencia de Bases , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Cromograninas , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Femenino , Displasia Fibrosa Poliostótica/genética , Humanos , Neoplasias Hepáticas/clasificación , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Modelos Biológicos , Transducción de Señal
10.
Oncogene ; 41(38): 4397-4404, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35962130

RESUMEN

The cellular prion protein PrPC partners with caveolin-1 (CAV1) in neurodegenerative diseases but whether this interplay occurs in cancer has never been investigated. By leveraging patient and cell line datasets, we uncover a molecular link between PrPC and CAV1 across cancer. Using cell-based assays, we show that PrPC regulates the expression of and interacts with CAV1. PrPC additionally controls the expression of the amyloid precursor protein APP and of the Aß generating enzyme BACE1, and regulates the levels of Aß, whose accumulation is a central event in Alzheimer's disease. We further identify DKK1 and DKK3, involved in both Alzheimer's disease and cancer progression, as targets of the PrPC-dependent axis. Finally, we establish that antibody-mediated blocking of the Aß-PrPC interaction delays the growth of prostate cancer cell line-derived xenografts and prevents the development of metastases. Our data additionally support an enrichment of the Aß-PrPC-dependent pathway in the basal subtype of prostate cancer, associated with anti-hormonal therapy resistance, and in mesenchymal colon cancer, associated with poor prognosis. Thus, based on a parallel with neurodegenerative diseases, our results bring to light an Aß-PrPC axis and support the potential of targeting this pathway in patients with selected subtypes of prostate and colon cancer.


Asunto(s)
Enfermedad de Alzheimer , Neoplasias del Colon , Neoplasias de la Próstata , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Caveolina 1/genética , Caveolina 1/metabolismo , Neoplasias del Colon/genética , Humanos , Masculino , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Neoplasias de la Próstata/genética
11.
Oncoimmunology ; 10(1): 1940674, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34249475

RESUMEN

The CMS4 mesenchymal subtype of colorectal cancer (CRC) is associated with poor prognosis and resistance to treatment. The cellular prion protein PrPC is overexpressed in CMS4 tumors and controls the expression of a panel of CMS4-specific genes in CRC cell lines. Here, we sought to investigate PrPC downstream pathways that may underlie its role in CMS4 CRC. By combining gene set enrichment analyses and gain and loss of function approaches in CRC cell lines, we identify the integrin-linked kinase ILK as a proximal effector of PrPC that mediates its control on the CMS4 phenotype. We further leveraged three independent large CRC cohorts to assess correlations in gene expression pattern with patient outcomes and found that ILK is overexpressed in CMS4 mesenchymal tumors and confers a poor prognosis, especially when combined with high expression of the PrPC encoding gene PRNP. Of note, we discovered that the PrPC-ILK signaling axis controls the expression and activity of the tryptophan metabolizing enzyme indoleamine 2,3 dioxygenase IDO1, a key player in immune tolerance. In addition, we monitored alterations in the levels of tryptophan and its metabolites of the kynurenine pathway in the plasma of metastatic CRC patients (n = 325) and we highlight their prognostic value in combination with plasma PrPC levels. Thus, the PrPC-ILK-IDO1 axis plays a key role in the mesenchymal subtype of CRC. PrPC and IDO1-targeted strategies may represent new avenues for patient stratification and treatment in CRC.


Asunto(s)
Neoplasias Colorrectales , Neoplasias Colorrectales/diagnóstico , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa , Proteínas Priónicas , Pronóstico , Proteínas Serina-Treonina Quinasas
12.
Cancer Res ; 81(10): 2730-2744, 2021 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-33741693

RESUMEN

Intestinal crypts are composed of heterogeneous and highly plastic cell populations. Lgr5high-stem cells (SC) are responsible for homeostatic renewal, but other cells can revert to an SC-like phenotype to maintain epithelial integrity. Despite their distinct roles in orchestrating homeostasis, both populations have been designated as the putative "cell-of-origin" of colorectal cancer. However, their respective involvement in the emergence of drug-resistant cancer SCs (CSC), responsible for tumor relapse and associated with poor outcome of colorectal cancer, remains elusive. In this context, the intestinal SC/progenitor-marker Musashi1 (MSI1) is interesting as it plays important functions in intestinal homeostasis and is frequently overexpressed in human colorectal cancer. Therefore, our aims were: (i) to study the impact of chemotherapy on Lgr5-expressing and MSI1-expressing cell populations, (ii) to explore the effect of increased MSI1 levels in response to treatment, and (iii) to evaluate the relevance in human colorectal cancer. Engineered mouse models treated with the therapeutic agent 5-fluorouracil showed that upon increased MSI1 levels, Lgr5high SCs remain sensitive while Lgr5low progenitors reprogram to a drug-resistant phenotype. This resulted in the expansion of an MSI1-expressing cell subpopulation with improved resistance to DNA damage and increased detoxification, typical properties of dormant-CSCs that can reactivate after chemotherapy. Analysis in patients with colorectal cancer revealed a correlation between MSI1 levels and tumor grading, CSC phenotype, and chemoresistance. Altogether, these results shed new light on the biology and plasticity of normal crypt and cancer cell populations and also open new perspectives to target MSI1 to improve chemotherapy outcome. SIGNIFICANCE: This study unveils paradoxical roles for MSI1, underlining its importance in facilitating intestinal regeneration upon injury but also unraveling its new function in drug-resistant colorectal cancer stem cells.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos , Fluorouracilo/farmacología , Mucosa Intestinal/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al ARN/metabolismo , Receptores Acoplados a Proteínas G/fisiología , Animales , Antimetabolitos Antineoplásicos/farmacología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Femenino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteínas del Tejido Nervioso/genética , Fenotipo , Proteínas de Unión al ARN/genética
13.
Clin Cancer Res ; 27(17): 4768-4780, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34168047

RESUMEN

PURPOSE: The consensus molecular subtypes (CMS) represent a significant advance in the understanding of intertumor heterogeneity in colon cancer. Intratumor heterogeneity (ITH) is the new frontier for refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of colon cancer and understanding its potential prognostic implications. EXPERIMENTAL DESIGN: We deconvoluted the transcriptomic profiles of 1,779 tumors from the PETACC8 trial and 155 colon cancer cell lines as weighted sums of the four CMSs, using the Weighted In Silico Pathology (WISP) algorithm. We assigned to each tumor and cell line a combination of up to three CMS subtypes with a threshold above 20%. RESULTS: Over 55% of tumors corresponded to mixtures of at least two CMSs, demonstrating pervasive ITH in colon cancer. Of note, ITH was associated with shorter disease-free survival (DFS) and overall survival, [HR, 1.34; 95% confidence interval (CI; 1.12-1.59), 1.40, 95% CI (1.14-1.71), respectively]. Moreover, we uncovered specific combinations of CMS associated with dismal prognosis. In multivariate analysis, ITH represents the third parameter explaining DFS variance, after T and N stages. At a cellular level, combined WISP and single-cell transcriptomic analysis revealed that most colon cancer cell lines are a mixture of cells falling into different CMSs, indicating that ITH may correspond to distinct functional statuses of colon cancer cells. CONCLUSIONS: This study shows that CMS-based transcriptomic ITH is frequent in colon cancer and impacts its prognosis. CMS-based transcriptomic ITH may correspond to distinct functional statuses of colon cancer cells, suggesting plasticity between CMS-related cell populations. Transcriptomic ITH deserves further assessment in the context of personalized medicine.


Asunto(s)
Neoplasias del Colon/genética , Neoplasias del Colon/patología , Perfilación de la Expresión Génica , Microambiente Tumoral , Anciano , Línea Celular Tumoral , Neoplasias del Colon/clasificación , Neoplasias del Colon/mortalidad , Femenino , Humanos , Masculino , Pronóstico , Tasa de Supervivencia
14.
Virchows Arch ; 474(1): 105-109, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30132130

RESUMEN

CD200 has been recently indicated as a robust marker of well-differentiated neuroendocrine neoplasms. Here, we evaluate its role in differential diagnosis of solid pancreatic neoplasms. We immunostained for CD200 22 solid pseudopapillary neoplasms (SPNs), 8 acinar carcinomas (ACs), 2 pancreatoblastomas (PBs), 138 neuroendocrine tumors (PanNETs), and 48 ductal adenocarcinomas. All SPNs showed strong cytoplasmic and membranous staining for CD200, while only one case of AC had focal positivity. The two PBs showed focal CD200 positivity, mainly located in squamoid nests. The vast majority of PanNETs (96%) showed strong cytoplasmic and membranous staining for CD200, whereas all PDACs were negative. As both PanNETs and SPNs express CD200, it has no role in the differential diagnosis between these two entities.


Asunto(s)
Antígenos CD/análisis , Biomarcadores de Tumor/análisis , Carcinoma Papilar/inmunología , Tumores Neuroendocrinos/inmunología , Neoplasias Pancreáticas/inmunología , Carcinoma de Células Acinares/inmunología , Carcinoma de Células Acinares/patología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Papilar/patología , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Valor Predictivo de las Pruebas
15.
Pancreas ; 48(1): 70-76, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30451797

RESUMEN

OBJECTIVE: Ampulla of Vater carcinoma (AVC) has a broad spectrum of different prognoses. As such, new moderators of survival are urgently needed. We aimed at clarifying the prognostic role of perineural invasion in AVC. METHODS: Using PubMed and SCOPUS databases, we conducted the first systematic review and meta-analysis on this topic. RESULTS: Analyzing 29 articles for a total of 2379 patients, we found that the presence of perineural invasion increased the risk of all-cause mortality more than 2 times (relative risk [RR], 2.07; 95% confidence interval [CI], 1.78-2.42 [P < 0.0001]; hazard ratio [HR], 2.72; 95% CI, 1.86-3.97 [P < 0.0001]), of cancer-specific mortality more than 6 times (RR, 6.12; 95% CI, 3.25-11.54 [P < 0.0001]; HR, 6.59; 95% CI, 2.29-3.49 [P < 0.0001]), and of recurrence more than 2 times (RR, 2.63; 95% CI, 1.89-3.67 [P < 0.0001]; HR, 2.54; 95% CI, 1.24-5.21 [P = 0.01]). CONCLUSIONS: Perineural invasion is strongly associated with a poorer prognosis in AVC, influencing both survival and risk of recurrence. It should be reported in the final pathology report and should be taken into account by future oncologic staging systems, identifying a group of AVC with a more malignant biological behavior.


Asunto(s)
Ampolla Hepatopancreática/patología , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Perineo/patología , Humanos , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Pronóstico , Factores de Riesgo
16.
EBioMedicine ; 46: 94-104, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31377347

RESUMEN

BACKGROUND: Comprehensive transcriptomic analyses have shown that colorectal cancer (CRC) is heterogeneous and have led to the definition of molecular subtypes among which the stem-cell, mesenchymal-like group is associated with poor prognosis. The molecular pathways orchestrating the emergence of this subtype are incompletely understood. In line with the contribution of the cellular prion protein PrPC to stemness, we hypothesize that deregulation of this protein could lead to a stem-cell, mesenchymal-like phenotype in CRC. METHODS: We assessed the distribution of the PrPC-encoding PRNP mRNA in two large CRC cohorts according to molecular classification and its association with patient survival. We developed cell-based assays to explore the impact of gain and loss of PrPC function on markers of the mesenchymal subtype and to delineate the signalling pathways recruited by PrPC. We measured soluble PrPC in the plasmas of 325 patients with metastatic CRC and probed associations with disease outcome. FINDINGS: We found that PRNP gene expression is enriched in tumours of the mesenchymal subtype and is associated with poor survival. Our in vitro analyses revealed that PrPC controls the expression of genes that specify the mesenchymal subtype through the recruitment of the Hippo pathway effectors YAP and TAZ and the TGFß pathway. We showed that plasma levels of PrPC are elevated in metastatic CRC and are associated with poor disease control. INTERPRETATION: Our findings define PrPC as a candidate driver of the poor-prognosis mesenchymal subtype of CRC. They suggest that PrPC may serve as a potential biomarker for patient stratification in CRC. FUNDING: Grant support was provided by the following: Cancéropôle Ile de France (grant number 2016-1-EMERG-36-UP 5-1), Association pour la Recherche sur le Cancer (grant number PJA 20171206220), SATT Ile de France Innov (grant number 415) as well as INSERM.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/genética , Proteínas Priónicas/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Biomarcadores , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Femenino , Expresión Génica , Vía de Señalización Hippo , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Proteínas Priónicas/metabolismo , Pronóstico , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/genética , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo
17.
J Gastrointest Oncol ; 9(4): E23-E27, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30151276

RESUMEN

Here we report the case of a 20-year-old patient who was diagnosed in 2002 with a metastatic colorectal cancer (CRC). He achieved a complete response under cetuximab-based therapy and remains without disease recurrence until now while chemotherapy was discontinued in 2009. The tumor exhibited high level of epidermal growth factor receptor (EGFR) amplification, no mutation in KRAS, NRAS or BRAF genes and a microsatellite-stable (MSS) phenotype. Intriguingly this young patient was carrying a monoallelic germline mutation of MUTYH that was associated with an inactivation of the second allele by loss of heterozygosity on tumor DNA. Moreover, this mutation was associated with a specific mutational signature on tumor level characterized by C > A single base substitutions and a higher mutational load than usually observed in MSS neoplasms. This case report paves the way for further researches on MUTYH-associated cancers' sensitivity to anticancer therapies.

18.
World J Gastrointest Oncol ; 10(10): 317-327, 2018 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-30364837

RESUMEN

Pancreatic cancer is a lethal malignancy, whose precursor lesions are pancreatic intraepithelial neoplasm, intraductal papillary mucinous neoplasm, intraductal tubulopapillary neoplasm, and mucinous cystic neoplasm. To better understand the biology of pancreatic cancer, it is fundamental to know its precursors and to study the mechanisms of carcinogenesis. Each of these precursors displays peculiar histological features, as well as specific molecular alterations. Starting from such pre-invasive lesions, this review aims at summarizing the most important aspects of carcinogenesis of pancreatic cancer, with a specific focus on the recent advances and the future perspectives of the research on this lethal tumor type.

19.
Virchows Arch ; 472(6): 939-947, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29392400

RESUMEN

Extranodal extension (ENE) of nodal metastasis is defined as the extension of metastatic cells through the nodal capsule into the perinodal tissue. This morphological parameter, recently proposed as an important prognostic factor in different types of malignancy, has not been included in the TNM staging system for non-small cell lung cancer (NSCLC). In this systematic review with meta-analysis, we weighted the prognostic role of ENE in patients with lymph node-positive NSCLC. Two independent authors searched SCOPUS and PubMed through 28 February 2017. Prospective and retrospective studies on NSCLC, comparing patients with presence of ENE (ENE+) ENE+) vs. only intranodal extension (ENE-) and including data regarding prognosis, were considered as eligible. Data were summarized using risk ratios (RR) for the number of deaths/recurrences, and hazard ratios (HR) with 95% confidence intervals (CI) for time-dependent risk related to ENE+, adjusted for potential confounders. We identified 13 studies, including 1709 patients (573 ENE+ and 1136 ENE-) with a median follow-up of 60 months. ENE was associated with a significantly increased risk of mortality of all causes (RR = 1.39, 95% CI: 1.18-1.65, P < 0.0001, I2 = 70%; HR = 1.30, 95% CI: 1.01-1.67, P = 0.04, I2 = 0%) and of disease recurrence (RR = 1.32, 95% CI: 1.04-1.68, P = 0.02, I2 = 42%; HR = 1.93, 95% CI: 1.53-2.44, P < 0.0001, I2 = 0%). We conclude that in NSCLC, requirements for assessment of ENE should be included in gross sampling and ENE status should be included in the pathology report. Inclusion of ENE status in oncology staging systems will allow further assessment of its role as prognostic parameter.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/patología , Neoplasias Pulmonares/diagnóstico , Ganglios Linfáticos/patología , Metástasis Linfática , Pronóstico
20.
Hum Pathol ; 81: 157-165, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30031096

RESUMEN

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has a striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1, and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extrapancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas were immunostained using antibodies against PD-1, PD-L1, and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17 (63%) of 27 cases, more often in cases with an associated PDAC (P = .04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1-positive UCOGCs had a risk of all-cause mortality that was 3 times higher than did patients with PD-L1-negative UCOGCs (hazard ratio, 3.397; 95% confidence interval, 1.023-18.375; P = .034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P = .035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extrapancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. Anaplastic carcinomas have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC.


Asunto(s)
Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Carcinoma Ductal Pancreático/inmunología , Diferenciación Celular , Células Gigantes/inmunología , Osteoclastos/inmunología , Neoplasias Pancreáticas/inmunología , Receptor de Muerte Celular Programada 1/análisis , Receptores de Superficie Celular/análisis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Europa (Continente) , Femenino , Células Gigantes/patología , Histiocitos/química , Histiocitos/patología , Humanos , Inmunohistoquímica , Indiana , Linfocitos/inmunología , Linfocitos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Osteoclastos/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Fenotipo
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