RESUMEN
Cancer patients often receive a combination of antibodies targeting programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA4). We conducted a window-of-opportunity study in head and neck squamous cell carcinoma (HNSCC) to examine the contribution of anti-CTLA4 to anti-PD-L1 therapy. Single-cell profiling of on- versus pre-treatment biopsies identified T cell expansion as an early response marker. In tumors, anti-PD-L1 triggered the expansion of mostly CD8+ T cells, whereas combination therapy expanded both CD4+ and CD8+ T cells. Such CD4+ T cells exhibited an activated T helper 1 (Th1) phenotype. CD4+ and CD8+ T cells co-localized with and were surrounded by dendritic cells expressing T cell homing factors or antibody-producing plasma cells. T cell receptor tracing suggests that anti-CTLA4, but not anti-PD-L1, triggers the trafficking of CD4+ naive/central-memory T cells from tumor-draining lymph nodes (tdLNs), via blood, to the tumor wherein T cells acquire a Th1 phenotype. Thus, CD4+ T cell activation and recruitment from tdLNs are hallmarks of early response to anti-PD-L1 plus anti-CTLA4 in HNSCC.
Asunto(s)
Linfocitos T CD8-positivos , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Antígeno B7-H1/genética , Antígeno CTLA-4 , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Linfocitos T CD4-Positivos , Microambiente TumoralRESUMEN
BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Vinblastina/análogos & derivados , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Células Cultivadas , Neoplasias del Colon/clasificación , Neoplasias del Colon/tratamiento farmacológico , Xenoinjertos , Humanos , Ratones , Ratones Desnudos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Chaperonas Moleculares/genética , Trasplante de Neoplasias , Proteínas de Complejo Poro Nuclear/genética , Proteínas Proto-Oncogénicas B-raf/genética , Vinblastina/administración & dosificación , Vinblastina/farmacología , VinorelbinaRESUMEN
Around 30-40% of patients with colorectal cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years1. Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumour cells responsible for CRC relapse. An analysis of single-cell transcriptomes of samples from patients with CRC revealed that the majority of genes associated with a poor prognosis are expressed by a unique tumour cell population that we named high-relapse cells (HRCs). We established a human-like mouse model of microsatellite-stable CRC that undergoes metastatic relapse after surgical resection of the primary tumour. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including LGR5+ stem-like tumour cells2-4, and caused overt metastatic disease. Using Emp1 (encoding epithelial membrane protein 1) as a marker gene for HRCs, we tracked and selectively eliminated this cell population. Genetic ablation of EMP1high cells prevented metastatic recurrence and mice remained disease-free after surgery. We also found that HRC-rich micrometastases were infiltrated with T cells, yet became progressively immune-excluded during outgrowth. Treatment with neoadjuvant immunotherapy eliminated residual metastatic cells and prevented mice from relapsing after surgery. Together, our findings reveal the cell-state dynamics of residual disease in CRC and anticipate that therapies targeting HRCs may help to avoid metastatic relapse.
Asunto(s)
Neoplasias Colorrectales , Metástasis de la Neoplasia , Proteínas de Neoplasias , Recurrencia Local de Neoplasia , Neoplasia Residual , Receptores de Superficie Celular , Animales , Humanos , Ratones , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Progresión de la Enfermedad , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/terapia , Neoplasia Residual/genética , Neoplasia Residual/patología , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/prevención & control , Metástasis de la Neoplasia/terapia , Modelos Animales de Enfermedad , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Terapia Neoadyuvante , InmunoterapiaRESUMEN
Although leucine zipper tumour suppressor 1 (LZTS1) has been considered a potential tumour suppressor, accumulating evidence suggests that LZTS1 is highly expressed in many cancer types. To unravel the exact role of LZTS1 in colorectal carcinogenesis, we performed the bioinformatic analysis of LZTS1, including expression differences, correlations between expression levels and survival, methylation status of LZTS1 promoter and related cellular pathways based on TCGA dataset, GEO databases and our own CRC patient cohort. Furthermore, we confirmed the oncogenic function of LZTS1 in human mammalian cells by employing a series of assays including tissue microarray, immunoblotting, cell proliferation and migration assay. We found that the expression of LZTS1 is higher in tumour samples compared to paired normal tissue in CRC cancer and its different clinical subtypes, which is, at least in part, due to the low methylation status of LZTS1 promoter in CRC tumour samples. Functional analysis identified the close relationship between high expression of LZTS1 and PI3K-AKT pathway and the epithelial-mesenchymal transition (EMT) process. Consistently, we found that the expression of LZTS1 positively correlated with the expression PIK3CD, N-cadherin in CRC tumour samples, while the expression of LZTS1 negatively correlated with the expression of E-cadherin and PTEN in CRC tumour samples. Experimental data further confirmed that overexpression of LZTS1 upregulated activity of AKT and promoted EMT process. Furthermore, depletion of LZTS1 repressed the proliferation and migration rate of CRC cells. Thus, this study indicates that LZTS1 plays an oncogenic role in colorectal carcinogenesis.
Asunto(s)
Neoplasias Colorrectales , Metilación de ADN , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Regiones Promotoras Genéticas , Humanos , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Metilación de ADN/genética , Transición Epitelial-Mesenquimal/genética , Oncogenes/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases, with a focus on terminology, diagnosis, and management. METHODS: This project was a multiorganizational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis, and management. Statements were refined during an online Delphi process, and those with 70 per cent agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising 12 key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term 'early metachronous metastases' applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour, the term 'late metachronous metastases' applies to those detected after 12 months. 'Disappearing metastases' applies to lesions that are no longer detectable on MRI after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards, and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways, including systemic chemotherapy, synchronous surgery, and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSION: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/patología , Consenso , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologíaRESUMEN
BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases with a focus on terminology, diagnosis and management. METHODS: This project was a multi-organisational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis and management. Statements were refined during an online Delphi process and those with 70% agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising twelve key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term "early metachronous metastases" applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour with "late metachronous metastases" applied to those detected after 12 months. Disappearing metastases applies to lesions which are no longer detectable on MR scan after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways including systemic chemotherapy, synchronous surgery and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSIONS: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.
Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Neoplasias Colorrectales/patología , Consenso , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologíaRESUMEN
OBJECTIVE: Despite regular colonoscopy surveillance, colorectal cancers still occur in patients with Lynch syndrome. Thus, detection of all relevant precancerous lesions remains very important. The present study investigates Linked Colour imaging (LCI), an image-enhancing technique, as compared with high-definition white light endoscopy (HD-WLE) for the detection of polyps in this patient group. DESIGN: This prospective, randomised controlled trial was performed by 22 experienced endoscopists from eight centres in six countries. Consecutive Lynch syndrome patients ≥18 years undergoing surveillance colonoscopy were randomised (1:1) and stratified by centre for inspection with either LCI or HD-WLE. Primary outcome was the polyp detection rate (PDR). RESULTS: Between January 2018 and March 2020, 357 patients were randomised and 332 patients analysed (160 LCI, 172 HD-WLE; 6 excluded due to incomplete colonoscopies and 19 due to insufficient bowel cleanliness). No significant difference was observed in PDR with LCI (44.4%; 95% CI 36.5% to 52.4%) compared with HD-WLE (36.0%; 95% CI 28.9% to 43.7%) (p=0.12). Of the secondary outcome parameters, more adenomas were found on a patient (adenoma detection rate 36.3%; vs 25.6%; p=0.04) and a colonoscopy basis (mean adenomas per colonoscopy 0.65 vs 0.42; p=0.04). The median withdrawal time was not statistically different between LCI and HD-WLE (12 vs 11 min; p=0.16). CONCLUSION: LCI did not improve the PDR compared with HD-WLE in patients with Lynch syndrome undergoing surveillance. The relevance of findings more adenomas by LCI has to be examined further. TRIAL REGISTRATION NUMBER: NCT03344289.
Asunto(s)
Adenoma/diagnóstico por imagen , Pólipos del Colon/diagnóstico por imagen , Colonoscopía , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico por imagen , Aumento de la Imagen , Adenoma/patología , Adulto , Anciano , Color , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
OBJECTIVE: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy. DESIGN: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours. RESULTS: By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002). CONCLUSION: This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC.
Asunto(s)
Biomarcadores de Tumor , Neoplasias del Colon , Humanos , Biomarcadores de Tumor/genética , Células del Estroma/patología , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/patología , Neoplasias del Colon/patología , PronósticoRESUMEN
BACKGROUND: Cell-free DNA (cfDNA) analysis holds great promise for non-invasive cancer screening, diagnosis, and monitoring. We hypothesized that mining the patterns of cfDNA shallow whole-genome sequencing datasets from patients with cancer could improve cancer detection. METHODS: By applying unsupervised clustering and supervised machine learning on large cfDNA shallow whole-genome sequencing datasets from healthy individuals (n = 367) and patients with different hematological (n = 238) and solid malignancies (n = 320), we identified cfDNA signatures that enabled cancer detection and typing. RESULTS: Unsupervised clustering revealed cancer type-specific sub-grouping. Classification using a supervised machine learning model yielded accuracies of 96% and 65% in discriminating hematological and solid malignancies from healthy controls, respectively. The accuracy of disease type prediction was 85% and 70% for the hematological and solid cancers, respectively. The potential utility of managing a specific cancer was demonstrated by classifying benign from invasive and borderline adnexal masses with an area under the curve of 0.87 and 0.74, respectively. CONCLUSIONS: This approach provides a generic analytical strategy for non-invasive pan-cancer detection and cancer type prediction.
Asunto(s)
Ácidos Nucleicos Libres de Células , Neoplasias , Biomarcadores de Tumor/genética , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Secuenciación Completa del GenomaRESUMEN
Immune checkpoint blockers (ICBs)-based immunotherapy has revolutionised oncology. However, the benefits of ICBs are limited to only a subset of patients. Herein, the biomarkers-driven application of ICBs promises to increase their efficacy. Such biomarkers include lymphocytic IFNγ-signalling and/or cytolytic activity (granzymes and perforin-1) footprints, whose levels in pre-treatment tumours can predict favourable patient survival following ICB-treatment. However, it is not clear whether such biomarkers have the same value in predicting survival of patients receiving first-line anti-CTLA4 ICB-therapy, and subsequently anti-PD1 ICB-therapy (i.e., sequential ICB-immunotherapy regimen). To address this, we applied highly integrated systems/computational immunology approaches to existing melanoma bulk-tumour transcriptomic and single-cell (sc)RNAseq data originating from immuno-oncology clinical studies applying ICB-treatment. Interestingly, we observed that CD8+/CD4+T cell-associated IFNγ-signalling or cytolytic activity signatures fail to predict tumour response in patients treated with anti-CTLA4 ICB-therapy as a first-line and anti-PD1 ICB-therapy in the second-line setting. On the contrary, signatures associated with early memory CD8+/CD4+T cells (integrating TCF1-driven stem-like transcriptional programme), capable of resisting cell death/apoptosis, better predicted objective response rates to ICB-immunotherapy, and favourable survival in the setting of sequential ICB-immunotherapy. These observations suggest that sequencing of ICB-therapy might have a specific impact on the T cell-repertoire and may influence the predictive value of tumoural immune biomarkers.
Asunto(s)
Melanoma , Receptor de Muerte Celular Programada 1 , Muerte Celular , Diferenciación Celular , Humanos , Inmunoterapia , Melanoma/tratamiento farmacológico , Linfocitos TRESUMEN
OBJECTIVE: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumours that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen-activated kinase pathway gene, BRAF, and epigenetic modifications termed the CpG Island Methylator Phenotype, leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein. DESIGN: We use organoid culture combined with CRISPR/Cas9 genome engineering to sequentially introduce genetic alterations associated with serrated CRC and which regulate the stem cell niche, senescence and DNA mismatch repair. RESULTS: Targeted biallelic gene alterations were verified by DNA sequencing. Organoid growth in the absence of niche factors was assessed, as well as analysis of downstream molecular pathway activity. Orthotopic engraftment of complex organoid lines, but not BrafV600E alone, quickly generated adenocarcinoma in vivo with serrated features consistent with human disease. Loss of the essential DNA mismatch repair enzyme, Mlh1, led to microsatellite instability. Sphingolipid metabolism genes are differentially regulated in both our mouse models of serrated CRC and human CRC, with key members of this pathway having prognostic significance in the human setting. CONCLUSION: We generate rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of our models alongside patient data has led to the identification of a potential susceptibility for this tumour type.
Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/patología , Colon/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Organoides/patología , Proteínas Proto-Oncogénicas B-raf/genética , Adenocarcinoma/metabolismo , Alelos , Colon/metabolismo , Neoplasias Colorrectales/metabolismo , Islas de CpG/genética , Reparación de la Incompatibilidad de ADN , Análisis Mutacional de ADN , Progresión de la Enfermedad , Epigenómica , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Modelos Genéticos , Mutación , Organoides/metabolismo , Fenotipo , Proteínas Proto-Oncogénicas B-raf/metabolismoRESUMEN
BACKGROUND: To improve detection of mucosal lesions during colonoscopy a number of imaging modalities have been suggested, including high definition and virtual chromoendoscopy. Given the theoretical advantage of these new imaging techniques, we aimed to investigate their use for the detection of polyps in patients referred for colonoscopy in a large tertiary hospital. METHODS: Demographic, endoscopic, and histological data from 1855 consecutive patients undergoing colonoscopy were collected prospectively. Patients were randomly assigned to three endoscopy systems (Fujinon, Olympus, or Pentax) in combination with four modalities: conventional white-light colonoscopy (nâ=â505), high definition white-light colonoscopy (nâ=â582), virtual chromoendoscopy (nâ=â285) and high definition virtual chromoendoscopy (nâ=â483). RESULTS: The mean adenoma detection rate (ADR) was 34.9â%, and the adenoma per colonoscopy rate (APCR) was 2.1. No significant differences were noted between the three endoscopy systems. Moreover, no differences in ADR or APCR were observed between the four imaging modalities. High definition white-light colonoscopy resulted in a significantly higher detection of sessile serrated adenomas (8.2â% vs. 3.8â%; Pâ<â0.01) and adenocarcinomas (2.6â% vs. 0.5â%; Pâ<â0.05) compared with the conventional procedure. CONCLUSIONS: No significant differences in ADR or APCR between different endoscopy systems, high definition, and/or virtual chromoendoscopy could be observed in routine colonoscopies in the general population. High definition endoscopy was associated with a significantly higher detection rate of serrated adenomas and adenocarcinomas.
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Adenocarcinoma/diagnóstico , Adenoma/diagnóstico , Colonoscopía/métodos , Neoplasias Colorrectales/diagnóstico , Bélgica , Diagnóstico Diferencial , Femenino , Humanos , Aumento de la Imagen/métodos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The ZIC2 transcription factor is one of the genes most commonly mutated in Holoprosencephaly (HPE) probands. Studies in cultured cell lines and mice have shown a loss of ZIC2 function is the pathogenic mechanism but the molecular details of this ZIC2 requirement remain elusive. HPE arises when signals that direct morphological and fate changes in the developing brain and facial primordia are not sent or received. One critical signal is sent from the prechordal plate (PrCP) which develops beneath the ventral forebrain. An intact NODAL signal transduction pathway and functional ZIC2 are both required for PrCP establishment. We now show that ZIC2 acts downstream of the NODAL signal during PrCP development. ZIC2 physically interacts with SMAD2 and SMAD3, the receptor activated proteins that control transcription in a NODAL dependent manner. Together SMAD3 and ZIC2 regulate FOXA2 transcription in cultured cells and Zic2 also controls the foxA2 expression during Xenopus development. Variant forms of the ZIC2 protein, associated with HPE in man or mouse, are deficient in their ability to influence SMAD-dependent transcription. These findings reveal a new mechanism of NODAL signal transduction in the mammalian node and provide the first molecular explanation of how ZIC2 loss-of-function precipitates HPE.
Asunto(s)
Factor Nuclear 3-beta del Hepatocito/genética , Holoprosencefalia/genética , Proteína Nodal/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Xenopus laevis/genética , Animales , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Regulación del Desarrollo de la Expresión Génica , Factor Nuclear 3-beta del Hepatocito/biosíntesis , Holoprosencefalia/fisiopatología , Humanos , Masculino , Ratones , Mutación , Proteína Nodal/metabolismo , Transducción de Señal/genética , Proteína Smad2/genética , Proteína smad3/genética , Xenopus laevis/crecimiento & desarrolloRESUMEN
BACKGROUND: Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesised that common germline variants within these pathways may also play similar roles. METHODS: We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 patients with aCRC treated with oxaliplatin-fluoropyrimidine chemotherapy plus cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%. RESULTS: We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab-in patients with KRAS wild-type CRCs, 36.4% with one allele encoding proline responded, as compared with 71.2% homozygous for allele encoding serine (OR 0.23, 95% CI 0.09 to 0.56, p=0.0014), and this association was predictive for cetuximab (pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated. CONCLUSIONS: Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity.
Asunto(s)
Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Receptores ErbB/genética , Compuestos Organoplatinos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores Farmacológicos , Femenino , Frecuencia de los Genes , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Oxaliplatino , Variantes Farmacogenómicas/genética , Transducción de Señal/genéticaRESUMEN
In the last decade, the amount of investigations on the involvement of ZIC genes in the cancer field have exponentially expanded. In most cancer types, promoter methylation leads to silenced ZIC family members, but specific subsets of patients clearly show increased expression of one or head-to-head located ZIC genes in the respective tumor tissue. It is unclear at this stage how these transcription factors contribute to tumorigenesis, but the potential implications in pathways that are most frequently mutated in cancer such as the canonical Wnt, TGF-beta, and STAT-3 pathway are evident. By exploring well-established developmental models, researchers were able to position ZIC genes not only as classical transcription factors but also as cofactors of chromatin remodeling complexes that are crucial for maintenance of the cell but also during differentiation and maturation of ZIC-expressing tissues in vivo. The translation of this obtained evidence to the cancer field will be challenging but will indisputably lead to a better understanding how the factors can contribute to the tumor development in the given subsets of patients.
Asunto(s)
Transformación Celular Neoplásica , Regulación Neoplásica de la Expresión Génica/genética , Proteínas de Neoplasias , Neoplasias , Factores de Transcripción , Vía de Señalización Wnt/genética , Dedos de Zinc , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Tumour budding, described as the presence of single cells or small clusters of up to five tumour cells at the invasive margin, is established as a prognostic marker in colorectal carcinoma. In the present study, we aimed to investigate the molecular signature of tumour budding cells and the corresponding tumour bulk. METHODS: Tumour bulk and budding areas were microdissected and processed for RNA-sequencing. As little RNA was obtained from budding cells, a special low-input mRNA library preparation protocol was used. Gene expression profiles of budding as compared with tumour bulk were investigated for established EMT signatures, consensus molecular subtype (CMS), gene set enrichment and pathway analysis. RESULTS: A total of 296 genes were differentially expressed with an FDR <0.05 and a twofold change between tumour bulk and budding regions. Genes that were upregulated in the budding signature were mainly involved in cell migration and survival while downregulated genes were important for cell proliferation. Supervised clustering according to an established EMT gene signature categorised budding regions as EMT-positive, whereas tumour bulk was considered EMT-negative. Furthermore, a shift from CMS2 (epithelial) to CMS4 (mesenchymal) was observed as tumour cells transit from the tumour bulk to the budding regions. CONCLUSIONS: Tumour budding regions are characterised by a phenotype switch compared with the tumour bulk, involving the acquisition of migratory characteristics and a decrease in cell proliferation. In particular, most tumour budding signatures were EMT-positive and switched from an epithelial subtype (CMS2) in the tumour bulk to a mesenchymal subtype (CMS4) in budding cells.
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División Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/genética , Genes de Cambio/genética , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular/genética , Neoplasias Colorrectales/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Márgenes de Escisión , Persona de Mediana Edad , Invasividad Neoplásica , Fenotipo , Análisis de Matrices TisularesRESUMEN
Background and study aims (Virtual) chromoendoscopy detects more polyps than standard white-light endoscopy in patients with Lynch syndrome. Previous back-to-back trials did not randomize for the examination order, creating a possible bias in favor of chromoendoscopy. We aimed to assess the difference in polyp detection between high definition white-light endoscopy (HD-WLE) and virtual chromoendoscopy with I-SCAN in patients with Lynch syndrome. Patients and methods In this prospective, controlled trial, patients were randomized to either HD-WLE followed by I-SCAN (Group 1; nâ=â31) or I-SCAN followed by HD-WLE (Group 2; nâ=â30). Polyps found during the first pass were removed. The primary end point of the study was the difference in adenoma detection between HD-WLE and I-SCAN, expressed as the miss rate for adenomas for each technique. Results In Group 1, I-SCAN detected four additional patients with at least one adenoma, whereas HD-WLE did not increase the adenoma detection rate in Group 2 (relative risk [RR] 0.4; Pâ=â0.08). In Group 1, five adenomas were detected and removed with HD-WLE and a second pass with I-SCAN detected a further eight adenomas. In Group 2, I-SCAN detected 15 adenomas and subsequent HD-WLE detected 2 additional adenomas. The adenoma miss rate was significantly higher for HD-WLE (62â%) compared with I-SCAN (12â%; RR 0.44, 95â% confidence interval [CI] 0.21 to 0.87; Pâ=â0.007). The miss rate for lesions was 57â% and 24â%, respectively, and was significantly different in favor of I-SCAN (RR 0.54, 95â%CI 0.3 to 0.85; Pâ=â0.005). The mean inspection time in both groups was not significantly different during first (485 vs. 536 seconds; 95â%CIâ-â139.91 to 33.34) or second pass (421 vs. 387 seconds; 95â%CIâ-â32.24 to 104.89). Conclusion Our data suggest that virtual chromoendoscopy with I-SCAN reduces the adenoma and polyp miss rate in patients with Lynch syndrome, independently of inspection time. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01823471).
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Adenoma/diagnóstico por imagen , Neoplasias del Colon/diagnóstico por imagen , Colonoscopía/métodos , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Adulto , Estudios Cruzados , Reacciones Falso Negativas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Estudios ProspectivosRESUMEN
BACKGROUND: Two separate multinational surveys of oncologists and patients with cancer were conducted to assess the awareness and use of biomarkers in clinical practice. These data explore the self-reported and physician-assessed levels of patient cancer literacy and factors affecting physicians' choice to use biomarkers in treatment decisions. PATIENTS AND METHODS: Interviews were conducted via telephone with patients and online with physicians. Physicians had 3-35 years of experience; were treating more than 15 patients/month; and specialized in breast, lung, or colorectal cancer. Patients had received treatment for breast, lung, or colorectal cancer within the previous 5 years. RESULTS: Interviews with 895 physicians and 811 patients were completed. Most patients and physicians reported that patients understood that a tumor could be tested to determine what treatment would be most effective (78% and 73%, respectively) and that patients would be willing to participate in a personalized treatment plan. Whereas 85% of patients felt that they understood their treatment when it was explained to them, only 23% of doctors felt that their patients were always fully informed. Most physicians (90%) reported using biomarkers; among the 10% not performing biomarker analysis, the most cited obstacles were local availability, speed of obtaining results, and cost. CONCLUSION: These data demonstrate wide global use of biomarker testing but with regional variations reflecting cultural and local practice. Self-reported and physician-assessed cancer literacy, although generally high, highlighted important regional variations and the need to provide patients with additional information.
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Actitud del Personal de Salud , Conocimientos, Actitudes y Práctica en Salud , Alfabetización en Salud , Pacientes/estadística & datos numéricos , Médicos/estadística & datos numéricos , Medicina de Precisión/estadística & datos numéricos , Adulto , Biomarcadores de Tumor , Neoplasias de la Mama/terapia , Neoplasias Colorrectales/terapia , Toma de Decisiones , Femenino , Humanos , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
BACKGROUND & AIMS: Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes. METHODS: We used a polymerase chain reaction-based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n = 783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models. RESULTS: Tumors were categorized into 5 subtypes based on MMR status and detection of BRAF or KRAS mutations which were mutually exclusive. Three subtypes were MMR proficient: those with mutations in BRAF (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAF or KRAS mutations (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAF mutation and/or or hypermethylation of MLH1 and the familial type (2.6%), which lacked BRAF(V600E) or hypermethylation of MLH1. A higher percentage of MMR-proficient tumors with BRAF(V600E) were proximal (76%), high-grade (44%), N2 stage (59%), and detected in women (59%), compared with MMR-proficient tumors without BRAF(V600E) or KRAS mutations (33%, 19%, 41%, and 42%, respectively; all P < .0001). A significantly lower proportion of patients with MMR-proficient tumors with mutant BRAF (hazard ratio = 1.43; 95% confidence interval: 1.11-1.85; Padjusted = .0065) or mutant KRAS (hazard ratio = 1.48; 95% confidence interval: 1.27-1.74; Padjusted < .0001) survived disease-free for 5 years compared with patients whose MMR-proficient tumors lacked mutations in either gene. Disease-free survival rates of patients with MMR-deficient sporadic or familial subtypes was similar to those of patients with MMR-proficient tumors without BRAF or KRAS mutations. The observed differences in survival rates of patients with different tumor subtypes were validated in an independent cohort. CONCLUSIONS: We identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAF or KRAS mutations had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAF(V600E) or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers.