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1.
Gastroenterology ; 158(4): 947-957.e4, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31622624

RESUMO

BACKGROUND & AIMS: Screening for colorectal cancer (CRC) is effective in the population at average risk. The most extended strategy in organized programs involves the fecal immunochemical test, which is limited by low sensitivity for the detection of advanced adenomas (AAs). We aimed to identify microRNA (miRNA) signatures in fecal samples that identify patients with AAs or CRC and might be used in noninvasive screening. METHODS: Our study comprised 4 stages. In the discovery phase, we performed genome-wide miRNA expression profiling of 124 fresh, paired colorectal tumor and nontumor samples (30 CRC; 32 AAs) from patients in Spain. In the technical validation stage, miRNAs with altered expression levels in tumor vs nontumor tissues were quantified by reverse-transcription polymerase chain reaction in fecal samples from a subset of patients included in the discovery phase (n = 39) and individuals without colorectal neoplasms (controls, n = 39). In the clinical validation stage, the miRNAs found to be most significantly up-regulated by quantitative reverse transcription polymerase chain reaction analysis were measured in an independent set of fecal samples (n = 767) from patients with positive results from fecal immunochemical tests in a CRC screening program. Finally, we developed a model to identify patients with advanced neoplasms (CRCs or AAs) based on their miRNA profiles, using findings from colonoscopy as the reference standard. RESULTS: Among 200 and 324 miRNAs significantly deregulated in CRC and AA tissues, respectively, 7 and 5 of these miRNAs were also found to be deregulated in feces (technical validation). Of them, MIR421, MIR130b-3p, and MIR27a-3p were confirmed to be upregulated in fecal samples from patients with advanced neoplasms. In our model, the combination of fecal level of MIR421, MIR27a-3p, and hemoglobin identified patients with CRC with an area under the curve (AUC) of 0.93, compared with an AUC of 0.67 for fecal hemoglobin concentration alone. CONCLUSIONS: We found that increased levels of 2 miRNAs and hemoglobin in feces can identify patients with AAs or CRC more accurately than fecal hemoglobin concentration alone. Assays for these miRNAs might be added to fecal tests for the detection of CRC or AAs.


Assuntos
Adenoma/diagnóstico , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/métodos , Fezes/química , MicroRNAs/análise , Adenoma/genética , Idoso , Área Sob a Curva , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Feminino , Perfilação da Expressão Gênica , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Espanha
2.
Cancer Discov ; 13(10): 2180-2191, 2023 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-37704212

RESUMO

Breast cancer occurring during pregnancy (PrBC) and postpartum (PPBC) is usually diagnosed at more advanced stages compared with other breast cancer, worsening its prognosis. PPBC is particularly aggressive, with increased metastatic risk and mortality. Thus, effective screening methods to detect early PrBC and PPBC are needed. We report for the first time that cell-free tumor DNA (ctDNA) is present in breast milk (BM) collected from patients with breast cancer. Analysis of ctDNA from BM detects tumor variants in 87% of the cases by droplet digital PCR, while variants remain undetected in 92% of matched plasma samples. Retrospective next-generation sequencing analysis in BM ctDNA recapitulates tumor variants, with an overall clinical sensitivity of 71.4% and specificity of 100%. In two cases, ctDNA was detectable in BM collected 18 and 6 months prior to standard diagnosis. Our results open up the potential use of BM as a new source for liquid biopsy for PPBC detection. SIGNIFICANCE: For the first time, we show that BM obtained from patients with breast cancer carries ctDNA, surpassing plasma-based liquid biopsy for detection and molecular profiling of early-stage breast cancer, even prior to diagnosis by image. See related commentary by Cunningham and Turner, p. 2125. This article is featured in Selected Articles from This Issue, p. 2109.


Assuntos
Neoplasias da Mama , DNA Tumoral Circulante , Feminino , Humanos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Estudos Retrospectivos , Leite Humano , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Mutação
3.
Med ; 4(10): 710-727.e5, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37572657

RESUMO

BACKGROUND: Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing. METHODS: We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types. VIGex was developed as a continuous variable, with cutoffs selected to detect three main categories (hot, intermediate-cold and cold) based on the different inflammatory status of the tumor microenvironment. FINDINGS: Hot tumors had the highest VIGex scores and exhibited an increased abundance of tumor-infiltrating lymphocytes as compared with the intermediate-cold and cold. VIGex scores varied depending on tumor origin and anatomic site of metastases, with liver metastases showing an immunosuppressive tumor microenvironment. The predictive power of VIGex-Hot was observed in a cohort of 98 refractory solid tumor from patients treated in early-phase immunotherapy trials and its clinical performance was confirmed through an extensive metanalysis across 13 clinically annotated gene expression datasets from 877 patients treated with immunotherapy agents. Last, we generated a pan-cancer biomarker platform that integrates VIGex categories with the expression levels of immunotherapy targets under development in early-phase clinical trials. CONCLUSIONS: Our results support the clinical utility of VIGex as a tool to aid clinicians for patient selection and personalized immunotherapy interventions. FUNDING: BBVA Foundation; 202-2021 Division of Medical Oncology and Hematology Fellowship award; Princess Margaret Cancer Center.


Assuntos
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Fatores Imunológicos/metabolismo , Fatores Imunológicos/uso terapêutico , Oncologia , Microambiente Tumoral/genética
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