Browsing by Author "Earl, Julie"
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Publication A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants.(Elsevier, 2020-03-27) Earl, Julie; Galindo-Pumariño, Cristina; Encinas, Jessica; Barreto, Emma; Castillo, Maria E; Pachón, Vanessa; Ferreiro, Reyes; Rodríguez-Garrote, Mercedes; González-Martínez, Silvia; Ramon Y Cajal, Teresa; Diaz, Luis Robles; Chirivella-Gonzalez, Isabel; Rodriguez, Montse; de Castro, Eva Martínez; García-Seisdedos, David; Muñoz, Gloria; Rosa, Juan Manuel Rosa; Marquez, Mirari; Carrato, Alfredo; Malats, Nuria; Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERONC (Cáncer); Red Temática de Investigación Cooperativa en Cáncer (RTICC) (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes. Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome. Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting the multigene phenotype of FPC. The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development. This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund ''A way to achieve Europe'' (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073) and La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016).Publication Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study.(2021-04-04) Conde, Elisa; Earl, Julie; Crespo-Toro, Lorena; Blanco-Agudo, Carolina; Ramos-Muñoz, Edurne; Rodríguez-Serrano, E Macarena; Martínez Ávila, Jose Carlos; Salinas-Muñoz, Laura; Serrano-Huertas, Silvia; Ferreiro, Reyes; Rodriguez-Garrote, Mercedes; Sainz, Bruno; Massuti, Bartomeu; Alfonso, Pilar García; Benavides, Manuel; Aranda, Enrique; García-Bermejo, María Laura; Carrato, AlfredoFirst-line treatment with regorafenib in frail metastatic colorectal cancer (mCRC) patients has shown some benefit. To accurately identify such patients before treatment, we studied blood biomarkers and primary tumor molecules. We unveiled serum microRNAs (miRNAs), single-nucleotide polymorphisms (SNPs) in angiogenic-related genes, and Notch 1 expression as biomarkers associated with response or toxicity. MicroRNA array profiling and genotyping of selected SNPs were performed in the blood of fragile mCRC patients treated with regorafenib. Notch 1 and CRC-associated miRNA expression was also analyzed in tumors. High levels of miR-185-5p in serum, rs7993418 in the vascular endothelial growth factor receptor 1 (VEGFR1) gene, and Notch 1 expression in biopsies were associated with a favorable response to treatment. Serum levels of miR-126-3p and miR-152-3p and tumor expression of miR-92a-1-5p were associated with treatment toxicity, particularly interesting in patients exhibiting comorbidities, and high levels of miR-362-3p were associated with asthenia. Additionally, several miRNAs were associated with the presence of metastasis, local recurrence, and peritoneal metastasis. Besides, miRNAs determined in primary tumors were associated with tumor-node-metastasis (TNM) staging. The rs2305948 and rs699947 SNPs in VEGFR2 and VEGFA, respectively, were markers of poor prognosis correlating with locoregional relapse, a higher N stage, and metastatic shedding. In conclusion, VEGF and VEGFR SNPs, miRNAs, and Notch 1 levels are potential useful biomarkers for the management of advanced CRC under regorafenib treatment.Publication Reply to 'Mosaic loss of chromosome Y in leukocytes matters'.(Nature Publishing Group, 2019-01) Zhou, Weiyin; Machiela, Mitchell J; Freedman, Neal D; Rothman, Nathaniel; Malats, Nuria; Dagnall, Casey; Caporaso, Neil; Teras, Lauren T; Gaudet, Mia M; Gapstur, Susan M; Stevens, Victoria L; Jacobs, Kevin B; Sampson, Joshua; Albanes, Demetrius; Weinstein, Stephanie; Virtamo, Jarmo; Berndt, Sonja; Hoover, Robert N; Black, Amanda; Silverman, Debra; Figueroa, Jonine; Garcia-Closas, Montserrat; Real Arribas, Francisco; Earl, Julie; Marenne, Gaelle; Rodriguez-Santiago, Benjamin; Karagas, Margaret; Johnson, Alison; Schwenn, Molly; Wu, Xifeng; Gu, Jian; Ye, Yuanqing; Hutchinson, Amy; Tucker, Margaret; Perez-Jurado, Luis A; Dean, Michael; Yeager, Meredith; Chanock, Stephen J; United States Department of Health and Human ServicesPublication The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.(BMJ Publishing Group, 2024-08-08) López-Gil, Juan Carlos; García-Silva, Susana; Ruiz-Cañas, Laura; Navarro, Diego; Palencia-Campos, Adrián; Giráldez-Trujillo, Antonio; Earl, Julie; Dorado, Jorge; Gómez-López, Gonzalo; Monfort-Vengut, Ana; Alcalá, Sonia; Gaida, Matthias M; García-Mulero, Sandra; Cabezas-Sáinz, Pablo; Batres-Ramos, Sandra; Barreto, Emma; Sánchez-Tomero, Patricia; Vallespinós, Mireia; Ambler, Leah; Lin, Meng-Lay; Aicher, Alexandra; García García de Paredes, Ana; de la Pinta, Carolina; Sanjuanbenito, Alfonso; Ruz-Caracuel, Ignacio; Rodríguez-Garrote, Mercedes; Guerra, Carmen; Carrato, Alfredo; de Cárcer, Guillermo; Sánchez, Laura; Nombela-Arrieta, César; Espinet, Elisa; Sanchez-Arevalo Lobo, Víctor Javier; Heeschen, Christopher; Sainz, Bruno; Fundación La Caixa; EMBO Scientific Exchange Fellowship; Juan de la Cierva Formacion; Fero Foundation Grant; Ministerio de Economía y Competitividad (España); Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERONC (Cáncer); Xunta de Galicia (España); University of Zurich; German Research Foundation (DFG); Unión Europea. Comisión Europea. European Research Council (ERC); Fondazione AIRC per la ricerca sul cancro; Shanghai Municipal Education Commission (SHMEC); National Natural Science Foundation of China (NSFC)OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNF?)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.