47 results on '"Vanesa García-Barberán"'
Search Results
2. Genomic mapping of copy number variations influencing immune response in breast cancer
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Igor López-Cade, Vanesa García-Barberán, Esther Cabañas Morafraile, Cristina Díaz-Tejeiro, Cristina Saiz-Ladera, Adrián Sanvicente, Pedro Pérez Segura, Atanasio Pandiella, Balázs Győrffy, and Alberto Ocaña
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breast cancer ,CNVs ,Gene Amplification ,immune response ,new surface targets ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Identification of genomic alterations that influence the immune response within the tumor microenvironment is mandatory in order to identify druggable vulnerabilities. In this article, by interrogating public genomic datasets we describe copy number variations (CNV) present in breast cancer (BC) tumors and corresponding subtypes, associated with different immune populations. We identified regulatory T-cells associated with the Basal-like subtype, and type 2 T-helper cells with HER2 positive and the luminal subtype. Using gene set enrichment analysis (GSEA) for the Type 2 T-helper cells, the most relevant processes included the ERBB2 signaling pathway and the Fibroblast Growth Factor Receptor (FGFR) signaling pathway, and for CD8+ T-cells, cellular response to growth hormone stimulus or the JAK-STAT signaling pathway. Amplification of ERBB2, GRB2, GRB7, and FGF receptor genes strongly correlated with the presence of type 2 T helper cells. Finally, only 8 genes were highly upregulated and present in the cellular membrane: MILR1, ACE, DCSTAMP, SLAMF8, CD160, IL2RA, ICAM2, and SLAMF6. In summary, we described immune populations associated with genomic alterations with different BC subtypes. We observed a clear presence of inhibitory cells, like Tregs or Th2 when specific chromosomic regions were amplified in basal-like or HER2 and luminal groups. Our data support further evaluation of specific therapeutic strategies in specific BC subtypes, like those targeting Tregs in the basal-like subtype.
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- 2022
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3. Real-World Use of Highly Sensitive Liquid Biopsy Monitoring in Metastatic Breast Cancer Patients Treated with Endocrine Agents after Exposure to Aromatase Inhibitors
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Jesús Fuentes-Antrás, Ana Martínez-Rodríguez, Kissy Guevara-Hoyer, Igor López-Cade, Víctor Lorca, Alejandro Pascual, Alicia de Luna, Carmen Ramírez-Ruda, Jennifer Swindell, Paloma Flores, Ana Lluch, David W. Cescon, Pedro Pérez-Segura, Alberto Ocaña, Frederick Jones, Fernando Moreno, Vanesa García-Barberán, and José Ángel García-Sáenz
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breast cancer ,liquid biopsy ,ctDNA ,endocrine resistance ,precision medicine ,real-world evidence ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Endocrine-resistant, hormone receptor-positive, and HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) is largely governed by acquired mutations in the estrogen receptor, which promote ligand-independent activation, and by truncal alterations in the PI3K signaling pathway, with a broader range of gene alterations occurring with less prevalence. Circulating tumor DNA (ctDNA)-based technologies are progressively permeating the clinical setting. However, their utility for serial monitoring has been hindered by their significant costs, inter-technique variability, and real-world patient heterogeneity. We interrogated a longitudinal collection of 180 plasma samples from 75 HR+/HER2- mBC patients who progressed or relapsed after exposure to aromatase inhibitors and were subsequently treated with endocrine therapy (ET) by means of highly sensitive and affordable digital PCR and SafeSEQ sequencing. Baseline PIK3CA and TP53 mutations were prognostic of a shorter progression-free survival in our population. Mutant PIK3CA was prognostic in the subset of patients receiving fulvestrant monotherapy after progression to a CDK4/6 inhibitor (CDK4/6i)-containing regimen, and its suppression was predictive in a case of long-term benefit with alpelisib. Mutant ESR1 was prognostic in patients who did not receive concurrent CDK4/6i, an impact influenced by the variant allele frequency, and its early suppression was strongly predictive of efficacy and associated with long-term benefit in the whole cohort. Mutations in ESR1, TP53, and KRAS emerged as putative drivers of acquired resistance. These findings collectively contribute to the characterization of longitudinal ctDNA in real-world cases of HR+/HER2- mBC previously exposed to aromatase inhibitors and support ongoing studies either targeting actionable alterations or leveraging the ultra-sensitive tracking of ctDNA.
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- 2023
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4. Durable benefit and change in TCR clonality with nivolumab in a Lynch syndrome–associated glioma
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Santiago Cabezas-Camarero, Rebeca Pérez-Alfayate, Vanesa García-Barberán, María Carmen Polidura, María Natividad Gómez-Ruiz, Isabel Casado-Fariñas, Issa Ahmad Subhi-Issa, José Carlos Plaza Hernández, Pilar Garre, Isabel Díaz-Millán, and Pedro Pérez-Segura
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Germline replication-repair deficient (gRRD) gliomas are exceptional events, and only a few of them have been treated with immune checkpoint inhibitors (ICIs). Contrary to sporadic gliomas, where ICIs have failed to show any objective benefit, the very few patients with gRRD gliomas treated with ICIs to date seem to benefit from programmed-death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, either in terms of durable responses or in terms of survival. T-cell immunohistochemistry (IHC) and T-cell receptor (TCR) repertoire using high-throughput next-generation sequencing (NGS) with the Oncomine TCR-Beta-SR assay (Thermo Fisher Scientific) were analyzed in pre- and post-nivolumab tumor biopsies obtained from a patient with a Lynch syndrome-associated glioma due to a germline pathogenic hMLH1 mutation. The aim was to describe changes in the T-cell quantity and clonality after treatment with nivolumab to better understand the role of acquired immunity in gRRD gliomas. The patient showed a slow disease progression and overall survival of 10 months since the start of anti-PD-1 therapy with excellent tolerance. A very scant T-cell infiltrate was observed both at initial diagnosis and after four cycles of nivolumab. The drastic change observed in TCR clonality in the post-nivolumab biopsy may be explained by the highly spatial and temporal heterogeneity of glioblastomas. Despite the durable benefit from nivolumab, the scant T-cell infiltrate possibly explains the lack of objective response to anti-PD-1 therapy. The major change in TCR clonality observed after nivolumab possibly reflects the evolving molecular heterogeneity in a highly pre-treated disease. An in-deep review of the available literature regarding the role of ICIs in both sporadic and gRRD gliomas was conducted.
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- 2022
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5. Cancer-associated fibroblast-derived gene signatures determine prognosis in colon cancer patients
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Mercedes Herrera, Alberto Berral-González, Igor López-Cade, Cristina Galindo-Pumariño, Santiago Bueno-Fortes, Manuel Martín-Merino, Alfredo Carrato, Alberto Ocaña, Carolina De La Pinta, Ana López-Alfonso, Cristina Peña, Vanesa García-Barberán, and Javier De Las Rivas
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Colon Cancer ,Tumor microenvironment ,Cancer-associated fibroblasts ,Exosomes ,Noncoding RNAs ,Prognostic signatures ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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6. Transcriptomic Correlates of Immunologic Activation in Head and Neck and Cervical Cancer
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Cristina Saiz-Ladera, Mariona Baliu-Piqué, Francisco J. Cimas, Aránzazu Manzano, Vanesa García-Barberán, Santiago Cabezas Camarero, Gonzalo Fernández Hinojal, Atanasio Pandiella, Balázs Győrffy, David Stewart, Juan J. Cruz-Hernández, Pedro Pérez-Segura, and Alberto Ocana
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head and neck squamous cell carcinoma (HNSCC) ,human papillomavirus ,transcriptome signature ,immune gene signatures ,cervical squamous cell carcinoma (CSCC) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Targeting the immune system has emerged as an effective therapeutic strategy for the treatment of various tumor types, including Head and Neck Squamous Cell Carcinoma (HNSCC) and Non-small-Cell Lung Cancer (NSCLC), and checkpoint inhibitors have shown to improve patient survival in these tumor types. Unfortunately, not all cancers respond to these agents, making it necessary to identify responsive tumors. Several biomarkers of response have been described and clinically tested. As of yet what seems to be clear is that a pre-activation state of the immune system is necessary for these agents to be efficient. In this study, using established transcriptomic signatures, we identified a group of gene combination associated with favorable outcome in HNSCC linked to a higher presence of immune effector cells. CD2, CD3D, CD3E, and CXCR6 combined gene expression is associated with improved outcome of HNSCC patients and an increase of infiltrating immune effector cells. This new signature also identifies a subset of cervical squamous cell carcinoma (CSCC) patients with favorable prognosis, who show an increased presence of immune effector cells in the tumor, which outcome shows similarities with the HP-positive HNSCC cohort of patients. In addition, CD2, CD3D, CD3E, and CXCR6 signature is able to predict the best favorable prognosis in terms of overall survival of CSSC patients. Of note, these findings were not reproduced in other squamous cell carcinomas like esophageal SCC or lung SCC. Prospective confirmatory studies should be employed to validate these findings.
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- 2021
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7. A Transcriptomic Immunologic Signature Predicts Favorable Outcome in Neoadjuvant Chemotherapy Treated Triple Negative Breast Tumors
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Javier Pérez-Pena, Janos Tibor Fekete, Raquel Páez, Mariona Baliu-Piqué, José Ángel García-Saenz, Vanesa García-Barberán, Aránzazu Manzano, Pedro Pérez-Segura, Azucena Esparis-Ogando, Atanasio Pandiella, Balázs Gyorffy, and Alberto Ocana
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immunotherapy ,triple negative breast cancer ,chemotherapy treated patients ,transcriptomic signature ,outcome ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Limited therapeutic options exist for the treatment of patients with triple negative breast cancer (TNBC). Neoadjuvant chemotherapy is currently the standard of care treatment in the early stages of the disease, although reliable biomarkers of response have been scarcely described. In our study we explored whether immunologic signatures associated with inflamed tumors or hot tumors could predict the outcome to neoadjuvant chemotherapy. Publicly available transcriptomic data of more than 2,000 patients were evaluated. ROC plots were generated to assess the response to therapy. Cox proportional hazards regression was computed. Kaplan-Meier plots were drawn to visualize the survival differences. Higher expression of IDO1, CXCL9, CXCL10, HLA-DRA, HLA-E, STAT1, and GZMB were associated with a higher proportion without relapse in the first 5 y after chemotherapy in TNBC. The expression of these genes was associated with a high presence of CD8 T cells in responder patients using the EPIC bioinformatic tool. The strongest effect was observed for STAT1 (p = 1.8e-05 and AUC 0.69, p = 2.7e-06). The best gene-set signature to predict favorable RFS was the combination of IDO1, LAG3, STAT1, and GZMB (HR = 0.28, CI = 0.17–0.46, p = 9.8 E-08, FDR = 1%). However, no influence on pathological complete response (pCR) was observed. Similarly, no benefit was identified in any other tumor subtype: HER2 or estrogen receptor positive. In conclusion, we describe a set of immunologic genes that predict the outcome to neoadjuvant chemotherapy in TNBC, but not pCR, suggesting that this non-time to event endpoint is not a good surrogate marker to detect the long term outcome for immune activated tumors.
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- 2019
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8. Differential distribution and enrichment of non-coding RNAs in exosomes from normal and Cancer-associated fibroblasts in colorectal cancer
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Mercedes Herrera, Carlos Llorens, Marta Rodríguez, Alberto Herrera, Ricardo Ramos, Beatriz Gil, Antonio Candia, María Jesús Larriba, Pilar Garre, Julie Earl, Mercedes Rodríguez-Garrote, Trinidad Caldés, Félix Bonilla, Alfredo Carrato, Vanesa García-Barberán, and Cristina Peña
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Colon Cancer ,Liquid biopsy ,Tumor microenvironment ,Exosomes ,Non-coding RNAs ,Next generation sequencing ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Exosome production from cancer-associated fibroblasts seems to be an important driver of tumor progression. We report the first in-depth biotype characterization of ncRNAs, analyzed by Next Generation Sequencing and Bioinformatics, expressed in established primary human normal and cancer-associated fibroblasts (CAFs) from cancer and normal mucosa tissues from 9 colorectal cancer patients, and/or packaged in their derived exosomes. Differential representation and enrichment analyses based on these ncRNAs revealed a significant number of differences between the ncRNA content of exosomes and the expression patterns of the normal and cancer-associated fibroblast cells. ncRNA regulatory elements are specifically packaged in CAF-derived exosomes, supporting a specific cross-talk between CAFs and colon cancer cells and/or other stromal cells, mediated by exosomes. These sncRNAs are potential biomarkers present in cancer-associated fibroblast-derived exosomes, which should thereby contribute to developing new non-invasive diagnostic, prognostic and predictive methods for clinical applications in management of cancer patients.
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- 2018
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9. Role of GALNT12 in the genetic predisposition to attenuated adenomatous polyposis syndrome.
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Víctor Lorca, Daniel Rueda, Lorena Martín-Morales, Carmen Poves, María Jesús Fernández-Aceñero, Clara Ruiz-Ponte, Patricia Llovet, David Marrupe, Vanesa García-Barberán, Beatriz García-Paredes, Pedro Pérez-Segura, Miguel de la Hoya, Eduardo Díaz-Rubio, Trinidad Caldés, and Pilar Garre
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Medicine ,Science - Abstract
The involvement of GALNT12 in colorectal carcinogenesis has been demonstrated but it is not clear to what extent it is implicated in familial CRC susceptibility. Partially inactivating variant, NM_024642.4:c.907G>A, p.(D303N), has been previously detected in familial CRC and proposed as the causative risk allele. Since phenotypes of the described carrier families showed not only CRC but also a polyp history, we hypothesized that GALNT12 could be involved in adenoma predisposition and consequently, in hereditary polyposis CRC syndromes. For that purpose, we have screened the GALNT12 gene in germline DNA from 183 unrelated attenuated polyposis patients. c.907G>A, p.(D303N) was detected in 4 cases (MAF = 1.1%) and no other candidate variants were found. After segregation studies, LOH analyses, glycosylation pattern tests and case-control studies, our results did not support the role of c.907G>A, p.(D303N) as a high-penetrance risk allele for polyposis CRC.
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- 2017
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10. Clinical Behavior, Mutational Profile and T-Cell Repertoire of High-Grade Neuroendocrine Tumors of the Head and Neck
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Santiago Cabezas-Camarero, Vanesa García-Barberán, Javier David Benítez-Fuentes, Miguel J. Sotelo, José Carlos Plaza, Alejandro Encinas-Bascones, Óscar De-la-Sen, Farzin Falahat, Jesús Gimeno-Hernández, Manuel Gómez-Serrano, Fernando Puebla-Díaz, Manuel De-Pedro-Marina, Maricruz Iglesias-Moreno, and Pedro Pérez-Segura
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Cancer Research ,Oncology ,head and neck cancer ,neuroendocrine ,T-cell repertoire ,tumor mutational burden ,immunotherapy - Abstract
Neuroendocrine carcinomas (NECs) of the head and neck (HN) account for
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- 2023
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11. Abstract P3-05-06: Genome-wide DNA methylation analysis identifies novel biomarkers associated with risk of relapse beyond oncotype DX recurrence-score risk assessment within HR+/HER2- early-stage breast cancer patients
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Jesus Fuentes-Antrás, Vanesa García-Barberán, Nicolas Costa-Fraga, Fernando Moreno, Aida Bao-Caamano, Aitor Rodríguez-Casanova, Alfonso López de Sá, Alicia De Luna, Igor Lopez-Cade, Carmen Ramirez-Ruda, Alejando Pascual, Pedro Perez-Segura, Balázs Győrffy, Alberto Ocaña, Angel Diaz-Lagares, and Jose Angel Garcia-Saenz
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Cancer Research ,Oncology - Abstract
Background: Early-stage, node-negative, hormone receptor positive (HR+) HER2 negative (HER2-) breast cancer (BC) patients comprise a subset with good prognosis. Based on gene expression panels, these patients may skip chemotherapy and complete adjuvant endocrine therapy as an individual genomic basis assessment. However, up to 15% of patients categorized as non-high risk by Oncotype DX (Recurrence Score, RS≤25) may experience disease relapse. The field of cancer epigenomics is emerging as a dynamic tool to complement prognostic expression analyses and to provide further insight into the biological underpinnings of early HR+/HER2- BC. Methods: A genome-wide DNA methylation profiling in tumor tissue samples, from node-negative HR+/HER2- BC patients with available Oncotype DX RS data, was analyzed using the Illumina MethylationEPIC 850K BeadChip. We evaluated all differential methylation patterns independently of their position to establish a bioinformatic analytical pipeline. The online tools KM Plotter and ROC Plotter were used to assess the impact of survival outcomes (5-year relapse-free survival, RFS) and response to therapy of the candidate genes. Individual patient data from TCGA was used to analyze the correlation between methylation and mRNA levels in HR+/HER2- BC patients. Statistical significance was defined by p Citation Format: Jesus Fuentes-Antrás, Vanesa García-Barberán, Nicolas Costa-Fraga, Fernando Moreno, Aida Bao-Caamano, Aitor Rodríguez-Casanova, Alfonso López de Sá, Alicia De Luna, Igor Lopez-Cade, Carmen Ramirez-Ruda, Alejando Pascual, Pedro Perez-Segura, Balázs Győrffy, Alberto Ocaña, Angel Diaz-Lagares, Jose Angel Garcia-Saenz. Genome-wide DNA methylation analysis identifies novel biomarkers associated with risk of relapse beyond oncotype DX recurrence-score risk assessment within HR+/HER2- early-stage breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-05-06.
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- 2022
12. BRIP1, a Gene Potentially Implicated in Familial Colorectal Cancer Type X
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Patricia Llovet, Vanesa García-Barberán, Víctor Lorca, Maria Luisa Gonzalez-Morales, Marta Cazorla, Lorena Martín-Morales, Clara Esteban-Jurado, Pilar Garre, Inmaculada Bando, Trinidad Caldés, Sergi Castellví-Bel, and Miguel de la Hoya
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Familial Colorectal Cancer Type X ,Colorectal cancer ,business.industry ,Genetic counseling ,BRIP1 ,Disease ,Molecular diagnostics ,medicine.disease ,Frameshift mutation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,Ovarian cancer - Abstract
Familial colorectal cancer Type X (FCCTX) comprises a heterogeneous group of families with an increased risk of developing colorectal cancer and other related tumors, but with mismatch repair–proficient, microsatellite-stable (MSS) tumors. Unfortunately, the genetic basis underlying their cancer predisposition remains unknown. Although pathogenic germline variants in BRIP1 increase the risk of developing hereditary ovarian cancer, the involvement of BRIP1 in hereditary colorectal cancer is still not well known. In order to identify new BRIP1 variants associated with inherited colorectal cancer, affected and nonaffected individuals from 18 FCCTX or high-risk MSS colorectal cancer families were evaluated by whole-exome sequencing, and another 62 colorectal cancer patients from FCCTX or high-risk MSS colorectal cancer families were screened by a next-generation sequencing (NGS) multigene panel. The families were recruited at the Genetic Counseling Unit of Hospital Clínico San Carlos of Madrid. A total of three different BRIP1 mutations in three unrelated families were identified. Among them, there were two frameshift variants [c.1702_1703del, p.(Asn568TrpfsTer9) and c.903del, p.(Leu301PhefsTer2)] that result in the truncation of the protein and are thus classified as pathogenic (class 5). The remaining was a missense variant [c.2220G>T, p.(Gln740His)] considered a variant of uncertain significance (class 3). The segregation and loss-of-heterozygosity studies provide evidence linking the two BRIP1 frameshift variants to colorectal cancer risk, with suggestive but not definitive evidence that the third variant may be benign. The results here presented suggest that germline BRIP1 pathogenic variants could be associated with hereditary colorectal cancer predisposition. Prevention Relevance: We suggest that BRIP1 pathogenic germline variants may have a causal role in CRC as moderate cancer susceptibility alleles and be associated with hereditary CRC predisposition. A better understanding of hereditary CRC may provide important clues to disease predisposition and could contribute to molecular diagnostics, improved risk stratification, and targeted therapeutic strategies.
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- 2021
13. Genomic Mapping of Splicing-Related Genes Identify Amplifications in LSM1, CLNS1A, and ILF2 in Luminal Breast Cancer
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Balázs Győrffy, Vanesa García-Barberán, Alberto Ocaña, María Del Mar Noblejas-López, Miguel de la Hoya, José A. García-Sáenz, Igor López-Cade, Atanasio Pandiella, Pedro Pérez-Segura, Jesús Fuentes-Antrás, Ada Esteban-Sánchez, Gonzalo Fernández-Hinojal, Aránzazu Manzano, Instituto de Salud Carlos III, Acepain Albacete, Fundación CRIS contra el Cáncer, Diputación de Albacete, European Commission, Ministerio de Educación (España), and Ministry of Innovation and Technology (Hungary)
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Cancer Research ,Alternative splicing ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Biology ,medicine.disease ,Article ,Novel gene ,Transcriptome ,Breast cancer ,luminal breast cancer ,Splicing pathway ,Luminal breast cancer ,Oncology ,RNA splicing ,splicing pathway ,medicine ,Cancer research ,splice ,Epigenetics ,BET inhibitors ,Gene ,RC254-282 - Abstract
© 2021 by the authors., Alternative splicing is an essential biological process, which increases the diversity and complexity of the human transcriptome. In our study, 304 splicing pathway-related genes were evaluated in tumors from breast cancer patients (TCGA dataset). A high number of alterations were detected, including mutations and copy number alterations (CNAs), although mutations were less frequently present compared with CNAs. In the four molecular subtypes, 14 common splice genes showed high level amplification in >5% of patients. Certain genes were only amplified in specific breast cancer subtypes. Most altered genes in each molecular subtype clustered to a few chromosomal regions. In the Luminal subtype, amplifications of LSM1, CLNS1A, and ILF2 showed a strong significant association with prognosis. An even more robust association with OS and RFS was observed when expression of these three genes was combined. Inhibition of LSM1, CLNS1A, and ILF2, using siRNA in MCF7 and T47D cells, showed a decrease in cell proliferation. The mRNA expression of these genes was reduced by treatment with BET inhibitors, a family of epigenetic modulators. We map the presence of splicing-related genes in breast cancer, describing three novel genes, LSM1, CLNS1A, and ILF2, that have an oncogenic role and can be modulated with BET inhibitors., A.O.’s lab is supported by the Instituto de Salud Carlos III (ISCIII, PI19/00808); ACEPAIN; CRIS Cancer Foundation and Diputación de Albacete. This research is also supported by PI18/01020 from the Instituto de Salud Carlos III and co-financed by the European Development Regional Fund (FEDER) “A way to achieve Europe” (ERDF); N.L. MDM was supported by the Spanish Ministry of Education (FPU grant; Ref.: FPU18/01319). B.G. was financed by the 2018-2.1.17-TETKR-00001, 2020-1.1.6-JÖVO-2021-00013, and 2018-1.3.1-VKE-2018-00032 grants and by the Higher ˝ Education Institutional Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary.
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- 2021
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14. Comparison of the Clinical Sensitivity of the Idylla Platform and the OncoBEAM RAS CRC Assay for KRAS Mutation Detection in Liquid Biopsy Samples
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Maria Rosario Chica Parrado, Maria Auxiliadora Gómez-España, Eduardo Díaz-Rubio, Manuel Benavides, Ana Vivancos, Marta Toledano, Enrique Aranda, Vanesa García-Barberán, Martina Alvarez, Elena Elez, Institut Català de la Salut, [Vivancos A] Grup de genòmica del Càncer, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. [Aranda E, Gómez-España MA] Department of Medical Oncology, Reina Sofía University Hospital, CIBERONC, Córdoba, Spain. [Benavides M] Department of Medical Oncology, Hospital Universitario Regional y Virgen de la Victoria, Málaga, Spain. [Élez E] Servei d’Oncologia Mèdica, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. [Toledano M] IMIBIC Instituto Maimonides Investigación Biomédica de Córdoba, Córdoba, Spain., and Hospital Verge de la Cinta de Tortosa
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0301 basic medicine ,Male ,Colorectal cancer ,Mutant ,DNA Mutational Analysis ,lcsh:Medicine ,medicine.disease_cause ,Gastroenterology ,0302 clinical medicine ,Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytodiagnosis::Biopsy::Liquid Biopsy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Other subheadings::/diagnosis [Other subheadings] ,lcsh:Science ,Early Detection of Cancer ,enzimas y coenzimas::enzimas::hidrolasas::ácido anhídrido hidrolasas::GTP fosfohidrolasas::proteínas de unión al GTP::proteínas de unión al GTP monoméricas::proteínas ras::proteínas protooncogénicas p21(ras) [COMPUESTOS QUÍMICOS Y DROGAS] ,Aged, 80 and over ,Mutation ,Multidisciplinary ,Otros calificadores::Otros calificadores::/genética [Otros calificadores] ,neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES] ,Enzimas y Coenzimas::Enzimas::Hidrolasas::Ácido Anhídrido Hidrolasas::GTP Fosfohidrolasas::Proteínas de Unión al GTP::Proteínas de Unión al GTP Monoméricas::Proteínas ras::Proteínas Proto-Oncogénicas p21(ras) [COMPUESTOS QUÍMICOS Y DROGAS] ,Middle Aged ,Prognosis ,diagnóstico::técnicas y procedimientos diagnósticos::técnicas de laboratorio clínico::técnicas citológicas::citodiagnóstico::biopsia::biopsia líquida [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Female ,KRAS ,Colorectal Neoplasms ,Biòpsia ,Cell-Free Nucleic Acids ,Oncogens Ras ,Neoplasias::Neoplasias por Localización::Neoplasias del Sistema Digestivo::Neoplasias Gastrointestinales::Neoplasias Intestinales::Neoplasias Colorrectales [ENFERMEDADES] ,Adult ,medicine.medical_specialty ,Concordance ,Otros calificadores::/diagnóstico [Otros calificadores] ,Article ,Cancer screening ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Gastrointestinal cancer ,Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES] ,Internal medicine ,medicine ,Biomarkers, Tumor ,Other subheadings::Other subheadings::/genetics [Other subheadings] ,Humans ,Liquid biopsy ,Allele ,neoplasms ,Aged ,Enzymes and Coenzymes::Enzymes::Hydrolases::Acid Anhydride Hydrolases::GTP Phosphohydrolases::GTP-Binding Proteins::Monomeric GTP-Binding Proteins::ras Proteins::Proto-Oncogene Proteins p21(ras) [CHEMICALS AND DRUGS] ,business.industry ,lcsh:R ,Liquid Biopsy ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Còlon - Càncer - Diagnòstic ,lcsh:Q ,business ,030217 neurology & neurosurgery ,Kras mutation - Abstract
KRAS mutations are common in colorectal cancer (CRC). In this setting, mutation status determination in circulating-free DNA from blood samples (liquid biopsy) has been shown to be a viable alternative to tissue testing. The objective of this study was to compare the sensitivity of two liquid biopsy methods for detecting KRAS mutations in plasma samples from metastatic CRC patients. Samples with a positive (KRAS-MUT+) result and a mutant allelic fraction (MAF) KRAS mutations in 81/116 OncoBEAM KRAS-MUT+ samples with MAF KRAS mutations than Idylla. Importantly, our data identified a “gray zone” below 1% MAF where Idylla showed reduced KRAS mutation detection, highlighting the importance of an accurate method to provide the mutational status of CRC patients.
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- 2019
15. Detection of IDH1 Mutations in Plasma Using BEAMing Technology in Patients with Gliomas
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Santiago Cabezas-Camarero, Vanesa García-Barberán, Rebeca Pérez-Alfayate, Isabel Casado-Fariñas, Hillary Sloane, Frederick S. Jones, and Pedro Pérez-Segura
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Cancer Research ,Oncology ,glioma ,IDH1 ,liquid biopsy ,circulating tumour DNA ,ctDNA - Abstract
Molecular testing using blood-based liquid biopsy approaches has not been widely investigated in patients with glioma. A prospective single-center study enrolled patients with gliomas ranging from grade II to IV. Peripheral blood (PB) was drawn at different timepoints for circulating tumour DNA (ctDNA) monitoring. Next-generation sequencing (NGS) was used for the study of isocitrate dehydrogenase 1 (IDH1) mutations in the primary tumor. Beads, Emulsion, Amplification and Magnetics (BEAMing) was used for the study of IDH1 mutations in plasma and correlated with the NGS results in the tumor. Between February 2017 and July 2018, ten patients were enrolled, six with IDH1-mutant and four with IDH1 wild-type gliomas. Among the six IDH-mutant gliomas, three had the same IDH1 mutation detected in plasma (50%), and the IDH1-positive ctDNA result was obtained in patients either at diagnosis (no treatment) or during progressive disease. While the false-negative rate reached 86% (18/21), 15 out of the 18 (83%) plasma-negative results were from PB collected from the six IDH-mutant patients at times at which there was no accompanying evidence of tumor progression, as assessed by MRI. There were no false-positive cases in plasma collected from patients with IDH1 wild-type tumors. BEAMing detected IDH1 mutations in the plasma of patients with gliomas, with a modest clinical sensitivity (true positivity rate) but with 100% clinical specificity, with complete agreement between the mutant loci detected in tumor and plasma. Larger prospective studies should be conducted to expand on these findings, and further explore the clearance of mutations in PB from IDH1-positive patients in response to therapy.
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- 2022
16. Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer
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Mariona Baliu-Piqué, María Del Mar Noblejas-López, Alberto Ocaña, Balázs Győrffy, Esther Cabañas Morafraile, Vanesa García-Barberán, Eva María Galán-Moya, Pedro Pérez-Segura, Ana Alcaraz-Sanabria, Atanasio Pandiella, Igor López-Cade, Jesús Fuentes-Antrás, Aránzazu Manzano, Instituto de Salud Carlos III, Acepain Albacete, Diputación de Albacete, Fundación CRIS contra el Cáncer, Ministerio de Economía y Competitividad (España), Junta de Castilla y León, Ministry of Innovation and Technology (Hungary), and Semmelweis University
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0301 basic medicine ,Cancer Research ,Estrogen receptor ,Gene mutation ,medicine.disease_cause ,ubiquitination ,NEDD8 ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,neddylation ,breast cancer ,medicine ,Neddylation ,Triple-negative breast cancer ,business.industry ,Ubiquitination ,Cancer ,biomarkers ,medicine.disease ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,SUMOylation ,030104 developmental biology ,Oncology ,post-translational modification ,030220 oncology & carcinogenesis ,Cancer research ,prognosis ,Post-translational modification ,Carcinogenesis ,business ,Biomarkers - Abstract
© 2021 by the authors., The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer., Work in Alberto Ocaña’s lab is supported by the Instituto de Salud Carlos III (ISCIII, PI19/00808); ACEPAIN; Diputación de Albacete; and the CRIS Cancer Foundation. Work in Atanasio Pandiella’s lab is supported by the Ministry of Economy and Competitiveness of Spain (BFU2015- 71371-R, the Junta de Castilla y León (CSI146P20), and the CRIS Foundation. Balázs Györffy is financed by the 2018-2.1.17-TET-KR-00001 grant and by the Higher Education Institutional Excellence Programme of the Ministry for Innovation and Technology (MIT) in Hungary, within the framework of the Bionic thematic programme of the Semmelweis University.
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- 2021
17. Cancer-associated fibroblast-derived gene signatures determine prognosis in colon cancer patients
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Vanesa García-Barberán, Carolina de la Pinta, Santiago Bueno-Fortes, Igor López-Cade, Alberto Berral-Gonzalez, Cristina Peña, Cristina Galindo-Pumariño, Ana López-Alfonso, Alfredo Carrato, Mercedes Herrera, M. Martin-Merino, Alberto Ocaña, Javier De Las Rivas, Instituto de Salud Carlos III, European Commission, and Asociación Española Contra el Cáncer
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Cancer Research ,Colorectal cancer ,Noncoding RNAs ,Cancer associated fibroblast ,Biology ,Exosomes ,medicine ,Biomarkers, Tumor ,Humans ,Liquid biopsy ,Gene ,Letter to the Editor ,RC254-282 ,Cancer-associated fibroblasts ,Neoplasm Staging ,Tumor microenvironment ,Colon Cancer ,Prognostic signatures ,Gene Expression Profiling ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Prognosis ,Microvesicles ,Gene Expression Regulation, Neoplastic ,Oncology ,Colonic Neoplasms ,Cancer research ,Molecular Medicine ,Cancer-Associated Fibroblasts - Abstract
© The Author(s), Paracrine communication between tumor and surrounding stroma arbitrates the malignant behavior of cancer progression [1]. Fibroblasts, which are the main cell type within the stroma and are called cancer-associated fibroblasts (CAFs), orchestrate the crosstalk with cancer cells [2, 3] and express several markers associated with prognosis [4]. There is increasing evidence that a stroma-specific signature could be used for risk assessment in colon cancer (CC). According to the Consensus Molecular Subtype classification (CMS) in CC, the mesenchymal or CMS4 group is characterized by stromal invasion, extracellular matrix remodeling and TGF-β signaling activation. It is associated with the worst prognosis rates [5, 6]. Genes correlating with the mesenchymal subtype are mostly expressed by CAFs and other stromal cells, rather than by tumor cells [7]. Accordingly, our group defined a gene expression profile associated with CAFs with high pro-migratory effects on colon tumor cells, which was associated with patients’ poor prognosis. These were mostly advanced-stage patients [8]., This research is supported by PI17/01847, PI18/01020 and PI20/00602 from the Instituto de Salud Carlos III and co-financed by the European Development Regional Fund (FEDER) “A way to achieve Europe” (ERDF); by “CIBER de Cáncer”, CB16/12/00273, CB16/12/00301 and CB16/12/00446, from the Instituto de Salud Carlos III-FEDER; and by the Fundación Científica AECC (a multifaceted approach to targeting pancreatic cancer). The JDLR group also acknowledges the funding provided by the Instituto de Salud Carlos III (ISCiii, AES) in grants PI18/00591 and PT17/0009/0008, co-financed by the European Development Regional Fund (FEDER).
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- 2021
18. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
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Pascal Guénel, John J. Spinelli, Hoda Anton-Culver, Veli-Matti Kosma, Beth Y. Karlan, Antonis C. Antoniou, Brian D. Carter, Drakoulis Yannoukakos, Orland Diez, Montserrat Garcia-Closas, Uffe Birk Jensen, Susan M. Gapstur, Christine L. Clarke, Florentia Fostira, Trinidad Caldés, Wei Zheng, Diana Eccles, Don M. Conroy, Kristan J. Aronson, Sara Margolin, Thomas U. Ahearn, Hedy S. Rennert, Evgeny N. Imyanitov, Rulla M. Tamimi, Mary Beth Terry, Jenny Chang-Claude, Per Hall, Daniel R. Barnes, Alex Teulé, D. Gareth Evans, Åke Borg, Frans B. L. Hogervorst, Yon-Dschun Ko, Celine M. Vachon, Graham G. Giles, Simona Agata, Gad Rennert, Yuan Chun Ding, J. Margriet Collée, Alison M. Dunning, Regina M. Santella, Banu Arun, William J. Tapper, Melissa C. Southey, Finn Cilius Nielsen, Michael T. Parsons, Marjanka K. Schmidt, Alfons Meindl, Vassilios Georgoulias, Simon A. Gayther, Debra Frost, Noura Mebirouk, Hebon Investigators, Austin Miller, Sue K. Park, Anthony J Swerdlow, Emmanouil Saloustros, Isabel dos-Santos-Silva, Laura Ottini, Jack A. Taylor, Siranoush Manoukian, Maria A. Caligo, Douglas F. Easton, Christoph Engel, Antoinette Hollestelle, Ana Vega, Muriel A. Adank, Mia M. Gaudet, Heko Becher, Lothar Haeberle, Priyanka Sharma, Katherine L. Nathanson, Mads Thomassen, Miriam Dwek, Manuela Gago-Dominguez, Hiltrud Brauch, Kamila Czene, Peter A. Fasching, Peter J. Hulick, David E. Goldgar, Lesley McGuffog, Anna Jakubowska, Paul D.P. Pharoah, Adrià López-Fernández, Bruce Poppe, Volker Arndt, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Jennifer Stone, Wendy K. Chung, Joseph Vijai, Qin Wang, Penny Soucy, Miquel Angel Pujana, Diether Lambrechts, Vanesa García-Barberán, Andrea Gehrig, Anna González-Neira, Thérèse Truong, Jenny Lester, Wei He, Dale P. Sandler, Rita K. Schmutzler, Julian Peto, A. Heather Eliassen, Paolo Radice, Yael Laitman, Johanna Rantala, Kelly-Anne Phillips, Amanda E. Toland, Bernardo Bonanni, Muhammad Usman Rashid, Heli Nevanlinna, John L. Hopper, Kevin Punie, kConFab Investigators, Thilo Dörk, Judy Garber, Alison H. Trainer, Irene L. Andrulis, Jeffrey N. Weitzel, Michael Jones, Caroline Baynes, David J. Hunter, Mark S. Goldberg, Kristiina Aittomäki, Barbara Burwinkel, Jonathan Beesley, Maria Rossing, Norbert Arnold, Kathleen Claes, Renske Keeman, Esther M. John, John W.M. Martens, Katie M. O'Brien, Paolo Peterlongo, Mark H. Greene, Tracy A. O'Mara, Saundra S. Buys, Craig Luccarini, Atocha Romero, Paul A. James, Siddhartha Yadav, Zoe Steinsnyder, Diana Torres, Rudolf Kaaks, Camilla Wendt, Fabienne Lesueur, Ana Osorio, Olufunmilayo I. Olopade, Christopher A. Haiman, Agnes Jager, Tricia Lindstrom, Peter Devilee, Kristin K. Zorn, Loic Le Marchand, Darling J. Horcasitas, Michael Lush, Mark E. Robson, Jennifer T. Loud, Roger L. Milne, Lin Fritschi, Johanna I. Kiiski, Eric Hahnen, Jacques Simard, Annelie Augustinsson, Stig E. Bojesen, Kenneth Offit, Nadine Andrieu, Xiaohong R. Yang, Pooja Middha Kapoor, Joe Dennis, Beth N. Peshkin, Nadege Presneau, Darcy L. Thull, Fergus J. Couch, Gunnar Schmidt, Ute Hamann, Susan M. Domchek, Henrik Flyger, Mary B. Daly, Håkan Olsson, Clarice R. Weinberg, Niclas Håkansson, Elza Khusnutdinova, Inge Søkilde Pedersen, Manjeet K. Bolla, Steven N. Hart, Carl Blomqvist, Janet E. Olson, Maren T. Scheuner, Barbara Wappenschmidt, Marc Tischkowitz, Dominique Stoppa-Lyonnet, Nadine Tung, Stephen J. Chanock, Leslie Bernstein, Mikael Eriksson, José A. García-Sáenz, Jonathan Tyrer, Jose E. Castelao, Peter Kraft, Goska Leslie, Arto Mannermaa, Christopher G. Scott, Jacopo Azzollini, Eitan Friedman, Allison W. Kurian, Katarzyna Białkowska, Argyrios Ziogas, Hermann Brenner, Andrew K. Godwin, Patricia Harrington, Juliette Coignard, Daniele Campa, Susan L. Neuhausen, Marco Montagna, Marina Bermisheva, Alicja Wolk, Eric C. Polley, Abctb Investigators, and Daniel Barrowdale
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Adult ,Genotype ,media_common.quotation_subject ,Science ,Quantitative Trait Loci ,General Physics and Astronomy ,Breast Neoplasms ,02 engineering and technology ,Brca1 brca2 ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Linkage Disequilibrium ,03 medical and health sciences ,Breast cancer ,Cancer epidemiology ,Humans ,Genetic Predisposition to Disease ,Author Correction ,Cancer genetics ,Alleles ,030304 developmental biology ,media_common ,BRCA2 Protein ,0303 health sciences ,Multidisciplinary ,BRCA1 Protein ,Published Erratum ,General Chemistry ,Art ,Middle Aged ,021001 nanoscience & nanotechnology ,3. Good health ,Risk factors ,Mutation ,Female ,0210 nano-technology ,Humanities ,Genome-Wide Association Study - Abstract
Author(s): Coignard, Juliette; Lush, Michael; Beesley, Jonathan; O'Mara, Tracy A; Dennis, Joe; Tyrer, Jonathan P; Barnes, Daniel R; McGuffog, Lesley; Leslie, Goska; Bolla, Manjeet K; Adank, Muriel A; Agata, Simona; Ahearn, Thomas; Aittomaki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Arun, Banu K; Augustinsson, Annelie; Azzollini, Jacopo; Barrowdale, Daniel; Baynes, Caroline; Becher, Heko; Bermisheva, Marina; Bernstein, Leslie; Bialkowska, Katarzyna; Blomqvist, Carl; Bojesen, Stig E; Bonanni, Bernardo; Borg, Ake; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Campa, Daniele; Carter, Brian D; Castelao, Jose E; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen BM; Clarke, Christine L; GEMO Study Collaborators; EMBRACE Collaborators; Collee, J Margriet; Conroy, Don M; Czene, Kamila; Daly, Mary B; Devilee, Peter; Diez, Orland; Ding, Yuan Chun; Domchek, Susan M; Dork, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M; Dwek, Miriam; Eccles, Diana M; Eliassen, A Heather; Engel, Christoph; Eriksson, Mikael; Evans, D Gareth; Fasching, Peter A; Flyger, Henrik; Fostira, Florentia; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gago-Dominguez, Manuela; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; Garcia-Closas, Montserrat; Garcia-Saenz, Jose A; Gaudet, Mia M; Gayther, Simon A; Gehrig, Andrea; Georgoulias, Vassilios; Giles, Graham G; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E | Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.
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- 2021
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19. Abstract P2-01-18: Orthogonal assessment of PIK3CA and ESR1 mutation detection in longitudinal cfDNA samples from endocrine-resistant HR+/HER2- advanced breast cancer patients using dPCR and NGS-based SafeSEQ technology
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Jesus Fuentes Antras, Vanesa García-Barberán, Fernando Moreno, Hillary Sloane, Igor López-Cade, Alicia De Luna, Alejandro Pascual, Carmen Ramirez-Ruda, Victor Lorca, Paloma Flores, Pedro Perez-Segura, Alberto Ocaña, Jennifer Preston, Hannah Quinn, Frederick Jones, and Jose Angel Garcia-Saenz
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Cancer Research ,Oncology - Abstract
Background: Indentification of actionable or therapy resistance-associated mutations may guide sequential treatments in Hormone Receptor-positive and HER2-negative (HR+/HER2-) Advanced Breast Cancer (ABC) patients with resistance to prior endocrine therapies. Molecular profiling from cell-free DNA (cfDNA) is progressively permeating the clinical setting as an alternative or adjunct to tissue biopsies. Digital PCR (dPCR) assays permit the detection of genomic alterations with high sensitivity but are associated with cumbersome workflows and limited genomic coverage. NGS-based cfDNA assays are being increasingly adopted, as they can offer broader coverage while maintaining competitive sensitivity. Methods:Mutation testing was performed on plasma samples obtained from patients with HR+/HER2- ABC who had recurred or progressed after receiving an aromatase inhibitor. Samples were collected at the start of new treatment, during therapy, and at progression. dPCR tests were carried out using QuantStudio3D Digital PCR at the Molecular Oncology Laboratory at Clínico San Carlos Hospital. dPCR targets included PIK3CA E542K, E545K, and H1047R, and ESR1 Y537S and D538G. Samples[CdS1] were also tested with the SafeSEQ Breast Cancer Panel to assess clinically relevant genomic regions across PIK3CA, ESR1, AKT1, TP53, KRAS, and ERBB2. SafeSEQ testing was performed in Sysmex Inostics’ CLIA-certified, CAP-accredited laboratory. Results: Mutational data obtained from both dPCR and SafeSEQ testing were available for concordance analysis in 107 samples from 50 patients for PIK3CA, and 86 samples from 41 patients for ESR1. Combined results showed PIK3CA mutations in 47 samples (43.9%), with H1047R (14%), E545K (11.2%), and E542K (9.3%) being the most frequent mutations detected. ESR1 mutations were present in 35 samples (32.7%), where D538G (19.6%) and Y537S (9.3%) were most commonly observed. Among samples with no mutations detected by dPCR, the expanded coverage of SafeSEQ enabled the detection of clinically relevant mutations in PIK3CA and ESR1 in 10 (9.3%) and 3 (2.8%) samples, respectively. The concordance rates for dPCR and SafeSEQ were 93.1% and 88.9% for PIK3CA and ESR1, with positive percent agreements (PPA) of 93.8% and 84.6%, and negative percent agreements (NPA) of 92.8% and 90.9% for PIK3CA and ESR1, respectively. A strong correlation was observed between MAF levels (Spearman's ρ = 0.87 [95% CI 0.79-0.93], p Citation Format: Jesus Fuentes Antras, Vanesa García-Barberán, Fernando Moreno, Hillary Sloane, Igor López-Cade, Alicia De Luna, Alejandro Pascual, Carmen Ramirez-Ruda, Victor Lorca, Paloma Flores, Pedro Perez-Segura, Alberto Ocaña, Jennifer Preston, Hannah Quinn, Frederick Jones, Jose Angel Garcia-Saenz. Orthogonal assessment of PIK3CA and ESR1 mutation detection in longitudinal cfDNA samples from endocrine-resistant HR+/HER2- advanced breast cancer patients using dPCR and NGS-based SafeSEQ technology [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-18.
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- 2022
20. In silico transcriptomic mapping of integrins and immune activation in Basal-like and HER2+ breast cancer
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Katerin Rojas, Vanesa García-Barberán, Atanasio Pandiella, Aránzazu Manzano, Pedro Pérez-Segura, Balázs Győrffy, Francisco J. Cimas, Cristina Saiz-Ladera, Alberto Ocaña, Mariona Baliu-Piqué, Instituto de Salud Carlos III, Acepain Albacete, Diputación de Albacete, Fundación CRIS contra el Cáncer, Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, European Commission, Ministry of Innovation and Technology (Hungary), and Semmelweis University
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0301 basic medicine ,HER2+ ,Cancer Research ,Integrins ,Receptor, ErbB-2 ,Antigen presentation ,Integrin ,Breast Neoplasms ,Biology ,Tumor-infiltrating lymphocytes ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Breast cancer ,medicine ,Tumor Microenvironment ,Humans ,ITGAV ,ITGB7 ,Tumor microenvironment ,Gene Expression Profiling ,Cancer ,Tumor biomarkers ,General Medicine ,medicine.disease ,Chemotaxis, Leukocyte ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Molecular Medicine ,Female ,Basal-like ,Transcriptome - Abstract
[Purpose]: Integrins, transmembrane receptors that mediate cell-extracellular matrix and cell-cell interactions, have been linked to several cancer-associated features. A less explored function of integrins in cancer is their role in leukocyte homing and activation. Understanding their relationship with immune cell infiltrates and immune checkpoints is an area of interest in cancer research. [Methods]: The expression of 33 different integrins was evaluated in relation with breast cancer patient outcome using transcriptomic data (Affymetrix dataset, exploratory cohort) and the METABRIC study (validation cohort). The TIMER online tool was used to assess the association of the identified integrin genes with immune cell infiltration, and the TCGA and METABRIC studies to assess correlations between integrin gene expression and genomic signatures of immune activation. [Results]: We identified 7 genes coding for integrin α and β subunits, i.e., ITGA4, ITGB2, ITGAX, ITGB7, ITGAM, ITGAL and ITGA8, which predict a favorable prognosis in Basal-like and HER2+ breast cancers. Their expression positively correlated with the presence of immune cell infiltrates within the tumor (dendritic cells, CD4+ T-cells, neutrophils, CD8+ T-cells and B-cells), with markers of T-cell activation and antigen presentation, and with gene signatures of immune surveillance (cytotoxic T lymphocyte activation and IFN gamma signature). By contrast, we found that genes coding for integrins that predicted a detrimental outcome (IBSP, ITGB3BP, ITGB6, ITGB1 and ITGAV) were not associated with any of these parameters. [Conclusions]: We identified an integrin signature composed of 7 genes with potential to recognize immune infiltrated and activated Basal-like and HER2+ breast cancers with a favorable prognosis., This work was supported by the Instituto de Salud Carlos III (PI19/00808), ACEPAIN, Diputación de Albacete, CIBERONC and CRIS Cancer Foundation (to A. Ocaña) and the Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, the scientific foundation of the AECC and the CRIS Foundation (to A. Pandiella). Our laboratories receive support from the European Community through the regional development funding program (FEDER). BG was supported by a 2018 − 2.1.17-TET-KR-00001 grant and by the Higher Education Institutional Excellence Programme (2020 − 4.1.1.-TKP2020) of the Ministry for Innovation and Technology of Hungary, within the framework of the Bionic thematic programme of the Semmelweis University.
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- 2020
21. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness
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Henriette Roed Nielsen, Judith Balmaña, Anne-Marie Gerdes, Ellen Honisch, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Douglas F. Easton, Linda Steele, Ava Kwong, Sung Won Kim, Bjarni A. Agnarsson, Piera Rizzolo, Angela R. Solano, Mads Thomassen, Johannes Lemke, Grazia Artioli, Heli Nevanlinna, Johanna I. Kiiski, Frans B. L. Hogervorst, Jong Won Lee, Diana Eccles, Mark H. Greene, Marc Tischkowitz, David E. Goldgar, Angela R. Bradbury, Javier Benitez, Marie Navratilova, Dominique Stoppa-Lyonnet, Arjen R. Mensenkamp, Alfons Meindl, Zisun Kim, Nadine Tung, Agnes Jager, Matthew L. Freedman, Ana Osorio, Norbert Arnold, Doris Steinemann, Inge Søkilde Pedersen, Patricia Llovet, Rob B. van der Luijt, Vivek L Patel, Munaza Ahmed, Lidia Moserle, Irene Konstantopoulou, Jackie Cook, Jacques Simard, Joan Brunet, Johanna Rantala, Kai-ren Ong, Carole Brewer, Joe Dennis, Sook-Yee Yoon, Hanne Meijers-Heijboer, Roberta Villa, Katie Snape, Louise Izatt, Ana Peixoto, Susan M. Domchek, Nina Ditsch, D. Gareth Evans, Tara M. Friebel, Sue K. Park, Katherine L. Nathanson, Lenka Foretova, Miguel Angel Pujana, Edith Olah, Hélène Schuster, Raymonda Varon-Mateeva, Silvia Tognazzo, Payal D. Shah, Oskar T. Johannsson, Hans Ehrencrona, Paul Gesta, Ian G. Campbell, Drakoulis Yannoukakos, Mirjam Larsen, Anthony V. D'Amico, Liene Nikitina-Zake, Davide Bondavalli, Valérie Bonadona, Paul A. James, Alan Donaldson, Antonis C. Antoniou, Bernd Auber, Andrew K. Godwin, Denise Molina Gomes, Jihyoun Lee, Laurence Faivre, Almuth Caliebe, Pilar Garre, Siddhartha Yadav, Julika Borde, Pedro Pérez-Segura, Birgitte Bertelsen, Paolo Peterlongo, Michael T. Parsons, John L. Hopper, Bruno Buecher, Goska Leslie, Shan Wang-Gohrke, Amanda B. Spurdle, T.M. Mooij, Juliane Ramser, kConFab Investigators, Lídia Feliubadaló, Susanne E. Boonen, Bernard Peissel, Anna von Wachenfeldt, Timothy R. Rebbeck, Christi J. van Asperen, Víctor Lorca, Estela Carrasco, Elisa Alducci, Ulrike Faust, Karin Kast, Gord Glendon, Saundra S. Buys, Fergus J. Couch, Mariarosaria Calvello, Istvan Bodrogi, Kathryn J. Ruddy, Philipp Wagner, Fabienne Lesueur, Evan L. Busch, Hebon Investigators, Laura Cortesi, Christian F. Singer, Ute Hamann, Giuseppe Damante, Stefania Tommasi, Esther M. John, Jacopo Azzollini, Cristina Zanzottera, Angelica M. Gutierrez-Barrera, Emmanuelle Mouret-Fourme, Claire Saule, Rosa B. Barkardottir, Kristin K. Zorn, Kerstin Rhiem, Uffe Birk Jensen, Mark Pomerantz, Yuan Chun Ding, Alison H. Trainer, Marco Montagna, Vijai Joseph, Domenico Palli, Kwang-Pil Ko, Angel M. Cronin, Susan L. Neuhausen, Dieter Niederacher, Laura Ottini, Angela Toss, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Caroline M. Seynaeve, Ileana Carnevali, Adalgeir Arason, Rosalind A. Eeles, Annie T W Chu, Florentia Fostira, Greet Wieme, Brita Arver, Charlotte Kvist Lautrup, Christoph Engel, Marion Gauthier-Villars, Daniel Barrowdale, Caroline Maria Rossing, Kenneth Offit, Kathleen Claes, Olufunmilayo I. Olopade, Penny Soucy, Alicia Barroso, Manuel R. Teixeira, Wendy K. Chung, Gero Kramer, Tsun Leung Chan, Agostina Stradella, Debra Frost, Noura Mebirouk, Liselotte P. van Hest, Esther Darder, Valentina Silvestri, Annabeth Høgh Petersen, Lesley McGuffog, Andrea Gehrig, Mary Porteous, Matti A. Rookus, Lizet E. van der Kolk, Siranoush Manoukian, Lone Sunde, Conxi Lázaro, Maria A. Caligo, Priyanka Sharma, Anne-Bine Skytte, Claus-Eric Ott, Christian Sutter, Paolo Radice, Veronica Medici, Georgia Chenevix-Trench, Vanesa García-Barberán, Kristiina Aittomäki, Amanda E. Toland, Anna Marie Mulligan, Véronique Mari, Bernd Dworniczak, Lynn Martin, Lara Della Puppa, Phuong L. Mai, George Fountzilas, Yen Y. Tan, Simona Agata, Torben A Kruse, Trinidad Caldés, Rosemarie Davidson, Daniel R. Barnes, Thomas Dyrso Jensen, Åke Borg, Mark E. Robson, Jennifer T. Loud, Vivian Y. Shin, Irene López-Perolio, Leigha Senter, Irene L. Andrulis, Rosa Scarpitta, Angela F. Brady, Annika Lindblom, Diana Torres, Lotte Nylandsted Krogh, Barbara Wappenschmidt, Muhammad Rashid, Jeroen Vierstraete, Mary B. Daly, Annelie Liljegren, Frederieke H. van der Baan, Eunyoung Kang, Alessandra Viel, Santiago Cabezas-Camarero, Eric Hahnen, Laura Matricardi, Marinus J. Blok, Edmond S. K. Ma, Maria Grazia Tibiletti, Catarina Santos, Julian Adlard, Soo Hwang Teo, Giuseppe Giannini, Jan Hauke, Peter J. Hulick, Miguel de la Hoya, Clare Miller, Bernardo Bonanni, Bent Ejlertsen, Lajos Géczi, Liliana Varesco, Orland Diez, N Herold, Christine Lasset, Adrià López-Fernández, Min Hyuk Lee, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Clinicum, Department of Obstetrics and Gynecology, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Medical Oncology, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Leslie, Goska [0000-0001-5756-6222], Adlard, Julian [0000-0002-1693-0435], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barnes, Daniel R [0000-0002-3781-7570], Brunet, Joan [0000-0003-1945-3512], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian G [0000-0002-7773-4155], Claes, Kathleen BM [0000-0003-0841-7372], Darder, Esther [0000-0002-7764-1397], Dennis, Joe [0000-0003-4591-1214], Dworniczak, Bernd [0000-0003-4981-7903], Eeles, Rosalind A [0000-0002-3698-6241], Ehrencrona, Hans [0000-0002-5589-3622], Ejlertsen, Bent [0000-0001-8761-714X], Evans, D Gareth [0000-0002-8482-5784], Garre, Pilar [0000-0001-8285-4138], Greene, Mark H [0000-0003-1852-9239], Hulick, Peter J [0000-0001-8397-4078], Jager, Agnes [0000-0002-7713-1450], James, Paul [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Joseph, Vijai [0000-0002-7933-151X], Kim, Sung-Won [0000-0002-1413-2800], Kim, Zisun [0000-0002-1413-2800], Konstantopoulou, Irene [0000-0002-0470-0309], Lesueur, Fabienne [0000-0001-7404-4549], Matricardi, Laura [0000-0002-0241-1810], Gomes, Denise Molina [0000-0002-2836-9008], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Palli, Domenico [0000-0002-5558-2437], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Peterlongo, Paolo [0000-0001-6951-6855], Petersen, Annabeth Høgh [0000-0002-4503-6942], Pujana, Miguel Angel [0000-0003-3222-4044], Ruddy, Kathryn J [0000-0001-6298-332X], Scarpitta, Rosa [0000-0001-7590-3827], Shah, Payal D [0000-0001-5874-3390], Silvestri, Valentina [0000-0003-0712-9379], Southey, Melissa C [0000-0002-6313-9005], Spurdle, Amanda B [0000-0003-1337-7897], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Sunde, Lone [0000-0002-8479-165X], Teixeira, Manuel R [0000-0002-4896-5982], Teo, Soo Hwang [0000-0002-0444-590X], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], van der Luijt, Rob B [0000-0002-0018-1089], Vierstraete, Jeroen [0000-0001-7909-6620], Wieme, Greet [0000-0003-2718-5300], Yadav, Siddhartha [0000-0003-4630-9903], Antoniou, Antonis C [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, and CCA - Cancer biology and immunology
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,endocrine system diseases ,PHENOTYPE ,INCREASE ,Prostate cancer ,0302 clinical medicine ,Risk Factors ,Young adult ,skin and connective tissue diseases ,Aged, 80 and over ,Prostate cancer risk ,Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] ,MESSENGER-RNA DECAY ,BRCA1 Protein ,Genomics ,GERMLINE MUTATIONS ,Middle Aged ,Prognosis ,OVARIAN ,CARRIERS ,3. Good health ,030220 oncology & carcinogenesis ,Adult ,Heterozygote ,medicine.medical_specialty ,Adolescent ,Tumor suppressor gene ,Urology ,Association (object-oriented programming) ,3122 Cancers ,MEDLINE ,Article ,Young Adult ,03 medical and health sciences ,Breast cancer ,Germline mutation ,SDG 3 - Good Health and Well-being ,Internal medicine ,BRCA1, BRCA2, Prostate Cancer, Pathogenic sequence variant location, Risk estimation ,Journal Article ,Genetic predisposition ,medicine ,Humans ,BREAST-CANCER ,Genetic Predisposition to Disease ,Risk factor ,Genetic Association Studies ,Aged ,BRCA2 Protein ,IDENTIFICATION ,business.industry ,Prostatic Neoplasms ,medicine.disease ,GENE ,Confidence interval ,APC ,030104 developmental biology ,Mutation ,3111 Biomedicine ,business - Abstract
Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
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- 2020
22. A Snapshot of the Tumor Microenvironment in Colorectal Cancer: The Liquid Biopsy
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Cristina Peña, Vanesa García-Barberán, Cristina Galindo-Pumariño, and Mercedes Herrera
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- 2020
23. A Snapshot of The Tumor Microenvironment in Colorectal Cancer: The Liquid Biopsy
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Vanesa García-Barberán, Cristina Peña, Mercedes Herrera, and Cristina Galindo-Pumariño
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Colorectal cancer ,colorectal cancer ,Review ,exosomes ,Exosome ,Catalysis ,Metastasis ,Inorganic Chemistry ,Circulating tumor cell ,Cancer-Associated Fibroblasts ,Biomarkers, Tumor ,Tumor Microenvironment ,Medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Liquid biopsy ,Molecular Biology ,Spectroscopy ,Tumor microenvironment ,liquid biopsy ,business.industry ,Organic Chemistry ,Mesenchymal Stem Cells ,General Medicine ,medicine.disease ,Primary tumor ,Computer Science Applications ,Tumor progression ,Cancer research ,business ,Colorectal Neoplasms - Abstract
The molecular profile of liquid biopsies is emerging as an alternative to tissue biopsies in the clinical management of malignant diseases. In colorectal cancer, significant liquid biopsy-based biomarkers have demonstrated an ability to discriminate between asymptomatic cancer patients and healthy controls. Furthermore, this non-invasive approach appears to provide relevant information regarding the stratification of tumors with different prognoses and the monitoring of treatment responses. This review focuses on the tumor microenvironment components which are detected in blood samples of colorectal cancer patients and might represent potential biomarkers. Exosomes released by tumor and stromal cells play a major role in the modulation of cancer progression in the primary tumor microenvironment and in the formation of an inflammatory pre-metastatic niche. Stromal cells-derived exosomes are involved in driving mechanisms that promote tumor growth, migration, metastasis, and drug resistance, therefore representing substantial signaling mediators in the tumor-stroma interaction. Besides, recent findings of specifically packaged exosome cargo in Cancer-Associated Fibroblasts of colorectal cancer patients identify novel exosomal biomarkers with potential clinical applicability. Furthermore, additional different signals emitted from the tumor microenvironment and also detectable in the blood, such as soluble factors and non-tumoral circulating cells, arise as novel promising biomarkers for cancer diagnosis, prognosis, and treatment response prediction. The therapeutic potential of these factors is still limited, and studies are in their infancy. However, innovative strategies aiming at the inhibition of tumor progression by systemic exosome depletion, exosome-mediated circulating tumor cell capturing, and exosome-drug delivery systems are currently being studied and may provide considerable advantages in the near future.
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- 2019
24. Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report
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kConFab Investigators, Melissa C. Southey, John F. Pearson, Tina Pesaran, Logan C. Walker, Miguel de la Hoya, Sitao Wu, Dominique Vaur, Peter Devilee, Vickie Hsuan, Vanesa García-Barberán, Raphaël Leman, Patricia Llovet, Johan Vallon-Christersson, Irene López-Perolio, Raquel Behar, Alexandra Martins, Grégoire Davy, Anders Kvist, Vanessa Lattimore, Nicolas Goardon, Trinidad Caldés, Åke Borg, Laurent Castera, Pedro Pérez-Segura, Maaike P.G. Vreeswijk, Rachid Karam, Pilar Garre, Eduardo Díaz-Rubio, Eladio Velasco, Sophie Krieger, Kathleen S. Hruska, Alberto Valenzuela-Palomo, Amanda B. Spurdle, American Breast Cancer Foundation, Cancer Australia, National Institutes of Health (US), National Health and Medical Research Council (Australia), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Otago [Dunedin, Nouvelle-Zélande], GeneDx [Gaithersburg, MD, USA], Ambry Genetics [Aliso Viejo, CA, USA], Lund University [Lund], University of Melbourne, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, 'Dr. Héctor N. Torres' [Buenos Aires] (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Facultad de Ciencias Exactas y Naturales [Buenos Aires] (FCEyN), Universidad de Buenos Aires [Buenos Aires] (UBA)-Universidad de Buenos Aires [Buenos Aires] (UBA), Leiden University Medical Center (LUMC), QIMR Berghofer Medical Research Institute, Normandie, Université, and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)
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0301 basic medicine ,medicine.medical_specialty ,palb2 ,PALB2 ,Computational biology ,Biology ,acmg-amp guidelines ,03 medical and health sciences ,Exon ,splicing ,0302 clinical medicine ,Neoplasms ,Genetics ,medicine ,Cancer Genetics ,Humans ,splice ,Genetic Predisposition to Disease ,variant classification ,Gene ,Genetics (clinical) ,Alleles ,Genetic Association Studies ,Germ-Line Mutation ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Molecular pathology ,Gene Expression Profiling ,Alternative splicing ,pvs1 ,3. Good health ,Nonsense Mediated mRNA Decay ,Alternative Splicing ,030104 developmental biology ,030220 oncology & carcinogenesis ,RNA splicing ,Mutation ,Medical genetics ,RNA Splice Sites ,Fanconi Anemia Complementation Group N Protein ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Cancer genetics: Original article., [Background] PALB2 monoallelic loss-of-function germ-line variants confer a breast cancer risk comparable to the average BRCA2 pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify loss-of-function variants in PALB2—without incurring overprediction—is thus of paramount clinical relevance. Towards this aim, we have performed a comprehensive characterisation of alternative splicing in PALB2, analysing its relevance for the classification of truncating and splice site variants according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines., [Methods] Alternative splicing was characterised in RNAs extracted from blood, breast and fimbriae/ovary-related human specimens (n=112). RNAseq, RT-PCR/CE and CloneSeq experiments were performed by five contributing laboratories. Centralised revision/curation was performed to assure high-quality annotations. Additional splicing analyses were performed in PALB2 c.212–1G>A, c.1684+1G>A, c.2748+2T>G, c.3113+5G>A, c.3350+1G>A, c.3350+4A>C and c.3350+5G>A carriers. The impact of the findings on PVS1 status was evaluated for truncating and splice site variant., [Results] We identified 88 naturally occurring alternative splicing events (81 newly described), including 4 in-frame events predicted relevant to evaluate PVS1 status of splice site variants. We did not identify tissue-specific alternate gene transcripts in breast or ovarian-related samples, supporting the clinical relevance of blood-based splicing studies., [Conclusions] PVS1 is not necessarily warranted for splice site variants targeting four PALB2 acceptor sites (exons 2, 5, 7 and 10). As a result, rare variants at these splice sites cannot be assumed pathogenic/likely pathogenic without further evidences. Our study puts a warning in up to five PALB2 genetic variants that are currently reported as pathogenic/likely pathogenic in ClinVar., Received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia and the National Institute of Health [USA].
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- 2019
25. Association of Genomic Domains in
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Vivek L, Patel, Evan L, Busch, Tara M, Friebel, Angel, Cronin, Goska, Leslie, Lesley, McGuffog, Julian, Adlard, Simona, Agata, Bjarni A, Agnarsson, Munaza, Ahmed, Kristiina, Aittomäki, Elisa, Alducci, Irene L, Andrulis, Adalgeir, Arason, Norbert, Arnold, Grazia, Artioli, Brita, Arver, Bernd, Auber, Jacopo, Azzollini, Judith, Balmaña, Rosa B, Barkardottir, Daniel R, Barnes, Alicia, Barroso, Daniel, Barrowdale, Muriel, Belotti, Javier, Benitez, Birgitte, Bertelsen, Marinus J, Blok, Istvan, Bodrogi, Valérie, Bonadona, Bernardo, Bonanni, Davide, Bondavalli, Susanne E, Boonen, Julika, Borde, Ake, Borg, Angela R, Bradbury, Angela, Brady, Carole, Brewer, Joan, Brunet, Bruno, Buecher, Saundra S, Buys, Santiago, Cabezas-Camarero, Trinidad, Caldés, Almuth, Caliebe, Maria A, Caligo, Mariarosaria, Calvello, Ian G, Campbell, Ileana, Carnevali, Estela, Carrasco, Tsun L, Chan, Annie T W, Chu, Wendy K, Chung, Kathleen B M, Claes, Gemo Study, Collaborators, Embrace, Collaborators, Jackie, Cook, Laura, Cortesi, Fergus J, Couch, Mary B, Daly, Giuseppe, Damante, Esther, Darder, Rosemarie, Davidson, Miguel, de la Hoya, Lara Della, Puppa, Joe, Dennis, Orland, Díez, Yuan Chun, Ding, Nina, Ditsch, Susan M, Domchek, Alan, Donaldson, Bernd, Dworniczak, Douglas F, Easton, Diana M, Eccles, Rosalind A, Eeles, Hans, Ehrencrona, Bent, Ejlertsen, Christoph, Engel, D Gareth, Evans, Laurence, Faivre, Ulrike, Faust, Lídia, Feliubadaló, Lenka, Foretova, Florentia, Fostira, George, Fountzilas, Debra, Frost, Vanesa, García-Barberán, Pilar, Garre, Marion, Gauthier-Villars, Lajos, Géczi, Andrea, Gehrig, Anne-Marie, Gerdes, Paul, Gesta, Giuseppe, Giannini, Gord, Glendon, Andrew K, Godwin, David E, Goldgar, Mark H, Greene, Angelica M, Gutierrez-Barrera, Eric, Hahnen, Ute, Hamann, Jan, Hauke, Natalie, Herold, Frans B L, Hogervorst, Ellen, Honisch, John L, Hopper, Peter J, Hulick, KConFab, Investigators, Hebon, Investigators, Louise, Izatt, Agnes, Jager, Paul, James, Ramunas, Janavicius, Uffe Birk, Jensen, Thomas Dyrso, Jensen, Oskar Th, Johannsson, Esther M, John, Vijai, Joseph, Eunyoung, Kang, Karin, Kast, Johanna I, Kiiski, Sung-Won, Kim, Zisun, Kim, Kwang-Pil, Ko, Irene, Konstantopoulou, Gero, Kramer, Lotte, Krogh, Torben A, Kruse, Ava, Kwong, Mirjam, Larsen, Christine, Lasset, Charlotte, Lautrup, Conxi, Lazaro, Jihyoun, Lee, Jong Won, Lee, Min Hyuk, Lee, Johannes, Lemke, Fabienne, Lesueur, Annelie, Liljegren, Annika, Lindblom, Patricia, Llovet, Adria, Lopez-Fernández, Irene, Lopez-Perolio, Victor, Lorca, Jennifer T, Loud, Edmond S K, Ma, Phuong L, Mai, Siranoush, Manoukian, Veronique, Mari, Lynn, Martin, Laura, Matricardi, Noura, Mebirouk, Veronica, Medici, Hanne E J, Meijers-Heijboer, Alfons, Meindl, Arjen R, Mensenkamp, Clare, Miller, Denise Molina, Gomes, Marco, Montagna, Thea M, Mooij, Lidia, Moserle, Emmanuelle, Mouret-Fourme, Anna Marie, Mulligan, Katherine L, Nathanson, Marie, Navratilova, Heli, Nevanlinna, Dieter, Niederacher, Finn C Cilius, Nielsen, Liene, Nikitina-Zake, Kenneth, Offit, Edith, Olah, Olufunmilayo I, Olopade, Kai-Ren, Ong, Ana, Osorio, Claus-Eric, Ott, Domenico, Palli, Sue K, Park, Michael T, Parsons, Inge Sokilde, Pedersen, Bernard, Peissel, Ana, Peixoto, Pedro, Pérez-Segura, Paolo, Peterlongo, Annabeth Høgh, Petersen, Mary E, Porteous, Miguel Angel, Pujana, Paolo, Radice, Juliane, Ramser, Johanna, Rantala, Muhammad U, Rashid, Kerstin, Rhiem, Piera, Rizzolo, Mark E, Robson, Matti A, Rookus, Caroline M, Rossing, Kathryn J, Ruddy, Catarina, Santos, Claire, Saule, Rosa, Scarpitta, Rita K, Schmutzler, Hélène, Schuster, Leigha, Senter, Caroline M, Seynaeve, Payal D, Shah, Priyanka, Sharma, Vivian Y, Shin, Valentina, Silvestri, Jacques, Simard, Christian F, Singer, Anne-Bine, Skytte, Katie, Snape, Angela R, Solano, Penny, Soucy, Melissa C, Southey, Amanda B, Spurdle, Linda, Steele, Doris, Steinemann, Dominique, Stoppa-Lyonnet, Agostina, Stradella, Lone, Sunde, Christian, Sutter, Yen Y, Tan, Manuel R, Teixeira, Soo Hwang, Teo, Mads, Thomassen, Maria Grazia, Tibiletti, Marc, Tischkowitz, Silvia, Tognazzo, Amanda E, Toland, Stefania, Tommasi, Diana, Torres, Angela, Toss, Alison H, Trainer, Nadine, Tung, Christi J, van Asperen, Frederieke H, van der Baan, Lizet E, van der Kolk, Rob B, van der Luijt, Liselotte P, van Hest, Liliana, Varesco, Raymonda, Varon-Mateeva, Alessandra, Viel, Jeroen, Vierstraete, Roberta, Villa, Anna, von Wachenfeldt, Philipp, Wagner, Shan, Wang-Gohrke, Barbara, Wappenschmidt, Jeffrey N, Weitzel, Greet, Wieme, Siddhartha, Yadav, Drakoulis, Yannoukakos, Sook-Yee, Yoon, Cristina, Zanzottera, Kristin K, Zorn, Anthony V, D'Amico, Matthew L, Freedman, Mark M, Pomerantz, Georgia, Chenevix-Trench, Antonis C, Antoniou, Susan L, Neuhausen, Laura, Ottini, Henriette Roed, Nielsen, and Timothy R, Rebbeck
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Adult ,Aged, 80 and over ,BRCA2 Protein ,Male ,Heterozygote ,Adolescent ,BRCA1 Protein ,Prostatic Neoplasms ,Genomics ,Middle Aged ,Prognosis ,Young Adult ,Risk Factors ,Mutation ,Humans ,Genetic Predisposition to Disease ,Genetic Association Studies ,Aged - Abstract
Pathogenic sequence variants (PSV) in
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- 2019
26. Circulating biomarkers for early detection and clinical management of colorectal cancer
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Guus van Dalum, Veronika Vymetalkova, Antoni Castells, Hege Marie Vedeld, Georg Flügen, Remond J.A. Fijneman, Ellen Heitzer, Emma Tham, Rui P L Neves, Nikolas H. Stoecklein, Saray Duran-Sanchon, Guro Elisabeth Lind, Pavel Vodicka, Meritxell Gironella, Vanesa García-Barberán, and María Marcuello
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Colorectal cancer ,Clinical Biochemistry ,Early detection ,Biochemistry ,Circulating Tumor DNA ,03 medical and health sciences ,0302 clinical medicine ,Circulating tumor cell ,Internal medicine ,microRNA ,medicine ,Biomarkers, Tumor ,Humans ,Circulating MicroRNA ,Liquid biopsy ,Molecular Biology ,Early Detection of Cancer ,business.industry ,Liquid Biopsy ,Disease Management ,General Medicine ,medicine.disease ,Neoplastic Cells, Circulating ,Prognosis ,digestive system diseases ,Circulating biomarkers ,030104 developmental biology ,Cell-free fetal DNA ,030220 oncology & carcinogenesis ,Molecular Medicine ,business ,Colorectal Neoplasms - Abstract
New non-invasive approaches that can complement and improve on current strategies for colorectal cancer (CRC) screening and management are urgently needed. A growing number of publications have documented that components of tumors, which are shed into the circulation, can be detected in the form of liquid biopsies and can be used to detect CRC at early stages, to predict response to certain therapies and to detect CRC recurrence in a minimally invasive way. The analysis of circulating tumor DNA (ctDNA), tumor-derived cells (CTC, circulating tumor cells) or circulating microRNA (miRNA) in blood and other body fluids, have a great potential to improve different aspects of CRC management. The challenge now is to find which types of components, biofluids and detection methods would be the most suitable to be applied in the different steps of CRC detection and treatment. This chapter will provide an up to date review on ctDNA, CTCs and circulating miRNAs as new biomarkers for CRC, either for clinical management or early detection, highlighting their advantages and limitations.
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- 2019
27. Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing
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Patricia Llovet, Miguel de la Hoya, Pedro Pérez-Segura, Víctor Lorca, Sandra Tapial, Daniel Rueda, Trinidad Caldés, Lorena Martín-Morales, Pilar Garre, Vanesa García-Barberán, Eduardo Díaz-Rubio, Richarda M. de Voer, Carmen Poves, María Jesús Fernández-Aceñero, Judith E. Grolleman, and Julián Sanz
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Adult ,Male ,0301 basic medicine ,Proband ,Genetic testing ,DNA Mutational Analysis ,Population ,lcsh:Medicine ,Penetrance ,Biology ,Article ,Frameshift mutation ,Cohort Studies ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,MUTYH ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,Genetic predisposition ,Humans ,Gene Regulatory Networks ,Genetic Predisposition to Disease ,Allele ,lcsh:Science ,education ,Cancer genetics ,Germ-Line Mutation ,Aged ,Aged, 80 and over ,Genetics ,education.field_of_study ,Multidisciplinary ,Sequence Analysis, RNA ,Genetic heterogeneity ,Gene Expression Profiling ,lcsh:R ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Middle Aged ,Colorectal cancer ,Pedigree ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Adenomatous Polyposis Coli ,Spain ,lcsh:Q ,Female ,030217 neurology & neurosurgery - Abstract
Attenuated adenomatous polyposis (AAP) is a heterogeneous syndrome in terms of clinical manifestations, heritability and etiology of the disease. Genetic heterogeneity and low penetrance alleles are probably the best explanation for this variability. Certainly, it is known that APC and MUTYH are high penetrance predisposition genes for adenomatous polyposis, but they only account for 5–10% of AAP. Other new predisposition genes, such as POLE, POLD1, NTHL1, AXIN2 or MSH3, have been recently described and have been associated with AAP, but their relative contribution is still not well defined. In order to evaluate the genetic predisposition to AAP in a hospital based population, germline DNAs from 158 AAP subjects were screened for genetic variants in the coding regions and intron-exon boundaries of seven associated genes through a next-generation sequencing (NGS) custom gene panel. Splicing, segregation studies, somatic mutational screening and RNA quantitative expression assays were conducted for selected variants. In four of the probands the adenoma susceptibility could be explained by actionable mutations in APC or MUTYH, and one other patient was a double carrier of two truncating variants in both POLE and NTHL1. Furthermore, 16 additional patients harbored uncertain significance variants in the remaining tested genes. This report gives information about the contribution of the newly described adenomatous polyposis predisposition genes in a Spanish attenuated polyposis cohort. Our results highly support the convenience of NGS multigene panels for attenuated polyposis genetic screening and reveals POLE frameshift variants as a plausible susceptibility mechanism for AAP.
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- 2019
28. Monitoring of PIK3CA and ESR1 mutations in circulating tumor DNA as predictive and prognostic biomarkers in patients with endocrine-resistant ER+/HER2- advanced breast cancer
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Vanesa García-Barberán, Jesús Fuentes Antrás, Irene Gonzalo, José A. García-Sáenz, Trinidad Caldés, Igor López-Cade, Alberto Ocaña, Ana Ascaso del Rio, Oskia Bueno, Fernando Moreno, Alejandro Pascual, and Carmen Ramírez-Ruda
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Oncology ,Cancer Research ,medicine.medical_specialty ,Standard of care ,business.industry ,Advanced breast ,Cancer ,Estrogen receptor ,medicine.disease ,Circulating tumor DNA ,Internal medicine ,medicine ,Endocrine system ,In patient ,business ,Estrogen receptor alpha - Abstract
e13045 Background: Combination therapeutic strategies including CDK4/6 inhibitors and an endocrine backbone are the standard of care of treatment for patients with estrogen receptor positive (ER+)/HER2- advanced breast cancer (ABC). Endocrine agents mainly include aromatase inhibitors, which target ER-driven transcription, and fulvestrant, which functions as ER antagonist. PI3K-AKT-mTOR is a key point of resistance to endocrine therapy, activated in 40% of these patients by mutations concentrated in critical regions of PIK3CA, coding for the p110 catalytic subunit α of PI3K. Additionally, 30% of patients previously exposed to non-steroidal aromatase inhibitors develop mutations in the ligand binding domain of ESR1, causing endocrine resistance by constitutive activation of the ER. Furthermore, metastasis and primary tumors may show a highly heterogenous mutational landscape. Monitoring the dynamic changes of these mutations in ctDNA may provide a non-invasive, real-time and accessible tool to convey predictive/prognostic information and guide decisions on sequential endocrine therapies. Methods: Pre-planned interim analysis results of an observational, prospective cohort pilot study to assess the predictive and prognostic value of monitoring PIK3CA and ESR1 mutations in ctDNA of patients with endocrine-resistant ER+/HER2- ABC. We have studied longitudinal liquid biopsies from 30 patients using digital PCR to interrogate PIK3CA mutations (H1047R / E545K) and ESR1 mutations (D538G / Y537S). Blood samples were drawn at the time of progression to endocrine therapy, at 8 weeks of subsequent endocrine line and at new progression. This exploratory analysis will provide preliminary data on clinical homogeneity, treatment regimens, median follow-up and progression-free survival, mutation incidence and intraindividual variation of mutant allele frequency and copy number. The percentage of progressors at 24 weeks of follow-up according to the mutational status will be evaluated by using the Fisher’s exact test. The predictive potential of ctDNA biomarkers will be characterized by ROC curve analysis. Tracking ctDNA mutations to predict endocrine resistance in a real-world setting represents a critical step towards precision medicine in oncology.
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- 2020
29. Plasma PD-L1 levels according to histologic grade and IDH status in patients with gliomas
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Vanesa García-Barberán, Isabel Díaz-Millán, Pedro Pérez-Segura, Santiago Cabezas-Camarero, Rebeca Pérez-Alfayate, and María L. Gandía
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Cancer ,medicine.disease ,Immune system ,Histologic grade ,Internal medicine ,PD-L1 ,mental disorders ,biology.protein ,Medicine ,In patient ,business - Abstract
69 Background: Plasma immune biomarkers such as soluble plasma PD-L1 (sPD-L1) may serve as surrogates of the immune condition of cancer patients and be potential markers of response to different immunotherapy modalities. Very few data exist regarding sPD-L1 in patients with primary brain tumors. Our aim was to study the levels of sPD-L1 in patients with gliomas according to histologic grade and IDH mutation status. Methods: Patients (pts) with grade II to IV gliomas were prospectively enrolled. Single-time-point plasma samples were obtained prior to adjuvant radiotherapy +/- chemotherapy. sPD-L1 determined using ELISA with a rabbit polyclonal anti-PDL1/CD274 antibody as capture reagent. Results: Between February 2017 and August 2019, 44 patients (pts) with gliomas and 12 healthy controls (HC) were enrolled. N=11 grade II, n=9 grade III, n=24 grade IV; n=26 IDHwt, n=18 IDHmut. Higher sPD-L1 levels in glioma pts compared to HC (60.8 vs 47.8 ng/ml, p=0.05). Higher sPD-L1 levels in grade II vs grades III-IV (73.3 vs 60 ng/ml, p=0.09). Higher sPD-L1 in IDHmut grades II-III vs IDHwt grades II-III + IDHmut/wt grade IV (73 vs 59 ng/ml, p=0.07). Non-significantly higher sPD-L1 in grades II-III vs grade IV (73 vs 59 ng/ml, p=0.46). No difference in sPD-L1 in IDHmut vs IDHwt (63.3 vs 59.1 ng/ml, p=0.496), nor in IDHwt vs HC (59.1 vs 47.8 ng/ml, p=0.109). Trend to significance in IDHmut vs HC (63.3 vs 47.8, p=0.062). Conclusions: sPD-L1 levels were significantly higher in glioma pts compared to HC. A trend was seen towards higher sPD-L1 levels in lower-grade (grades II, III) IDHmut gliomas. These findings may indicate a different systemic immune profile for currently defined glioma groups based on histologic grade and IDH status and merit confirmation in a larger sample.
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- 2020
30. Nasoethmoidal Intestinal-Type Adenocarcinoma Treated with Cetuximab: Role of Liquid Biopsy and BEAMing in Predicting Response to Anti-Epidermal Growth Factor Receptor Therapy
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Ahmad Issa Subhi-Issa, Vanesa García-Barberán, Beatriz Mediero-Valeros, Salomé Merino Menéndez, Patricia Llovet García, Inmaculada Bando-Polaino, Santiago Cabezas-Camarero, Virginia de la Orden García, Pedro Pérez-Segura, and Eduardo Díaz-Rubio
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0301 basic medicine ,Male ,Cancer Research ,Genotype ,Colorectal cancer ,Cetuximab ,Adenocarcinoma ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Circulating tumor cell ,Antineoplastic Agents, Immunological ,Biopsy ,Antineoplastic Combined Chemotherapy Protocols ,Intestinal Neoplasms ,medicine ,Humans ,Liquid biopsy ,Melphalan ,Etoposide ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Cytarabine ,Liquid Biopsy ,Cancer ,medicine.disease ,Primary tumor ,Carmustine ,ErbB Receptors ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Precision Medicine Clinic: Molecular Tumor Board ,KRAS ,business ,Paranasal Sinus Neoplasms ,medicine.drug - Abstract
Sinonasal intestinal-type adenocarcinomas (SNS-ITAC) are very rare tumors that resemble colorectal cancer in many of their pathological and molecular characteristics. Indeed, in most published series, 10%–14% of SNS-ITAC harbor mutations in KRAS. There is no standard systemic treatment in recurrent or metastatic SNS-ITAC, and there is no evidence of the use of any targeted agent in this entity. We present the case of a recurrent nasoethmoidal ITAC informed as RAS and BRAF wild-type by standard real-time polymerase chain reaction methods and treated with first-line cetuximab and irinotecan without response. Circulating tumor cells coupled to highly sensitive DNA analyses unveiled a mutation in KRAS exon 2 codon 12. Subsequent studies in the primary tumor using BEAMing detected a mutation in the same codon, confirming the KRAS mutated status of the tumor, and possibly explaining the absence of treatment response. This case exemplifies how liquid biopsy can aid in the correct and real-time molecular characterization of tumors even in a rare nonmetastatic cancer of the head and neck. Key Points Sinonasal intestinal type adenocarcinomas (SNS-ITAC) are rare tumors that commonly develop after a prolonged exposure to organic dusts (wood, leather, etc.), and that resemble colorectal cancer in some of their morphological and molecular characteristics. KRAS mutations have been described in 10%–14% in most series. However, its predictive value for guiding treatment decisions with targeted therapies (i.e., anti-epidermal growth factor receptor [EGFR] therapy) has not been defined. The first case of an SNS-ITAC treated with anti-EGFR therapy (cetuximab) is reported. Analysis of DNA from circulating tumor cells (CTCs) unveiled a mutation in KRAS not detected by standard methods in the primary tumor. However, RAS analysis using BEAMing detected a mutation in the primary tumor in the same codon of KRAS originally detected in CTCs, altogether possibly explaining the lack of treatment response. Liquid biopsy may allow for an accurate molecular diagnosis in rare, organ-confined tumors where few therapeutic options exist. Highly sensitive molecular diagnostics may aid in better characterizing rare entities harboring potentially druggable targets.
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- 2018
31. Differential distribution and enrichment of non-coding RNAs in exosomes from normal and Cancer-associated fibroblasts in colorectal cancer
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Antonio Candia, Julie Earl, Trinidad Caldés, Félix Bonilla, María Jesús Larriba, Marta Rodríguez, Vanesa García-Barberán, Beatriz Gil, Alberto Herrera, Mercedes Herrera, Pilar Garre, Ricardo Alan Verdú Ramos, Carlos Llorens, Alfredo Carrato, Cristina Peña, Mercedes Rodríguez-Garrote, Instituto de Salud Carlos III, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Economía y Competitividad (España), Comunidad de Madrid, European Commission, Fundación Banco Santander, Federación Española de Enfermedades Raras, Peña, Cristina [0000-0003-4406-8640], and Peña, Cristina
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0301 basic medicine ,Cancer Research ,Stromal cell ,RNA, Untranslated ,Colorectal cancer ,Biology ,Exosomes ,lcsh:RC254-282 ,Non-coding RNAs ,03 medical and health sciences ,Cancer-Associated Fibroblasts ,Cell Movement ,Next generation sequencing ,medicine ,Biomarkers, Tumor ,Humans ,Liquid biopsy ,Letter to the Editor ,Cells, Cultured ,Cell Proliferation ,Tumor microenvironment ,Colon Cancer ,Sequence Analysis, RNA ,Cancer ,High-Throughput Nucleotide Sequencing ,Fibroblasts ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,Microvesicles ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Tumor progression ,Cancer research ,Molecular Medicine ,Colorectal Neoplasms - Abstract
Exosome production from cancer-associated fibroblasts seems to be an important driver of tumor progression. We report the first in-depth biotype characterization of ncRNAs, analyzed by Next Generation Sequencing and Bioinformatics, expressed in established primary human normal and cancer-associated fibroblasts (CAFs) from cancer and normal mucosa tissues from 9 colorectal cancer patients, and/or packaged in their derived exosomes. Differential representation and enrichment analyses based on these ncRNAs revealed a significant number of differences between the ncRNA content of exosomes and the expression patterns of the normal and cancer-associated fibroblast cells. ncRNA regulatory elements are specifically packaged in CAF-derived exosomes, supporting a specific cross-talk between CAFs and colon cancer cells and/or other stromal cells, mediated by exosomes. These sncRNAs are potential biomarkers present in cancer-associated fibroblast-derived exosomes, which should thereby contribute to developing new non-invasive diagnostic, prognostic and predictive methods for clinical applications in management of cancer patients., This research is supported by PI12/02037, PI12/01635, PI15/02101, PI17/01847 and RD12/0036/0041 from the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013–2016) and cofinanced by the European Development Regional Fund “A way to achieve Europe” (ERDF); by “CIBER de Cáncer”, CB16/12/00273, CB16/12/00301, CB16/12/00446 and CB16/12/00291, from the Instituto de Salud Carlos III-FEDER; by the Fundación Científica AECC (a multifaceted approach to target pancreatic cancer); by SAF2010–20750, and SAF2016-76377-R from the Ministerio de Economía y Competitividad of SpainFEDER; by S2010/BMD-2344 from the Comunidad de Madrid; and by the Fundación Banco Santander. Cristina Peña is a recipient of a Miguel Servet Contract from the Instituto de Salud Carlos III.
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- 2018
32. Role of GALNT12 in the genetic predisposition to attenuated adenomatous polyposis syndrome
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Pedro Pérez-Segura, David Marrupe, Carmen Poves, Vanesa García-Barberán, Patricia Llovet, Víctor Lorca, Miguel de la Hoya, Daniel Rueda, Beatriz García-Paredes, María Jesús Fernández-Aceñero, Pilar Garre, Clara Ruiz-Ponte, Eduardo Díaz-Rubio, Trinidad Caldés, and Lorena Martín-Morales
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0301 basic medicine ,Male ,Genetic Screens ,Glycosylation ,Colorectal cancer ,Carcinogenesis ,Gene Identification and Analysis ,Glycobiology ,lcsh:Medicine ,Loss of Heterozygosity ,medicine.disease_cause ,Biochemistry ,Germline ,Loss of heterozygosity ,Cohort Studies ,Medicine and Health Sciences ,Medicine ,Gardner Syndrome ,Post-Translational Modification ,lcsh:Science ,Aged, 80 and over ,Multidisciplinary ,Middle Aged ,Adenomas ,Pedigree ,Oncology ,Research Design ,N-Acetylgalactosaminyltransferases ,Female ,Research Article ,Adult ,Adenoma ,Genetic Predisposition ,Research and Analysis Methods ,03 medical and health sciences ,Genetic predisposition ,Genetics ,Humans ,Genetic Predisposition to Disease ,Allele ,neoplasms ,Alleles ,Aged ,Colorectal Cancer ,business.industry ,lcsh:R ,Case-control study ,Cancers and Neoplasms ,Biology and Life Sciences ,Proteins ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Genetic Loci ,Case-Control Studies ,Genetics of Disease ,Cancer research ,lcsh:Q ,business - Abstract
The involvement of GALNT12 in colorectal carcinogenesis has been demonstrated but it is not clear to what extent it is implicated in familial CRC susceptibility. Partially inactivating variant, NM_024642.4:c.907G>A, p.(D303N), has been previously detected in familial CRC and proposed as the causative risk allele. Since phenotypes of the described carrier families showed not only CRC but also a polyp history, we hypothesized that GALNT12 could be involved in adenoma predisposition and consequently, in hereditary polyposis CRC syndromes. For that purpose, we have screened the GALNT12 gene in germline DNA from 183 unrelated attenuated polyposis patients. c.907G>A, p.(D303N) was detected in 4 cases (MAF = 1.1%) and no other candidate variants were found. After segregation studies, LOH analyses, glycosylation pattern tests and case-control studies, our results did not support the role of c.907G>A, p.(D303N) as a high-penetrance risk allele for polyposis CRC.
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- 2017
33. A novel TP53 germline inframe deletion identified in a Spanish series of Li-fraumeni syndrome suspected families
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Francisco J. Illana, Vanesa García-Barberán, Pilar Garre, Patricia Llovet, Lorena Martín-Morales, Trinidad Caldés, Miguel de la Hoya, M. Dolores Ibañez-Royo, and Pedro Pérez-Segura
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0301 basic medicine ,Adult ,Male ,Cancer Research ,Loss of Heterozygosity ,Biology ,medicine.disease_cause ,Germline ,Loss of heterozygosity ,Li-Fraumeni Syndrome ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Genetics ,medicine ,Missense mutation ,Humans ,Genetics (clinical) ,Germ-Line Mutation ,Mutation ,Point mutation ,medicine.disease ,Pedigree ,030104 developmental biology ,Oncology ,Inframe Mutation ,Li–Fraumeni syndrome ,Spain ,030220 oncology & carcinogenesis ,Female ,Tumor Suppressor Protein p53 - Abstract
Li-Fraumeni syndrome (LFS) is an autosomal dominant, inherited tumor predisposition syndrome associated with heterozygous germline mutations in the TP53 gene. The molecular diagnosis of LFS is important to develop strategies for early detection and access to the genetic counseling. Our study evaluated germline TP53 mutations in Spanish families with a history suggestive of LFS. Germline TP53 alterations in 22 families with a history suggestive of LFS were evaluated by Sanger sequencing and multiplex ligation-dependent probe amplification. Loss of heterozygosity analysis and immunohistochemistry of the protein in the tumor were performed in order to evaluate the pathogenicity of a novel alteration detected. A total of seven TP53 mutations were detected, six point mutations (4 missense and 2 nonsense) and a novel inframe deletion. 93% of mutation carriers developed at least one malignancy (mainly breast cancer and sarcomas), with a mean age at diagnosis of the first tumor of 30.2 years. Two missense mutations acted as dominant-negative. The novel inframe mutation c.437_445del was located in the DNA-binding domain. This mutation segregated with cancer in the family, and both high expression of the protein and loss of the wild-type TP53 allele were detected in the tumor of the carrier. We have found a novel inframe deletion in TP53 that likely results in the loss of p53 function and acts in a non-dominant negative way, although further studies are necessary to clarify this issue. The identification of novel TP53 alterations is crucial for a personalized cancer-risk management of the Li-Fraumeni syndrome.
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- 2017
34. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer
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Eitan Friedman, Mattias Van Heetvelde, Jennifer B. Permuth, Joseph Vijai, Patricia A. Ganz, Jennifer A. Doherty, Argyrios Ziogas, Bernard Peissel, Edwin S. Iversen, Angela Brooks-Wilson, Ingo B. Runnebaum, Amanda B. Spurdle, Heli Nevanlinna, Kenneth Offit, Laura Papi, Georgia Chenevix-Trench, Saundra S. Buys, Martin Köbel, Fabienne Lesueur, Elizabeth W. Pugh, Joe Dennis, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Jolanta Lissowska, Judy Garber, Pascal Pujol, Kristin K. Zorn, Orland Diez, Marcia Adams, Thomas Conner, Renée T. Fortner, Tjoung-Won Park-Simon, Vanesa García-Barberán, Kerstin Rhiem, Norbert Arnold, Karoline Kuchenbaecker, Susan M. Domchek, María Josefa Mosteiro García, Matthias W. Beckmann, Alex Henderson, Melissa C. Larson, Jane Romm, Anja Rudolph, Steven A. Narod, Mats Jernetz, Jolanta Kupryjanczyk, Natalia Bogdanova, Jacob Musinsky, Helga B. Salvesen, Jonathan Beesley, Paolo Peterlongo, Arif B. Ekici, Clarice R. Weinberg, Marion Piedmonte, Christian F. Singer, Robert L. Nussbaum, Katja K.H. Aben, Michael J. Birrer, Juul T. Wijnen, Elizabeth M. Poole, Phuong L. Mai, David J. Hunter, Tanja Pejovic, Athanassios Vratimos, Barbara Wappenschmidt, Nicolas Wentzensen, Marcus Q. Bernardini, Leigha Senter, Terence Cescon, Daniel W. Cramer, Silvia Tognazzo, Drakoulis Yannoukakos, Jacopo Azzollini, Ignace Vergote, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Tomasz Huzarski, Mark H. Greene, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Paulo C Lyra, Usha Menon, Ralf Bützow, Siddhartha Kar, Manuel R. Teixeira, Conxi Lázaro, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Zsofia K. Stadler, Melissa C. Southey, Ramunas Janavicius, Douglas F. Easton, Digna R. Velez Edwards, Jocelyne Chiquette, Karin Kast, Jonathan Tyrer, Georg Pfeiler, Tara M. Friebel, Bruno Buecher, Goska Leslie, Jackie Cook, Catherine M. Phelan, Steve Ellis, Estrid Høgdall, Beth Y. Karlan, Anthony J. Swerdlow, Sarah E. Ferguson, Rosalind Glasspool, Frans B. L. Hogervorst, Lotte Nedergaard, Britton Trabert, Jack A. Taylor, Irene L. Andrulis, Paolo Radice, Dennis J. Hazelett, Mads Thomassen, Dong Liang, Joseph H. Rothstein, Loren Lipworth, Melissa A. Merritt, Ana Vega, Petra H.M. Peeters, Claus Høgdall, Anna M. Piskorz, Bernardo Bonanni, Janet M. Lee, Malcolm C. Pike, Clemens Liebrich, Zachary C. Fogarty, Bent Ejlertsen, Yuan Chun Ding, Dieter Niederacher, Michael E. Carney, Dominique Stoppa-Lyonnet, Nadine Tung, Curtis Olswold, Ana Osorio, Fiona Bruinsma, Christine Walsh, Fabienne Prieur, Lara E. Sucheston-Campbell, Stephen B. Gruber, Maartje J. Hooning, George Fountzilas, Amanda Black, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Angela R. Bradbury, Helene Holland, Ruth C. Travis, Susana Banerjee, Penelope M. Webb, Brooke L. Fridley, Clara Bodelon, Mary Anne Rossing, Yen Y. Tan, Rosa B. Barkardottir, Jong Won Lee, Stephen J. Chanock, Bruce Poppe, Sandra Fert Ferrer, Melissa Moffitt, Taymaa May, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Alicia Beeghly-Fadiel, Rebecca Sutphen, Michelle A.T. Hildebrandt, Lambertus A. Kiemeney, Thilo Dörk, Douglas A. Levine, Gerasimos Aravantinos, Celeste Leigh Pearce, Sue K. Park, David Van Den Berg, Louise Izatt, Hannah P. Yang, Graham G. Giles, Linda S. Cook, John R. McLaughlin, Nick Orr, Weiva Sieh, Raymonda Varon-Mateeva, Marco Montagna, Honglin Song, Laura Ottini, Ruea-Yea Huang, Joanna Moes-Sosnowska, Anders Bojesen, David M. O'Malley, Andrew K. Godwin, Lucy Side, Sung-Won Kim, Lukasz Szafron, Christoph Engel, Harvey A. Risch, Alexander Hein, Penny Soucy, Elza Khusnutdinova, Ana Peixoto, Arto Leminen, Cora M. Aalfs, Matthias Dürst, Mary B. Daly, Patricia Rice, Nadeem Siddiqui, Dale P. Sandler, Ava Kwong, Madalene Earp, Marjorie J. Riggan, Inge Søkilde Pedersen, Susanne K. Kjaer, Mercedes Durán, Joellen M. Schildkraut, James D. Brenton, D. Gareth Evans, Liisa M. Pelttari, Kimberly F. Doheny, Karen Hosking, Miquel Angel Pujana, Salina B. Chan, Joan Brunet, Trinidad Caldés, Rosemarie Davidson, Jessica N. McAlpine, Jenny Lester, Niclas Håkansson, Kai-ren Ong, Ros Eeles, Francesmary Modugno, Martin Gore, Loic Le Marchand, Robert A. Vierkant, Wendy K. Chung, Christopher I. Amos, N. Charlotte Onland-Moret, Brita Arver, Marc Tischkowitz, Craig Luccarini, Daniel Barrowdale, Laima Tihomirova, Louise A. Brinton, Fergus J. Couch, Alfons Meindl, Nerea Larrañaga, Cristina Rodríguez-Antona, Alice S. Whittemore, Johanna I. Kiiski, Todd L. Edwards, Eric Hahnen, Grzegorz Sukiennicki, Els Van Nieuwenhuysen, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Edith Olah, Ute Hamann, Liv Cecilie Vestrheim Thomsen, Xiaoqing Chen, Ganna Chornokur, Minouk J. Schoemaker, Marc T. Goodman, Fanny Dao, Andrea Gehrig, Hagay Sobol, Nhu D. Le, Esther M. John, Adriaan Vanderstichele, Antonia Trichopoulou, Kunle Odunsi, Yukie Bean, David G. Huntsman, Lidia Pezzani, V. Wendy Setiawan, Marinus J. Blok, Yael Laitman, Mary Porteous, Patricia Harrington, Samantha Poblete, Shashikant Lele, Anne M. van Altena, Mingajeva Elvira, Lene Lundvall, Dominique Leroux, Annemarie H. van der Hout, Darya Prokofyeva, Debra Frost, Yoke-Eng Chiew, Gad Rennert, Stacey J. Winham, Muy-Kheng Tea, Kirsten B. Moysich, Angel Izquierdo, Anna H. Wu, Christine Rappaport-Fuerhauser, Peter Hillemanns, Rob B. van der Luijt, Gord Glendon, Jan Lubinński, Csilla Szabo, Gillian Mitchell, Andrea L. Richardson, Mark E. Robson, Roger L. Milne, Thomas Hansen, Francesca Damiola, Tameka Shelford, Natalia Antonenkova, Julie Lecarpentier, Paul A. James, Claudine Isaacs, Gianluca Severi, Maria A. Caligo, Teodora Goranova, Kate Lawrenson, Sandra Orsulic, Priyanka Sharma, Holly R. Harris, Peter A. Fasching, Christian Sutter, Torben A Kruse, Line Bjørge, Lesley McGuffog, Leon F.A.G. Massuger, Lynne R. Wilkens, Reidun K. Kopperud, Jillian Hung, Iain A. McNeish, Hanne Meijers-Heijboer, Uffe Birk Jensen, Diether Lambrechts, Johanna Rantala, Kelly-Anne Phillips, Michelle M.M. Woo, Kathryn L. Terry, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Darcy L. Thull, Ailith Pirie, Sharon E. Johnatty, Soo Hwang Teo, Aimee A D'Aloisio, Evgeny N. Imyanitov, Domenico Palli, Andrew Berchuck, Banu Arun, Florentia Fostira, Jan Hauke, Jenny Chang-Claude, Pamela J. Thompson, Peter J. Hulick, Per Broberg, Arjen R. Mensenkamp, Xifeng Wu, Alicia A. Tone, Jacques Simard, Ursula Eilber, Jacek Gronwald, Kenneth Blankstein, James M. Flanagan, Alvaro N.A. Monteiro, Timea Pocza, Rita K. Schmutzler, Jeffrey N. Weitzel, Simon A. Gayther, William D. Foulkes, Valerie McGuire, Katherine L. Nathanson, Kevin H. Eng, Anna deFazio, Ian G. Campbell, Capucine Delnatte, Shan Wang-Gohrke, Jenna Lilyquist, Matti A. Rookus, Sakaeva Dina Damirovna, Laure Dossus, Simon G. Coetzee, Catherine J. Kennedy, Roberta B. Ness, James Paul, Andrew Lee, Linda E. Kelemen, Judith Balmaña, Anne-Marie Gerdes, Laure Barjhoux, Håkan Olsson, Lisa Walker, Doris Steinemann, Cecilia M. Dorfling, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Javier Benitez, Anthony N. Karnezis, Hoda Anton-Culver, Carole Brewer, Siranoush Manoukian, Dorothea Wand, Ed Dicks, Antonis C. Antoniou, Amanda E. Toland, Anna Marie Mulligan, Päivi Kannisto, Rikki Cannioto, Bernd Dworniczak, Susan J. Ramus, Anna V. Tinker, Epidemiology and Data Science, Amsterdam Reproduction & Development (AR&D), CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Government of Canada, Cancer Research Foundation, Canadian Institutes of Health Research, National Institutes of Health (US), Fonds de Recherche du Québec, Ministry of Health and Welfare (South Korea), Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Genome Canada, Medical Oncology, Clinical Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Centre Léon Bérard [Lyon], Service de Génétique Oncologique, Institut Curie [Paris], CRLCC René Gauducheau, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Métropole Savoie [Chambéry], CHU Grenoble, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Leslie, Goska [0000-0001-5756-6222], Brenton, James [0000-0002-5738-6683], Song, Honglin [0000-0001-5076-7371], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
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0301 basic medicine ,endocrine system diseases ,Epidemiology ,Càncer d'ovari ,Genome-wide association study ,Carcinoma, Ovarian Epithelial ,Genome-wide association studies ,susceptibility ,Risk Factors ,Genotype ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,Medicine and Health Sciences ,Neoplasms, Glandular and Epithelial ,POPULATION ,Genetics & Heredity ,Genetics ,Ovarian Neoplasms ,RISK ,education.field_of_study ,Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] ,cancer ,ovary ,BRCA1 Protein ,COMMON VARIANTS ,11 Medical And Health Sciences ,ASSOCIATION ,female genital diseases and pregnancy complications ,Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] ,3. Good health ,Serous fluid ,ovarian cancer ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Female ,Life Sciences & Biomedicine ,epithelial ovarian cancer, BRCA1, BRCA2 ,Population ,Telomere-Binding Proteins ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Meta-Analysis as Topic ,CLEAR-CELL CARCINOMA ,Ovarian cancer ,medicine ,Journal Article ,Humans ,BREAST-CANCER ,Genetic Predisposition to Disease ,Allele ,education ,Genotyping ,Alleles ,METAANALYSIS ,BRCA2 Protein ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Science & Technology ,MUTATIONS ,ENDOMETRIOSIS ,Biology and Life Sciences ,06 Biological Sciences ,medicine.disease ,030104 developmental biology ,Genetic Loci ,Mutation ,TELOMERE LENGTH ,Cancer research ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Developmental Biology ,Genome-Wide Association Study - Abstract
The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).
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- 2017
35. Tumor burden monitoring using cell-free tumor DNA could be limited by tumor heterogeneity in advanced breast cancer and should be evaluated together with radiographic imaging
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Atocha Romero, Julián Sanz, Miguel Barquín, Fernando Salvador Moreno, Marta García García-Esquinas, Trinidad Caldés, José A. García-Sáenz, Myriam Montes, Marion Laig, Eduardo Díaz-Rubio, Vanesa García-Barberán, Daniel Acosta-Eyzaguirre, and Patricia Ayllón
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0301 basic medicine ,Adult ,Cancer Research ,Pathology ,medicine.medical_specialty ,Class I Phosphatidylinositol 3-Kinases ,Mutant ,DNA Mutational Analysis ,Mutation, Missense ,Breast Neoplasms ,Lesion ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Breast cancer ,Surgical oncology ,Biopsy ,Genetics ,medicine ,Biomarkers, Tumor ,Mammography ,Humans ,Digital polymerase chain reaction ,cfDNA ,Aged ,Neoplasm Staging ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,dPCR ,Cancer ,PIK3CA ,DNA, Neoplasm ,Middle Aged ,medicine.disease ,Tumor Burden ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,business ,Research Article - Abstract
Background Accurate measurement of tumor burden in breast cancer disease is essential to improve the clinical management of patients. In this study, we evaluate whether the fluctuations in the fraction of PIK3CA mutant allele correlates with tumor response according to RECIST criteria and tumor markers quantification. Methods Eighty six plasma samples were analyzed by digital PCR using Rare Mutation Assays for E542K, E545K and H1047R. Mutant cfDNA and tumor markers CA15-3 and CEA were compared with radiographic imaging. Results The agreement between PIK3CA mutation status in FFPE samples and circulating tumor DNA (ctDNA) was moderate (K = 0.591; 95% IC = 0.371–0.811). Restricting the analysis to the metastatic patients, we found a good agreement between PIK3CA mutation status assessed in liquid and solid biopsy (K = 0.798 95%; IC = 0.586–1). ctDNA showed serial changes with fluctuations correlating with tumor markers 15.3 and CEA in 7 out of 8 cases with Pearson correlation coefficients ranging from 0.99 to 0.46 and from 0.99 to 0.38 respectively. Similarly, fluctuations in the fraction of PIK3CA mutant allele always correlated with changes in lesion size seen on images, although in two cases it did not correlate with treatment responses as defined by RECIST criteria. Conclusion oncogenic mutation quantification in plasma samples can be useful to monitor treatment outcome. However, it might be limited by tumor heterogeneity in advanced disease and it should be evaluated together with radiographic imaging. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3185-9) contains supplementary material, which is available to authorized users.
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- 2017
36. A transcriptomic immunologic signature predicts favorable outcome in neoadjuvant chemotherapy treated triple negative breast tumours
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Vanesa García-Barberán, José A. García-Sáenz, Alberto Ocaña, A. Manzano, R. Páez, János Tibor Fekete, Javier Pérez-Peña, Balazs Gyorffy, Atanasio Pandiella, and Pedro Pérez-Segura
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Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Estrogen receptor ,Hematology ,Gene signature ,Chemotherapy regimen ,GZMB ,Atezolizumab ,Internal medicine ,medicine ,business ,Survival analysis ,Triple-negative breast cancer - Abstract
Background Limited therapeutic options exist for the treatment of patients with triple negative breast cancer (TNBC) tumors beyond the administration of chemotherapy, and very recently, the approval of the anti PD-L1 inhibitor atezolizumab. Neoadjuvant chemotherapy is currently the standard of care treatment in the early stage disease, although reliable biomarkers of response have been scarcely described. In our study we explored whether immunologic signatures associated with inflamed tumors or hot tumors could predict outcome to neoadjuvant chemotherapy. Methods Publicly available transcriptomic data of more than 2,000 patients were evaluated. ROC plots were generated to assess response to therapy. Cox proportional hazards regression was computed to explore the association between gene expression and outcomes. Kaplan-Meier plots were drawn to visualize the survival differences. Results Higher expression of IDO1, CXCL9, CXCL10, HLA-DRA, ISGF-3 from the IFN gamma signature, CXCL13, HLA-E, LAG3 and STAT1 from the expanded gene signature and GZMB from the CTL-level signature were associated with higher proportion without relapse in the first five years after chemotherapy in TNBC. The strongest effect was observed for STAT1 (p value =1.8e-05 and AUC 0.69, p = 2.7e-06). The best gene-set signature to predict favorable RFS was the combination of IDO1, LAG3, STAT1 and GZMB (HR 0.28 CI 0.17-0.46 p = 9.8 E-08). However, no influence on pathological complete response (pCR) was observed. Similar, no benefit was identified in any other tumor subtype: HER2 or estrogen receptor positive. Conclusions In conclusion, we describe a set of immunologic genes that predict outcome to neoadjuvant chemotherapy in TNBC. Legal entity responsible for the study The authors. Funding Instituto de Salud Carlos III. Disclosure All authors have declared no conflicts of interest.
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- 2019
37. RAS analysis of circulating tumor cells from advanced colorectal cancer using BEAMing technology
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Miguel Jhonatan Sotelo Lezama, Ana López-Alfonso, Javier Sastre, Eduardo Díaz-Rubio, Beatriz Mediero-Valeros, Virginia De la Orden-García, Ana Ruiz-Casado, Antonio Carlos Sánchez Ruiz, Mateo Paz Cabezas, Santiago Cabezas-Camarero, Vanesa García-Barberán, and Isabel Díaz-Millán
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Advanced colorectal cancer ,Cancer Research ,Circulating tumor cell ,Oncology ,business.industry ,Colorectal cancer ,Cancer research ,Medicine ,business ,medicine.disease ,digestive system diseases - Abstract
e15151 Background: RAS mutations predict a lack of response to anti-EGFR therapies in metastatic colorectal cancer (mCRC). BEAMing technology is useful for detecting hot-spot mutations in ctDNA in mCRC. Analysis of these mutations in DNA from Circulating Tumor Cells (CTC) may increase the predictive value in mCRC patients (pts). Our aim was to explore the feasibility of studying RAS status using BEAMing in DNA from CTC. Methods: First, spiking experiments (SE) using wild-type (WT) and KRAS-mutated (MUT) cell lines were performed to establish the limit of detection (LOD) for RAS analysis with BEAMing. Second, SE were performed with CTC collected by CellCelector (removes non-CTC background achieving 100% purity of CTC). Finally, BEAMing was used for RAS analysis in ctDNA and in DNA from CTC isolated either with IsoFlux or with CellCelector in 9 mCRC pts with confirmed RAS mutation in primary tumor. Total DNA from CTC was preamplified using RepliG. Results: In SE, 10 and 5 KRAS MUT-cells using different backgrounds of WT-cells (10-0.2% MUT-cells) were detected using BEAMing. However, 3 and 1 MUT-cells (0.009-0%) were not detected. In SE of CTCs collected with CellCelector, BEAMing detected KRAS mutations with 50, 20, 10, 6, 4, 2 and 1 cell (MAF: 23.8%±3.8). A mutation (codon 13) was detected in CTC from one patient positive in tissue and ctDNA (CellCelector; 15 CTCs; MAF: 11.4%). Discordant results were found in 8 patients when CTCs were isolated using Isoflux (min: 0, max: 9 CTCs). CTC from another patient were possibly mutated but WT in ctDNA. Conclusions: This pilot study indicates that RAS mutations can be detected in CTCs using BEAMing. Reducing the non-CTC cellular background may be needed in cases with low CTC number. Molecular information provided by CTC and ctDNA may prove complementary and useful for taking therapeutic decisions in mCRC. These results merit confirmation in larger, prospective studies.
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- 2019
38. Mutational profile of dysplastic lesions evolving to laryngeal cancer
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Melchor Saiz-Pardo-Sanz, Pedro Pérez-Segura, Diana Hernanpérez-Hidalgo, Víctor Lorca, Mari Cruz Iglesias, David De Pablo Velasco, Vanesa García-Barberán, and Santiago Cabezas-Camarero
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Cancer Research ,Oncology ,business.industry ,Cancer research ,medicine ,Mutational status ,Cancer ,medicine.disease ,business ,Carcinogenic process - Abstract
e17551 Background: Few studies have addressed the carcinogenic process of laryngeal cancer from its premalignant phases. Our aim was to compare mutational status of laryngeal dysplasias (LD) evolving to laryngeal cancer (ELC) and not evolving to LC (NELC). Methods: Retrospective study of LD diagnosed between 2007 and 2011. A customized 15-gene NGS panel (DICER, IRF6, NOTCH1, NOTCH2, NOTCH3, NOTCH2NLA, PIK3CA, PTEN, RB1, RIPK4, SYNE1, SYNE2, TP53, TP63, CASP8) was used for mutational analysis with Truseq Custom Amplicon (Illumina) performed in FFPE LD samples and results compared between LD-ELC and LD-NELC. Results: Sixty-four patients (pts) with LD were identified. LD-ELC (N = 23) and LD-NELC (N = 41) were scored as mild (N = 40; NELC: 32 / ELC:8), moderate (N = 8; NELC: 4/ ELC: 4) and severe (N = 16; NELC:5 / ELC: 11). Prior or current moderate-to-heavy tobacco smoking ( > 10 pack-year): 53/64 (83%). Males: N = 50 (ELC: 21; NELC: 29); Female: N = 14 (ELC: 2; NELC: 12). Median time to cancer among 23 LD-ELC: 8 m (range: 0-46). Forty-seven gene variants were detected in ELC not found in NELC, of which 27 were pathogenic/likely pathogenic: Frameshift: 8 (1 in NOTCH2, 1 in PTEN, 2 in RB1, 2 in SYNE1 y 2 in SYNE2); Stop-gained: 3 (1 in NOTCH2NL, 2 in SYNE2); Splicing: 3 (1 in RB1, 1 in RIPK4 y 1 in TP53); Missense: 12 (1 in IRF6, 2 in NOTCH1, 1 in RB1, 2 in RIPK4, 6 in SYNE1). Conclusions: LD from pts ELC showed a different mutational profile than LD-NELC. These results show promise for identifying pts at higher risk for developing LC and should be validated in a larger, prospective study.
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- 2019
39. Relation between IDH1 status, histologic grade, immune-cell infiltration and expression of immune-related genes in patients with gliomas
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Vanesa García-Barberán, Santiago Cabezas-Camarero, M. Sáiz-Pardo Sanz, R. Pérez-Alfayate, I. Subhi-Issa, Pedro Pérez-Segura, and I. Casado Fariñas
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Pathology ,medicine.medical_specialty ,IDH1 ,Oncology ,business.industry ,Histologic grade ,medicine ,In patient ,Hematology ,business ,Immune cell infiltration ,Immune related genes - Published
- 2018
40. Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition
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Vanesa García-Barberán, Paula Rofes, Patricia Llovet, T. Caldes, Inmaculada Bando, Eduardo Díaz-Rubio, Víctor Lorca, Pilar Garre, Miguel de la Hoya, Pedro Pérez-Segura, and Lorena Martín-Morales
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Male ,0301 basic medicine ,Genetic Screens ,Molecular biology ,DNA Mutational Analysis ,Gene Identification and Analysis ,lcsh:Medicine ,Gene Sequencing ,Penetrance ,DNA Mismatch Repair ,Database and Informatics Methods ,Sequencing techniques ,0302 clinical medicine ,Medicine and Health Sciences ,DNA sequencing ,lcsh:Science ,Frameshift Mutation ,Genetics ,Multidisciplinary ,medicine.diagnostic_test ,High-Throughput Nucleotide Sequencing ,Genomics ,Middle Aged ,Lynch syndrome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Colorectal Neoplasms ,Transcriptome Analysis ,Research Article ,Adult ,Next-Generation Sequencing ,congenital, hereditary, and neonatal diseases and abnormalities ,Biology ,MLH1 ,03 medical and health sciences ,Germline mutation ,Diagnostic Medicine ,MUTYH ,Cancer Detection and Diagnosis ,medicine ,Humans ,Genetic Predisposition to Disease ,Mutation Detection ,Aged ,Genetic testing ,Colorectal Cancer ,lcsh:R ,Cancers and Neoplasms ,Biology and Life Sciences ,Computational Biology ,Cancer ,Genome Analysis ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,digestive system diseases ,Research and analysis methods ,MSH6 ,Molecular biology techniques ,Biological Databases ,030104 developmental biology ,Mutation ,Mutation Databases ,lcsh:Q - Abstract
Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening methods. The aim of this study is the use of a Next Generation Sequencing panel in order to find the genes involved in the cancer predisposition of these families. For this study, 98 patients from these unexplained families were tested with a multigene panel targeting 94 genes involved in cancer predisposition. The mutations found were validated by Sanger sequencing and the segregation was studied when possible. We identified 19 likely pathogenic variants in 18 patients. Out of these, 8 were found in MMR genes (5 in MLH1, 1 in MSH6 and 2 in PMS2). In addition, 11 mutations were detected in other genes, including high penetrance genes (APC, SMAD4 and TP53) and moderate penetrance genes (BRIP1, CHEK2, MUTYH, HNF1A and XPC). Mutations c.1194G>A in SMAD4, c.714_720dup in PMS2, c.2050T>G in MLH1 and c.1635_1636del in MSH6 were novel. In conclusion, the detection of new pathogenic mutations in high and moderate penetrance genes could contribute to the explanation of the heritability of colorectal cancer, changing the individual clinical management. Multigene panel testing is a more effective method to identify germline variants in cancer patients compared to single-gene approaches and should be therefore included in clinical laboratories.
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- 2018
41. Evaluation of the sensitivity of RAS mutation detection of the Idylla platform in comparison to the OncoBEAM RAS CRC assay
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Auxiliadora Gómez-España, Ana Vivancos, M. Toledano, M. Benavides, Martina Alvarez, E. Diaz Rubio, Vanesa García-Barberán, M.R. Chica-Parrao, E. Aranda Aguilar, and E. Elez Fernandez
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0301 basic medicine ,Cancer Research ,Colorectal cancer ,business.industry ,Hematology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,RAS Mutation ,Cancer research ,medicine ,Sensitivity (control systems) ,business ,Selection (genetic algorithm) - Abstract
592 Background: Accurate detection of RAS mutations in metastatic colorectal cancer (mCRC) patients is of high clinical importance for therapy selection as RAS detection methods lacking sensitivity may lead to poor patient outcomes. Liquid biopsy has emerged as a viable alternative to individualize the management and treatment of mCRC patients. However, there is a current need to cross-compare the performance of liquid biopsy platforms. The OncoBEAM RAS dPCR assay offers highly sensitive RAS mutation detection in clinical practice, achieving > 90% concordance when compared to results obtained by tumor mutation testing. The Idylla platform offers a highly-automated qPCR platform for RAS mutation testing of tissue samples, and has shown potential for liquid biopsy. The objective of this study was to provide a head-to-head comparison of the sensitivity of OncoBEAM and Idylla for KRAS mutation detection in plasma from mCRC patients. Methods: Plasma samples from 92 mCRC patients determined to be KRAS-positive using OncoBEAM were re-tested using Idylla. Samples with mutant allelic fractions (MAF) below 5% were selected for analysis. The positive percent agreement (PPA) of KRAS mutation results was compared for replicate samples analyzed by OncoBEAM and Idylla. Results: So far, Idylla detected KRAS mutations in 63 out of 92 (68.4%) OncoBEAM KRAS-positive plasma samples. Categorization of results based on MAF% revealed distinct differences in sensitivity between the two technologies. Conclusions: OncoBEAM demonstrated significantly greater sensitivity for plasma detection of RAS mutations than Idylla. Moreover, these data identify a “gray zone” below 1% MAF where Idylla fails to identify RAS-positivity in patient plasma samples. These findings serve as a reminder that liquid biopsy assays with diminished sensitivity may lack the dynamic range to provide accurate and timely RAS mutational status information to properly guide highly individualized anti-EGFR therapy and chemotherapy treatment decisions that may benefit patient outcomes. [Table: see text]
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- 2018
42. Noninvasive EGFR testing in plasma circulating free DNA (cfDNA) by a new diagnostic method to detect point mutations, deletions and insertions associated to non small cell lung cancer: CLART CMA EGFR LB
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Ana Aragon, Javier Hernández-Losa, Rosario Cospedal, Maria Jesus Sanz, Trinidad Caldés, Mariano Provencio, J. Carrillo, Marta Sanchez, Maria Luisa Villahermosa, Atocha Romero, Vanesa García-Barberán, Nuria Manjon, and José Luis Rodríguez-Peralto
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Cancer Research ,Diagnostic methods ,business.industry ,Point mutation ,Gene mutation ,medicine.disease ,Molecular biology ,respiratory tract diseases ,Oncology ,Circulating free DNA ,Medicine ,Non small cell ,business ,Lung cancer ,Epidermal growth factor receptor tyrosine kinase - Abstract
e20008 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are current treatments for advanced non-small cell lung cancer (NSCLC) with activating EGFR gene mutations. Histological samples are the standard tumor materials for EGFR mutation analysis. However, the accessibility of tumor samples is not always possible in advanced NSCLC patients. Moreover, a high percentage of EGFR mutated NSCLC patients will develop resistance to EGFR-TKIs such as T790M mutation. CLART CMA EGFR LB is a novel diagnostic assay able to detect 39 high-prevalence mutations associated with sensitivity or resistance to tyrosine kinase inhibitor treatment. Methods: A highly sensitive and specific method was developed for detection of EGFR mutations (G719X, T790M, L858R, L861Q, insertions in exon 20, and deletions in exon 19) in plasma samples (cfDNA). CLART CMA EGFR LB is based on a preamplification step with a multiplex ARMS-PCR and microarray detection system. Clinical testing was performed using 51 clinical plasma samples: 27 contained L858R, T790M, and deletions in exon 19; 24 contained wild type alleles. 20 samples were cross checked by next generation sequencing performed on the PGM platform (Ion Ampliseq™ Custom, deep-coverage 15000x). Results: Analytical sensitivity was assessed using recombinant plasmids, results ranged between 10-1000 copies/5µl for all mutations. cfDNA from cell lines with the mutations L858R, T790M and deletions in exon 19 at different frequencies (cfDNA Reference Standard, Horizon) were assessed. The system was able to detect the mutations present in a frequency of 2%. The analysis of 51 samples allowed establishing the diagnostic sensitivity and specificity in 93.33% and 100% respectively. CLART CMA EGFR LB showed similar analytical and diagnostic sensitivity than NGS for detecting L858R, T790M and deletions in exon 19. Conclusions: Our data support the use of CLART CMA EGFR LB for clinical testing prior to the selection of the appropriate treatment in NSCLC, monitoring the patient evolution and the emergence of resistance mutations such as T790M in plasma samples.
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- 2017
43. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
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Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou
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Science - Abstract
Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.
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- 2021
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44. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
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Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou
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Science - Abstract
A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4
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- 2021
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45. Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition.
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Lorena Martin-Morales, Paula Rofes, Eduardo Diaz-Rubio, Patricia Llovet, Victor Lorca, Inmaculada Bando, Pedro Perez-Segura, Miguel de la Hoya, Pilar Garre, Vanesa Garcia-Barberan, and Trinidad Caldes
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Medicine ,Science - Abstract
Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening methods. The aim of this study is the use of a Next Generation Sequencing panel in order to find the genes involved in the cancer predisposition of these families. For this study, 98 patients from these unexplained families were tested with a multigene panel targeting 94 genes involved in cancer predisposition. The mutations found were validated by Sanger sequencing and the segregation was studied when possible. We identified 19 likely pathogenic variants in 18 patients. Out of these, 8 were found in MMR genes (5 in MLH1, 1 in MSH6 and 2 in PMS2). In addition, 11 mutations were detected in other genes, including high penetrance genes (APC, SMAD4 and TP53) and moderate penetrance genes (BRIP1, CHEK2, MUTYH, HNF1A and XPC). Mutations c.1194G>A in SMAD4, c.714_720dup in PMS2, c.2050T>G in MLH1 and c.1635_1636del in MSH6 were novel. In conclusion, the detection of new pathogenic mutations in high and moderate penetrance genes could contribute to the explanation of the heritability of colorectal cancer, changing the individual clinical management. Multigene panel testing is a more effective method to identify germline variants in cancer patients compared to single-gene approaches and should be therefore included in clinical laboratories.
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- 2018
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46. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
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Elena Vigorito, Karoline B Kuchenbaecker, Jonathan Beesley, Julian Adlard, Bjarni A Agnarsson, Irene L Andrulis, Banu K Arun, Laure Barjhoux, Muriel Belotti, Javier Benitez, Andreas Berger, Anders Bojesen, Bernardo Bonanni, Carole Brewer, Trinidad Caldes, Maria A Caligo, Ian Campbell, Salina B Chan, Kathleen B M Claes, David E Cohn, Jackie Cook, Mary B Daly, Francesca Damiola, Rosemarie Davidson, Antoine de Pauw, Capucine Delnatte, Orland Diez, Susan M Domchek, Martine Dumont, Katarzyna Durda, Bernd Dworniczak, Douglas F Easton, Diana Eccles, Christina Edwinsdotter Ardnor, Ros Eeles, Bent Ejlertsen, Steve Ellis, D Gareth Evans, Lidia Feliubadalo, Florentia Fostira, William D Foulkes, Eitan Friedman, Debra Frost, Pragna Gaddam, Patricia A Ganz, Judy Garber, Vanesa Garcia-Barberan, Marion Gauthier-Villars, Andrea Gehrig, Anne-Marie Gerdes, Sophie Giraud, Andrew K Godwin, David E Goldgar, Christopher R Hake, Thomas V O Hansen, Sue Healey, Shirley Hodgson, Frans B L Hogervorst, Claude Houdayer, Peter J Hulick, Evgeny N Imyanitov, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Lauren Jacobs, Anna Jakubowska, Ramunas Janavicius, Katarzyna Jaworska-Bieniek, Uffe Birk Jensen, Esther M John, Joseph Vijai, Beth Y Karlan, Karin Kast, KConFab Investigators, Sofia Khan, Ava Kwong, Yael Laitman, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jan Lubinski, Phuong L Mai, Siranoush Manoukian, Sylvie Mazoyer, Alfons Meindl, Arjen R Mensenkamp, Marco Montagna, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Dieter Niederacher, Edith Olah, Olufunmilayo I Olopade, Kai-Ren Ong, Ana Osorio, Sue Kyung Park, Ylva Paulsson-Karlsson, Inge Sokilde Pedersen, Bernard Peissel, Paolo Peterlongo, Georg Pfeiler, Catherine M Phelan, Marion Piedmonte, Bruce Poppe, Miquel Angel Pujana, Paolo Radice, Gad Rennert, Gustavo C Rodriguez, Matti A Rookus, Eric A Ross, Rita Katharina Schmutzler, Jacques Simard, Christian F Singer, Thomas P Slavin, Penny Soucy, Melissa Southey, Doris Steinemann, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Christian Sutter, Csilla I Szabo, Muy-Kheng Tea, Manuel R Teixeira, Soo-Hwang Teo, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Elizabeth J van Rensburg, Liliana Varesco, Raymonda Varon-Mateeva, Athanassios Vratimos, Jeffrey N Weitzel, Lesley McGuffog, Judy Kirk, Amanda Ewart Toland, Ute Hamann, Noralane Lindor, Susan J Ramus, Mark H Greene, Fergus J Couch, Kenneth Offit, Paul D P Pharoah, Georgia Chenevix-Trench, and Antonis C Antoniou
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Medicine ,Science - Abstract
Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
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- 2016
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47. Comparison of circulating tumor cells and cell-free DNA in the molecular characterization of patients with head and neck cancer
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Pedro Pérez-Segura, Virginia De la Orden-García, Vanesa García-Barberán, Igor López-Cade, Mariona Baliu Piqué, Alberto Ocaña, Irene Gonzalo, Isabel Díaz-Millán, Cristina Saiz-Ladera, Beatriz Mediero-Valeros, Santiago Cabezas-Camarero, and Eduardo Díaz-Rubio
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Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Head and neck cancer ,medicine.disease ,Circulating tumor cell ,Oncology ,Cell-free fetal DNA ,medicine ,In patient ,Therapy monitoring ,Liquid biopsy ,business ,neoplasms - Abstract
e18521 Background: The role of liquid biopsy in diagnosis and therapy monitoring in patients with head and neck cancer has been much less studied compared to other cancers. Our aim was to evaluate the perfomance in the isolation and recovery for molecular characterization of circulating tumour cells (CTC) of a new immunoafinity-based method and to compare it with the molecular diagnostic yield of plasma cell-free DNA. Methods: Patients with recurrent/metastatic (RM) head and neck cancer (HNC) were enrolled prospectively. Forty mililiters (ml) of plasma were collected at one or several time-points. First blood draw was always collected before starting a new therapeutic intervention or at the time of radiologic progression. For CTC detection and isolation, either anti-EpCAM or both anti-EpCAM + anti-EGFR antibodies were used. Digital PCR and castPCR were used to study KRAS and PI3KCA mutations in non-squamous HNC. A 15-gene customized NGS panel was used to characterized both CTC and cfDNA in patients with squamous HNC. Results: Between February 2016 and October 2018, 14 patients with R/M HNC were included (n = 1 local-only disease, n = 10 local and distant disease, n = 3 distant-only disease). Squamous histology (S): n = 9. Non-squamous (NS): n = 5 (1 naso-ethmoidal intestinal-type adenocarcinoma, 1 parotid gland exadenoma pleomorfic carcinoma, 2 parotid-gland salivary duct carcinomas (SDC), 1 parotid-gland high-grade neuroendocrine carcinoma). Twenty-five CTC determinations were performed. In 5 patients serial CTC determinations were performed. Median CTC was 4 (min-max: 0-49). Median CTC among 11 CTC determinations in S-HNC was 4 (min-max: 0-49). Median CTC was 3 CTC (min-max: 0-26) among the 14 determinations performed in NS-HNC. Digital PCR unveiled mutations in CTC and in cfDNA in 2 of 4 patients tested with NS histology (KRAS, PIK3CA), with one of them being concordant for the specific mutation. NGS unveiled mutations in CTC in 7/9 patients and in cfDNA in 6/9 patients, with only one loci-concordant case between CTC and plasma. Conclusions: IsoFlux detected CTC in the majority of patients with R/M HNC, regardless of the histologic type, and allowed for molecular characterization of CTC using different techniques for mutational analysis. Both NGS and digital PCR allowed for the detection in cell-free DNA of commonly mutated genes in HNC. Liquid biopsy should be more actively studied in this disease in order to better define its role in diagnosis and therapeutic monitoring.
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