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5 results on '"Sammut SJ"'

1. The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer.

Author

De Mattos-Arruda L, Sammut SJ, Ross EM, Bashford-Rogers R, Greenstein E, Markus H, Morganella S, Teng Y, Maruvka Y, Pereira B, Rueda OM, Chin SF, Contente-Cuomo T, Mayor R, Arias A, Ali HR, Cope W, Tiezzi D, Dariush A, Dias Amarante T, Reshef D, Ciriaco N, Martinez-Saez E, Peg V, Ramon Y Cajal S, Cortes J, Vassiliou G, Getz G, Nik-Zainal S, Murtaza M, Friedman N, Markowetz F, Seoane J, and Caldas C

Subjects
Breast Neoplasms secondary, Female, Gene Expression Profiling, Humans, Loss of Heterozygosity, Neoplasm Metastasis, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Exome Sequencing, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Breast Neoplasms immunology, Gene Expression Regulation, Neoplastic, Genomics methods, Mutation
Abstract

The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2019
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2. Intersect-then-combine approach: improving the performance of somatic variant calling in whole exome sequencing data using multiple aligners and callers.

Author

Callari M, Sammut SJ, De Mattos-Arruda L, Bruna A, Rueda OM, Chin SF, and Caldas C

Subjects
Algorithms, DNA, Neoplasm, Exome, Humans, INDEL Mutation, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Computational Biology methods, Genome, Human, Mutation, Neoplasms genetics, Sequence Analysis, DNA methods
Abstract

Bioinformatic analysis of genomic sequencing data to identify somatic mutations in cancer samples is far from achieving the required robustness and standardisation. In this study we generated a whole exome sequencing benchmark dataset using the platinum genome sample NA12878 and developed an intersect-then-combine (ITC) approach to increase the accuracy in calling single nucleotide variants (SNVs) and indels in tumour-normal pairs. We evaluated the effect of alignment, base quality recalibration, mutation caller and filtering on sensitivity and false positive rate. The ITC approach increased the sensitivity up to 17.1%, without increasing the false positive rate per megabase (FPR/Mb) and its validity was confirmed in a set of clinical samples.

Published
2017
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3. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes.

Author

Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA, Pugh M, Jones L, Russell R, Sammut SJ, Tsui DW, Liu B, Dawson SJ, Abraham J, Northen H, Peden JF, Mukherjee A, Turashvili G, Green AR, McKinney S, Oloumi A, Shah S, Rosenfeld N, Murphy L, Bentley DR, Ellis IO, Purushotham A, Pinder SE, Børresen-Dale AL, Earl HM, Pharoah PD, Ross MT, Aparicio S, and Caldas C

Subjects
Adult, Aged, Breast Neoplasms mortality, Breast Neoplasms pathology, Class I Phosphatidylinositol 3-Kinases genetics, DNA Copy Number Variations, Female, Genes, Tumor Suppressor, Genetic Association Studies, Humans, Kaplan-Meier Estimate, Middle Aged, Prognosis, Proportional Hazards Models, Transcriptome, Breast Neoplasms genetics, Mutation
Abstract

The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13-14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13-14 amplification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.

Published
2016
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4. Next Generation-Targeted Amplicon Sequencing (NG-TAS): An optimised protocol and computational pipeline for cost-effective profiling of circulating tumour DNA

Author

Maurizio Callari, Suet-Feung Chin, Mafalda Oliveira, Richard D. Baird, Carlos Caldas, Javier Cortés, Marta Grzelak, Heather Biggs, Emma Beddowes, Stephen John Sammut, Sabine C. Linn, Meiling Gao, Linda Jones, Abdelhamid Boumertit, Beddowes, Emma [0000-0001-7649-2863], Caldas, Carlos [0000-0003-3547-1489], Apollo - University of Cambridge Repository, Institut Català de la Salut, [Gao M, Callari M] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK. [Beddowes E] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK. Breast Cancer Programme, Cancer Research UK Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. [Sammut SJ, Grzelak M] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK. [Biggs H] Breast Cancer Programme, Cancer Research UK Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. [Cortes J] Ramon y Cajal University Hospital, Madrid, Spain. Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. [Oliveira M] Vall d'Hebron Institut d'Oncologia, Barcelona, Spain., Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, Callari, Maurizio [0000-0001-5239-0918], Sammut, Stephen [0000-0003-4472-904X], Jones, Linda [0000-0001-9347-5715], Baird, Richard [0000-0001-7071-6483], and Chin, Suet-Feung [0000-0001-5697-1082]

Subjects
0301 basic medicine, Other subheadings::/methods [Other subheadings], Deep sequencing, lcsh:Medicine, Method, 32 Biomedical and Clinical Sciences, Multiplexing, Circulating Tumor DNA, chemistry.chemical_compound, 0302 clinical medicine, Otros calificadores::/métodos [Otros calificadores], NG-TAS, International HapMap Project, Càncer, Genetics (clinical), Cancer, 0303 health sciences, High-Throughput Nucleotide Sequencing, 3 Good Health and Well Being, Amplicon, 3. Good health, Plasma.cfDNA, 030220 oncology & carcinogenesis, Costs and Cost Analysis, Amplicon sequencing, Molecular Medicine, Cancer gene, Female, ADN - Anàlisi, Ciencias de la información::metodologías computacionales [CIENCIA DE LA INFORMACIÓN], Técnicas de Investigación::Técnicas Genéticas::Análisis de Secuencia::Análisis de Secuencia de ADN [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], animal structures, lcsh:QH426-470, técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ADN [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Computational biology, Biology, Biologia computacional, Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT], neoplasias [ENFERMEDADES], 03 medical and health sciences, Clinical Research, Cell Line, Tumor, Breast Cancer, Genetics, Biomarkers, Tumor, Humans, Genetic Testing, Heterogeneous, Liquid biopsy, Allele, Molecular Biology, Gene, Information Science::Computing Methodologies [INFORMATION SCIENCE], 030304 developmental biology, lcsh:R, Human Genome, Computational pipeline, ctDNA, Sequence Analysis, DNA, 3211 Oncology and Carcinogenesis, Human genetics, 4.1 Discovery and preclinical testing of markers and technologies, Neoplasms [DISEASES], lcsh:Genetics, 030104 developmental biology, chemistry, Mutation, Ciencia de la Información::Metodologias Computacionales [CIENCIA DE LA INFORMACIÓN], 4 Detection, screening and diagnosis, Software, DNA, 31 Biological Sciences
Abstract

Circulating tumour DNA (ctDNA) detection and monitoring has enormous potential clinical utility in oncology. We describe here a fast, flexible and cost-effective method to profile multiple genes simultaneously in low input cell-free DNA (cfDNA): Next Generation-Targeted Amplicon Sequencing (NG-TAS). We designed a panel of 377 amplicons spanning 20 cancer genes and tested the NG-TAS pipeline using cell-free DNA from two hapmap lymphoblastoid cell lines. NG-TAS consistently detected mutations in cfDNA when mutation allele fraction was >1%. We applied NG-TAS to a clinical cohort of metastatic breast cancer patients, demonstrating its potential in monitoring the disease. The computational pipeline is available at: https://github.com/cclab-brca/NGTAS_pipeline.

Published
2018
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5. The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer

Author

Alexandra Arias, Edith M. Ross, Oscar M. Rueda, Regina Mayor, Vicente Peg, Carlos Caldas, Dan Reshef, Tania Contente-Cuomo, Stephen John Sammut, Joan Seoane, Elena Martínez-Sáez, Tauanne Dias Amarante, Daniel Guimarães Tiezzi, Nikaoly Ciriaco, Wei Cope, Aliakbar Dariush, Bernard Pereira, H. Raza Ali, Havell Markus, Erez Greenstein, Muhammed Murtaza, Serena Nik-Zainal, Santiago Ramón y Cajal, Yosef E. Maruvka, Nir Friedman, Javier Cortes, Florian Markowetz, Gad Getz, Suet-Feung Chin, Yvonne Hui-Fang Teng, George S. Vassiliou, Leticia De Mattos-Arruda, Rachael Bashford-Rogers, Sandro Morganella, Sammut, Stephen [0000-0003-4472-904X], Bashford-Rogers, Rachael [0000-0002-6838-0711], Chin, Suet-Feung [0000-0001-5697-1082], Ali, Raza [0000-0001-7587-0906], Cope, Wei [0000-0002-5661-3522], Dias Amarante, Tauanne [0000-0002-1999-9753], Vassiliou, George [0000-0003-4337-8022], Nik-Zainal, Serena [0000-0001-5054-1727], Markowetz, Florian [0000-0002-2784-5308], Caldas, Carlos [0000-0003-3547-1489], Apollo - University of Cambridge Repository, Institut Català de la Salut, [De Mattos-Arruda L] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK. University of Cambridge, Cambridge, UK. Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. Hospital Universitari Vall d'Hebron, Barcelona, Spain. [Sammut SJ, Ross EM] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK. University of Cambridge, Cambridge, UK. [Bashford-Rogers R] Department of Medicine, University of Cambridge, Cambridge, UK. [Greenstein E] Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. [Markus H] Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, USA. Mayo Clinic Center for Individualized Medicine, Scottsdale, USA. [Mayor R, Arias A] Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. Hospital Universitari Vall d'Hebron, Barcelona, Spain. Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain. [Ciriaco N] Servei d’Anatomia Patològica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. [Martinez-Saez E] Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain. Servei d’Anatomia Patològica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. [Peg V, Ramon Y Cajal S] Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain. Servei d’Anatomia Patològica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Vall d’Hebron Institut de Recerca, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [Cortes J] Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. Hospital Universitari Vall d'Hebron, Barcelona, Spain. Ramon y Cajal Hospital, Madrid, Spain. [Seoane J] Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. Hospital Universitari Vall d'Hebron, Barcelona, Spain. Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain, Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, Hospital Universitari Vall d'Hebron, and Vall d'Hebron Barcelona Hospital Campus

Subjects
0301 basic medicine, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], metastatic phylogenies, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Loss of Heterozygosity, Metastases, immunoediting, Loss of heterozygosity, 0302 clinical medicine, Tumor Microenvironment, Otros calificadores::Otros calificadores::/inmunología [Otros calificadores], Neoplasm Metastasis, lcsh:QH301-705.5, immune landscapes, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Neoplasms::Neoplastic Processes::Neoplasm Metastasis [DISEASES], Genomics, Nreast cancer, Genomic landscapes, Metastatic breast cancer, 3. Good health, Gene Expression Regulation, Neoplastic, Female, Mama - Càncer - Aspectes immunològics, Immune landscapes, clade mutations, Clade mutations, genomic landscapes, Breast Neoplasms, Human leukocyte antigen, Biology, Stem mutations, Article, General Biochemistry, Genetics and Molecular Biology, private mutations, 03 medical and health sciences, breast cancer, Breast cancer, Immune system, Metàstasi, Immunoediting, Other subheadings::Other subheadings::/immunology [Other subheadings], Exome Sequencing, Other subheadings::Other subheadings::/genetics [Other subheadings], Biomarkers, Tumor, medicine, Humans, metastases, Tumor microenvironment, Gene Expression Profiling, Neoplasias::Neoplasias por Localización::Neoplasias de la Mama [ENFERMEDADES], stem mutations, medicine.disease, Metastatic phylogenies, Gene expression profiling, TCR repertoire, 030104 developmental biology, lcsh:Biology (General), neoplasias::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES], Mutation, Cancer research, Mama - Càncer - Aspectes genètics, Private mutations, 030217 neurology & neurosurgery
Abstract

Summary The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer., Graphical Abstract, Highlights • Genomic and transcriptomic landscapes for 10 lethal breast cancers • Within a patient, metastases group in limited clades with shared genomic ancestry • Tumor immune microenvironments across metastases are not uniform • Phylogenetic trees are correlated with TIL-TCR trees across metastases, De Mattos-Arruda et al. profiled multiple metastases from autopsies of patients with therapy-resistant breast cancer, showing that multi-clonal spreading occurs in a small number of founder events. The analysis characterizes predicted neo-antigen landscapes, tumor microenvironments, and accumulation of HLA LOH. T cell immune responses appear to co-evolve with metastatic cancer genomes.

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