Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers
| Autor: | Stephen H. Kazakoff, Julie Johnson, Nicola Waddell, Oliver Holmes, Sunil R. Lakhani, K. K. Khanna, Conrad Leonard, Michael T. Parsons, Peter T. Simpson, Vanessa Lakis, Katia Nones, Serena Nik-Zainal, Aimee L Davidson, Scott Wood, Andrea Degasperi, Georgia Chenevix-Trench, A.E. McCart Reed, Lynne Reid, John V. Pearson, Ann-Marie Patch, Kaltin Ferguson, X. M. De Luca, Sriganesh Srihari, Jonathan M. Harris, Jonathan Beesley, Mark A. Ragan, David G. Barnes, Heather Thorne, Pamela Mukhopadhyay, Felicity Newell, Qinying Xu, Amanda B. Spurdle |
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| Přispěvatelé: | Barnes, Daniel [0000-0002-3781-7570], Degasperi, Andrea [0000-0001-6879-0596], Nik-Zainal, Serena [0000-0001-5054-1727], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult endocrine system diseases mutation signatures Somatic cell PALB2 Breast Neoplasms Germline 03 medical and health sciences 0302 clinical medicine Germline mutation MUTYH Medicine Humans Genetic Predisposition to Disease skin and connective tissue diseases CHEK2 Germ-Line Mutation Genetics BRCA2 Protein Whole Genome Sequencing business.industry BRCA1 Protein Editorials Hematology DNA Neoplasm Middle Aged BRCA1 Prognosis BRCA2 3. Good health 030104 developmental biology Oncology whole-genome sequencing 030220 oncology & carcinogenesis PARP inhibitor familial breast cancers Female business Fanconi Anemia Complementation Group N Protein |
| Zdroj: | Ann Oncol |
| ISSN: | 1569-8041 |
| Popis: | Background Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. Patients and methods We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). Results Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. Conclusions Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases. |
| Databáze: | OpenAIRE |
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