دورية أكاديمية
Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers
| العنوان: | Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers |
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| المؤلفون: | Nones, K., Johnson, J., Newell, F., Patch, A. M., Thorne, H., Kazakoff, S. H., De Luca, X. M., Parsons, Michael T., Ferguson, K., Reid, L. E., Mccart Reed, A. E., Srihari, S., Lakis, V., Davidson, A. L., Mukhopadhyay, P., Holmes, O., Xu, Qinying, Wood, S., Leonard, C., Beesley, J., Harris, J. M., Barnes, D., Degasperi, A., Ragan, M. A., Spurdle, A. B., Khanna, K. K., Lakhani, S. R., Pearson, J. V., Nik-Zainal, S., Chenevix-Trench, G., Waddell, N., Simpson, P. T. |
| المصدر: | Annals of Oncology |
| بيانات النشر: | Oxford University Press |
| سنة النشر: | 2019 |
| المجموعة: | Queensland University of Technology: QUT ePrints |
| مصطلحات موضوعية: | BRCA1, BRCA2, familial breast cancers, mutation signatures, whole-genome sequencing |
| الوصف: | 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| العلاقة: | https://eprints.qut.edu.au/229992/1/108710426.pdfTest; Nones, K., Johnson, J., Newell, F., Patch, A. M., Thorne, H., Kazakoff, S. H., De Luca, X. M., Parsons, Michael T., Ferguson, K., Reid, L. E., Mccart Reed, A. E., Srihari, S., Lakis, V., Davidson, A. L., Mukhopadhyay, P., Holmes, O., Xu, Qinying, Wood, S., Leonard, C., Beesley, J., Harris, J. M., Barnes, D., Degasperi, A., Ragan, M. A., Spurdle, A. B., Khanna, K. K., Lakhani, S. R., Pearson, J. V., Nik-Zainal, S., Chenevix-Trench, G., Waddell, N., & Simpson, P. T. (2019) Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers. Annals of Oncology, 30(7), pp. 1071-1079.; https://eprints.qut.edu.au/229992Test/; Institute of Health and Biomedical Innovation |
| الإتاحة: | https://doi.org/10.1093/annonc/mdz132Test https://eprints.qut.edu.au/229992Test/ |
| حقوق: | free_to_read ; http://creativecommons.org/licenses/by-nc/4.0Test/ ; 2019 The Author(s) ; This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au |
| رقم الانضمام: | edsbas.6F8F9ECA |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |