Pan-cancer whole-genome analyses of metastatic solid tumours.

Autor: Priestley P; Hartwig Medical Foundation, Amsterdam, The Netherlands.; Hartwig Medical Foundation Australia, Sydney, New South Wales, Australia., Baber J; Hartwig Medical Foundation, Amsterdam, The Netherlands.; Hartwig Medical Foundation Australia, Sydney, New South Wales, Australia., Lolkema MP; Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.; Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Steeghs N; Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.; Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands., de Bruijn E; Hartwig Medical Foundation, Amsterdam, The Netherlands., Shale C; Hartwig Medical Foundation Australia, Sydney, New South Wales, Australia., Duyvesteyn K; Hartwig Medical Foundation, Amsterdam, The Netherlands., Haidari S; Hartwig Medical Foundation, Amsterdam, The Netherlands.; Center for Personalized Cancer Treatment, Rotterdam, The Netherlands., van Hoeck A; Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands., Onstenk W; Hartwig Medical Foundation, Amsterdam, The Netherlands.; Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.; Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Roepman P; Hartwig Medical Foundation, Amsterdam, The Netherlands., Voda M; Hartwig Medical Foundation, Amsterdam, The Netherlands., Bloemendal HJ; Meander Medisch Centrum, Amersfoort, The Netherlands.; Radboud University Medical Center, Nijmegen, The Netherlands., Tjan-Heijnen VCG; Maastricht University Medical Center, Maastricht, The Netherlands., van Herpen CML; Radboud University Medical Center, Nijmegen, The Netherlands., Labots M; VU Medical Center, Amsterdam, The Netherlands., Witteveen PO; Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands., Smit EF; Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.; Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands., Sleijfer S; Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.; Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Voest EE; Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.; Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands., Cuppen E; Hartwig Medical Foundation, Amsterdam, The Netherlands. e.cuppen@hartwigmedicalfoundation.nl.; Center for Personalized Cancer Treatment, Rotterdam, The Netherlands. e.cuppen@hartwigmedicalfoundation.nl.; Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands. e.cuppen@hartwigmedicalfoundation.nl.
Jazyk: angličtina
Zdroj: Nature [Nature] 2019 Nov; Vol. 575 (7781), pp. 210-216. Date of Electronic Publication: 2019 Oct 23.
DOI: 10.1038/s41586-019-1689-y
Abstrakt: Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.
Databáze: MEDLINE
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