TY - JOUR
T1 - The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies
AU - Angus, Lindsay
AU - Smid, Marcel
AU - Wilting, Saskia M
AU - van Riet, Job
AU - Van Hoeck, Arne
AU - Nguyen, Luan
AU - Nik-Zainal, Serena
AU - Steenbruggen, Tessa G
AU - Tjan-Heijnen, Vivianne C G
AU - Labots, Mariette
AU - van Riel, Johanna M G H
AU - Bloemendal, Haiko J
AU - Steeghs, Neeltje
AU - Lolkema, Martijn P
AU - Voest, Emile E
AU - van de Werken, Harmen J G
AU - Jager, Agnes
AU - Cuppen, Edwin
AU - Sleijfer, Stefan
AU - Martens, John W M
PY - 2019/10/1
Y1 - 2019/10/1
N2 - The whole-genome sequencing of prospectively collected tissue biopsies from 442 patients with metastatic breast cancer reveals that, compared to primary breast cancer, tumor mutational burden doubles, the relative contributions of mutational signatures shift and the mutation frequency of six known driver genes increases in metastatic breast cancer. Significant associations with pretreatment are also observed. The contribution of mutational signature 17 is significantly enriched in patients pretreated with fluorouracil, taxanes, platinum and/or eribulin, whereas the de novo mutational signature I identified in this study is significantly associated with pretreatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumors are identified, exhibiting either homologous recombination deficiency (13%), high tumor mutational burden (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides insights into the biology of metastatic breast cancer and identifies clinically useful genomic features for the future improvement of patient management.
AB - The whole-genome sequencing of prospectively collected tissue biopsies from 442 patients with metastatic breast cancer reveals that, compared to primary breast cancer, tumor mutational burden doubles, the relative contributions of mutational signatures shift and the mutation frequency of six known driver genes increases in metastatic breast cancer. Significant associations with pretreatment are also observed. The contribution of mutational signature 17 is significantly enriched in patients pretreated with fluorouracil, taxanes, platinum and/or eribulin, whereas the de novo mutational signature I identified in this study is significantly associated with pretreatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumors are identified, exhibiting either homologous recombination deficiency (13%), high tumor mutational burden (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides insights into the biology of metastatic breast cancer and identifies clinically useful genomic features for the future improvement of patient management.
UR - http://www.scopus.com/inward/record.url?scp=85074187592&partnerID=8YFLogxK
U2 - 10.1038/s41588-019-0507-7
DO - 10.1038/s41588-019-0507-7
M3 - Article
C2 - 31570896
VL - 51
SP - 1450
EP - 1458
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 10
ER -