TY - JOUR
T1 - Divergent mutational processes distinguish hypoxic and normoxic tumours
AU - PCAWG Consortium
AU - Bhandari, Vinayak
AU - Li, Constance H.
AU - Bristow, Robert G.
AU - Boutros, Paul C.
AU - Aaltonen, Lauri A.
AU - Abascal, Federico
AU - Abeshouse, Adam
AU - Aburatani, Hiroyuki
AU - Adams, David J.
AU - Agrawal, Nishant
AU - Ahn, Keun Soo
AU - Ahn, Sung Min
AU - Aikata, Hiroshi
AU - Akbani, Rehan
AU - Akdemir, Kadir C.
AU - Al-Ahmadie, Hikmat
AU - Al-Sedairy, Sultan T.
AU - Al-Shahrour, Fatima
AU - Alawi, Malik
AU - Albert, Monique
AU - Aldape, Kenneth
AU - Alexandrov, Ludmil B.
AU - Ally, Adrian
AU - Alsop, Kathryn
AU - Alvarez, Eva G.
AU - Amary, Fernanda
AU - Amin, Samirkumar B.
AU - Aminou, Brice
AU - Ammerpohl, Ole
AU - Anderson, Matthew J.
AU - Ang, Yeng
AU - Antonello, Davide
AU - Anur, Pavana
AU - Aparicio, Samuel
AU - Appelbaum, Elizabeth L.
AU - Arai, Yasuhito
AU - Aretz, Axel
AU - Arihiro, Koji
AU - Ariizumi, Shun ichi
AU - Armenia, Joshua
AU - Arnould, Laurent
AU - Asa, Sylvia
AU - Assenov, Yassen
AU - Atwal, Gurnit
AU - Aukema, Sietse
AU - Auman, J. Todd
AU - Aure, Miriam R.R.
AU - Wang, Jiayin
AU - Yang, Huanming
AU - Ye, Kai
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.
AB - Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.
UR - https://www.scopus.com/pages/publications/85079073682
U2 - 10.1038/s41467-019-14052-x
DO - 10.1038/s41467-019-14052-x
M3 - 文章
C2 - 32024819
AN - SCOPUS:85079073682
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 737
ER -
可持续发展目标 3 良好健康与福祉