TY - JOUR
T1 - Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
AU - Fraser, Michael
AU - Livingstone, Julie
AU - Wrana, Jeffrey L
AU - Finelli, Antonio
AU - He, Housheng Hansen
AU - van der Kwast, Theodorus
AU - Zlotta, Alexandre R
AU - Bristow, Robert G
AU - Boutros, Paul C
N1 - Funding Information:
Thanks to Drs. Kathleen Houlahan, Viniyak Bhandari, and John Watson for assistance with experimental design and statistical analysis and to all members of the Boutros lab for suggestions and support. This study was conducted with the support of Movember funds through Prostate Cancer Canada, and with the additional support of the Ontario Institute for Cancer Research, funded by the Government of Ontario. This work was supported by funds from the Department of Surgical Oncology and the Genetics and Epigenetics program, Princess Margaret Cancer Centre and the University of Toronto, Department of Surgery (Division of Urology) to Michael Fraser. Hansen H. He is supported by a Project Grant from the CIHR. This work was supported by Prostate Cancer Canada and is proudly funded by the Movember Foundation Team Grant T2013 and #RS2014-01 and a Prostate Cancer Canada Movember Discovery Grant (D2014-26) to Alexandre R. Zlotta. Paul C. Boutros was supported by a Terry Fox Research Institute New Investigator Award, a Prostate Cancer Canada Rising Star Fellowship, a CIHR New Investigator Award, a CIHR Project Grant, the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-125), Canadian Cancer Society (grant #705649) and by the University of California. The authors gratefully thank the Princess Margaret Cancer Centre Foundation and Radiation Medicine Programme Academic Enrichment Fund for support (to Robert G. Bristow). This work was supported by a Terry Fox Research Institute Programme Project Grant. Robert G. Bristow is a recipient of a Canadian Cancer Society Research Scientist Award. Laboratory work for R.G.B. is supported by the CRUK Manchester Institute through Cancer Research UK. This work was supported by the NIH/NCI through awards P30CA016042, U01CA214194, and U24CA248265.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/10/29
Y1 - 2021/10/29
N2 - Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer.
AB - Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer.
U2 - 10.1038/s41467-021-26489-0
DO - 10.1038/s41467-021-26489-0
M3 - Article
C2 - 34716314
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6248
ER -
