Germline polymorphisms associated with impaired survival outcomes and somatic tumor alterations in advanced prostate cancer.
Journal
Prostate cancer and prostatic diseases
ISSN: 1476-5608
Titre abrégé: Prostate Cancer Prostatic Dis
Pays: England
ID NLM: 9815755
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
13
09
2019
accepted:
04
11
2019
revised:
19
10
2019
pubmed:
21
11
2019
medline:
9
3
2021
entrez:
21
11
2019
Statut:
ppublish
Résumé
Germline variants in androgen metabolism genes may influence clinical response to androgen deprivation therapy (ADT) in advanced prostate cancer. We sought to investigate the prognostic significance of germline variants in androgen metabolism genes with respect to overall survival (OS) after ADT, and to associate germline variants with tumor genomic features. Germline and somatic whole-genome sequencing (WGS) data were evaluated in a cohort of 101 men with metastatic castration-resistant prostate cancer (mCRPC). Survival analyses were performed to identify polymorphisms associated with impaired OS after primary ADT. Germline variants found to be prognostic of OS were associated with tumor somatic DNA-sequence alterations based on WGS performed on paired metastasis biopsies from the same 101 patients. Gene set enrichment analysis was performed based on tumor RNA-sequencing data to identify genomic pathways differentially expressed in patients with germline variants. A comprehensive literature review identified 17 candidate polymorphisms in nine androgen metabolism genes that have been previously shown to have an association with response to ADT in prostate cancer. Of these, the variant rs1856888 allele located 13 kb upstream of HSD3B1 was found to be significantly associated with impaired OS (P = 0.029). Variant rs1856888 was commonly co-inherited with the well-characterized HSD3B1(1245A>C) polymorphism, and there was a trend toward shorter median OS in patients with HSD3B1(1245A>C) compared with homozygous wild-type patients (P = 0.052). While HSD3B1 germline variants were not associated with common somatic tumor DNA alterations, they were associated with increased tumor expression of cell proliferation and cell cycle genes. This study presents a comprehensive assessment of germline variants in androgen metabolism genes and highlights HSD3B1 polymorphisms as prognostic of OS after ADT and associated with an aggressive gene expression tumor profile in mCRPC.
Identifiants
pubmed: 31745256
doi: 10.1038/s41391-019-0188-4
pii: 10.1038/s41391-019-0188-4
pmc: PMC7529063
mid: NIHMS1626035
doi:
Substances chimiques
Androgen Antagonists
0
Biomarkers, Tumor
0
DNA, Neoplasm
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
316-323Subventions
Organisme : NCI NIH HHS
ID : U10 CA180834
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180801
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA035281
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA180830
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA046282
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233340
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA035431
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA011083
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180888
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172382
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233178
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA142559
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA045808
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180835
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA035421
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180846
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA063848
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233324
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190289
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA067575
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180818
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180828
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA189957
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA046368
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180819
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA035090
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233328
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180830
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA045807
Pays : United States
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