SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity.
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Date
2018-11-15ICR Author
Author
Boysen, G
Rodrigues, DN
Rescigno, P
Seed, G
Dolling, D
Riisnaes, R
Crespo, M
Zafeiriou, Z
Sumanasuriya, S
Bianchini, D
Hunt, J
Moloney, D
Perez-Lopez, R
Tunariu, N
Miranda, S
Figueiredo, I
Ferreira, A
Christova, R
Gil, V
Aziz, S
Bertan, C
de Oliveira, FM
Atkin, M
Clarke, M
Goodall, J
Sharp, A
MacDonald, T
Rubin, MA
Yuan, W
Barbieri, CE
Carreira, S
Mateo, J
de Bono, JS
Type
Journal Article
Metadata
Show full item recordAbstract
Purpose: CHD1 deletions and SPOP mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of CHD1-deleted/SPOP-mutated metastatic CRPC (mCRPC).Experimental Design: We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC. SPOP status was determined by targeted next-generation sequencing (NGS). We studied the correlations between these biomarkers and (i) overall survival from diagnosis; (ii) overall survival from CRPC; (iii) duration of abiraterone treatment; and (iv) response to abiraterone. Relationship with outcome was analyzed using Cox regression and log-rank analyses.Results: CHD1 protein loss was detected in 11 (15%) and 13 (17%) of hormone-sensitive prostate cancer (HSPC) and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic SPOP mutations, with six of these mutations not reported previously in prostate cancer. SPOP mutations and/or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR, 14.50 P = 0.001; CHD1: OR, 7.30, P = 0.08) and a longer time on abiraterone (SPOP: HR, 0.37, P = 0.002, CHD1: HR, 0.50, P = 0.06).Conclusions: SPOP-mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment. Clin Cancer Res; 24(22); 5585-93. ©2018 AACR.
Collections
Subject
Cell Line, Tumor
Humans
Prostatic Neoplasms
Disease Progression
Androstenes
DNA Helicases
DNA-Binding Proteins
Nuclear Proteins
Repressor Proteins
RNA, Small Interfering
Neoplasm Staging
Gene Expression
Gene Deletion
Drug Resistance, Neoplasm
Mutation
Aged
Middle Aged
Male
Neoplasm Grading
Synthetic Lethal Mutations
Research team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Language
eng
Date accepted
2018-07-25
License start date
2018-11
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2018, 24 (22), pp. 5585 - 5593
Publisher
AMER ASSOC CANCER RESEARCH