SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity.
SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity.
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DOI：
10.1158/1078-0432.ccr-18-0937
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发表时间：
2018-11-15
期刊：
影响因子：
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通讯作者：
de Bono JS
中科院分区：
文献类型：
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作者：
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
CHD1 缺失和 SPOP 突变经常在前列腺癌中同时发生，而在去势抵抗性前列腺癌 (CRPC) 中报道的频率较低。我们监测了疾病进展过程中的 CHD1 表达，并评估了 CHD1 缺失/SPOP 突变的转移性 CRPC (mCRPC) 的分子和临床特征。我们确定了 89 名 mCRPC 患者，他们拥有未接受过激素治疗和去势抵抗的肿瘤样本：通过 IHC 分析这些样本的 CHD1、PTEN 和 ERG 表达。 SPOP 状态由靶向下一代测序 (NGS) 确定。我们研究了这些生物标志物与（i）诊断后的总生存期之间的相关性； (ii) CRPC 的总体生存率； (iii) 阿比特龙治疗的持续时间； (iv) 对阿比特龙的反应。使用 Cox 回归和对数秩分析来分析与结果的关系。分别在 11 例 (15%) 和 13 例 (17%) 激素敏感性前列腺癌 (HSPC) 和 CRPC 活检中检测到 CHD1 蛋白丢失。在 56 例匹配的同一患者 HSPC 和 CRPC 活检中比较 CHD1 表达是可行的。 56 例病例中有 55 例 (98%) 的 HSPC 和 CRPC 中的 CHD1 蛋白状态相关。我们鉴定了 22 名患有体细胞 SPOP 突变的患者，其中 6 种突变以前在前列腺癌中未曾报道过。 SPOP 突变和/或 CHD1 缺失与阿比特龙的较高反应率（SPOP：OR，14.50 P = 0.001；CHD1：OR，7.30，P = 0.08）和较长的阿比特龙治疗时间相关（SPOP：HR，0.37，P = 0.002，CHD1：HR，0.50，P = 0.06）。 SPOP 突变的 mCRPC 因 CHD1 丢失而大量富集。这些肿瘤似乎对阿比特龙治疗高度敏感。
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). 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. 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). SPOP-mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment.