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SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity

Gunther Boysen1, Daniel N Rodrigues1, Pasquale Rescigno2

  • 1Institute of Cancer Research, London, United Kingdom.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|August 3, 2018
PubMed

Insights

Chromatin-binding protein 1 (CHD1) loss and Spexin (SPOP) mutations frequently co-occur in metastatic castration-resistant prostate cancer (mCRPC). These genetic alterations predict a heightened sensitivity to abiraterone treatment, improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Prostate cancer frequently exhibits alterations in CHD1 and SPOP genes.
  • The co-occurrence of CHD1 deletions and SPOP mutations is observed, with varying frequencies in castration-resistant prostate cancer (CRPC).
  • Understanding the role of these genetic changes during prostate cancer progression is crucial.

Purpose of the Study:

  • To monitor CHD1 expression throughout prostate cancer progression.
  • To evaluate the molecular and clinical characteristics of metastatic CRPC (mCRPC) with combined CHD1 deletions and SPOP mutations.
  • To assess the association of these biomarkers with treatment response and survival outcomes.

Main Methods:

  • Analysis of 89 mCRPC patients with available hormone-naive and castration-resistant tumor samples.
  • Immunohistochemistry (IHC) used to assess CHD1, PTEN, and ERG protein expression.
  • Targeted next-generation sequencing (NGS) determined SPOP mutation status.
  • Correlation analysis with overall survival, abiraterone treatment duration, and response rates using Cox regression and log-rank tests.

Main Results:

  • CHD1 protein loss was observed in 15% of hormone-sensitive prostate cancer (HSPC) and 17% of CRPC biopsies.
  • CHD1 protein status showed high concordance (98%) between matched HSPC and CRPC samples.
  • Twenty-two patients had somatic SPOP mutations; six were previously unreported in prostate cancer.
  • SPOP mutations and/or CHD1 loss were significantly associated with higher response rates (OR 14.50, P=0.001 for SPOP; OR 7.30, P=0.08 for CHD1) and longer duration on abiraterone treatment (HR 0.37, P=0.002 for SPOP; HR 0.50, P=0.06 for CHD1).

Conclusions:

  • SPOP-mutated mCRPCs demonstrate a strong enrichment for CHD1 loss.
  • Tumors with these combined alterations exhibit high sensitivity to abiraterone therapy.
  • These findings highlight potential predictive biomarkers for abiraterone response in mCRPC.

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