Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Prostate cancers with aggressive clinical behavior, termed aggressive variant prostate cancer (AVPC), often resemble small-cell prostate cancer (SCPC) in their response to chemotherapy.
• This study investigates whether morphologically diverse AVPC also shares molecular characteristics with SCPC.

Purpose of the Study:

• To determine if clinically defined aggressive variant prostate cancer (AVPC) exhibits molecular similarities to small-cell prostate cancer (SCPC).
• To identify a potential molecular signature for AVPC based on shared features with SCPC.

Main Methods:

• Analysis of 59 AVPC samples and 8 patient-tumor derived xenografts (PDX) for aberrant SCPC markers.
• DNA copy number analysis (Oncoscan) for gains and losses in AVPC samples and PDX.
• Comparison with publicly available datasets and unselected castration-resistant prostate cancer (CRPC) samples.

Main Results:

• High expression of Ki67 (≥10% cells in 80%) and Tp53 (≥10% cells in 41%) observed across AVPC samples.
• Frequent alterations including MYC copy number gain (54%), RB1 copy number loss (54%), and PTEN copy number loss (48%).
• RB1 copy number loss was a key differentiator between AVPC and unselected CRPC; combined RB1, Tp53, and/or PTEN alterations were more prevalent in AVPC.

Conclusions:

• Clinically defined aggressive variant prostate cancer (AVPC) shares significant molecular features with small-cell prostate cancer (SCPC).
• AVPC is molecularly characterized by the combined presence of alterations in RB1, Tp53, and/or PTEN.