Genomic Analysis of Localized High-Risk Prostate Cancer Circulating Tumor Cells at the Single-Cell Level.

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Accurate risk classification is crucial for localized high-risk prostate cancer treatment decisions.
• Existing risk assessments have limitations in distinguishing indolent from aggressive prostate cancers.
• Circulating tumor cells (CTCs) offer a potential source for precise genetic information beyond tissue biopsies.

Purpose of the Study:

• To combine CTC isolation and immunophenotyping with 3-D telomere profiling and single-cell whole-exome sequencing (WES).
• To analyze the genetic heterogeneity and telomere characteristics of CTCs from localized high-risk prostate cancer patients.
• To identify potential therapeutic targets and resistance mechanisms in high-risk prostate cancer.

Main Methods:

• Filtration-based CTC isolation and prostate cancer CTC immunophenotyping.
• 3-D telomere profiling, laser microdissection, and single-cell whole-exome sequencing (WES).
• Analysis of genetic variations (SNVs, indels, CNAs) and pathway enrichment.

Main Results:

• CTCs from high-risk prostate cancer patients showed short telomeres (high telomere signals, lower intensities).
• WES identified significant genetic heterogeneity with numerous SNVs, indels, and CNAs.
• Pathway analysis revealed variations in telomere maintenance and DNA damage repair (DDR) pathways.
• Identified genetic variations associated with response to docetaxel and other cancer drugs.

Conclusions:

• Single-cell WES and 3-D telomere profiling effectively reveal CTC heterogeneity in high-risk prostate cancer.
• DDR pathway mutations and frequent CNA amplifications in CTCs may contribute to therapeutic resistance.
• Understanding CTC genetic profiles can inform personalized treatment strategies for prostate cancer.