Quantifying Y chromosome loss in primary and metastatic prostate cancer by chromosome painting

Area of Science:

• Genetics and Genomics
• Cancer Biology
• Urology

Background:

• Somatic Y chromosome loss in blood cells correlates with increased mortality in males.
• The Y chromosome's status in cancer tissues is poorly understood due to technical sequencing and labeling challenges.
• Prostate cancer, particularly metastatic castration-resistant prostate cancer (mCRPC), represents a significant clinical challenge.

Purpose of the Study:

• To develop and apply a novel system for quantifying Y chromosome copy number alterations (gain or loss) in patient-derived prostate cancer organoids.
• To investigate the prevalence and patterns of Y chromosome loss in metastatic castration-resistant prostate cancer (mCRPC).
• To explore the potential early occurrence of Y chromosome loss during prostate cancer evolution.

Main Methods:

• Development of a specialized system to accurately quantify Y chromosome gain or loss.
• Application of the system to 13 patient-derived metastatic castration-resistant prostate cancer (mCRPC) organoids.
• Comparative analysis of Y chromosome status in primary versus metastatic prostate cancer tissues.

Main Results:

• Y chromosome loss was detected in 4 out of 13 (31%) patient-derived mCRPC organoids.
• Loss of the Yq arm (long arm of the Y chromosome) was observed in 38% of the organoids.
• Y chromosome nullisomy showed potential associations with mCRPC, and loss prevalence was similar in primary and metastatic tissues.

Conclusions:

• Y chromosome loss is a potentially early event in prostate cancer development, not solely a consequence of drug resistance or organoid culture.
• The developed system enables precise quantification of Y chromosome alterations in prostate cancer.
• Further research is warranted to elucidate the clinical significance of Y chromosome loss or gain in mCRPC.