Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Research

Background:

• Genomic sequencing identifies drivers in most cancers, but some tumors lack discernible genetic alterations.
• Clear cell papillary renal cell carcinoma (CCPAP) is a type of kidney cancer with an unusual molecular profile.

Purpose of the Study:

• To investigate the molecular and metabolic characteristics of genomically quiet CCPAP tumors.
• To understand the underlying mechanisms contributing to the phenotype of CCPAP.

Main Methods:

• Analysis of nuclear genome sequencing.
• Assessment of mitochondrial DNA (mtDNA) and RNA levels.
• Measurement of oxidative stress markers.
• Metabolic profiling, including sorbitol accumulation.
• Immunohistochemical staining of tumor specimens for mtDNA-encoded proteins and metabolic markers.

Main Results:

• CCPAP tumors exhibit a largely wild-type nuclear genome.
• Significant depletion of mtDNA and RNA was observed, indicating impaired respiratory metabolism.
• High levels of oxidative stress were detected.
• A unique metabolic phenotype characterized by sorbitol accumulation was identified.
• Immunohistochemistry confirmed mtDNA-encoded protein depletion and revealed a lipid-depleted phenotype attributed to glycogen accumulation.

Conclusions:

• CCPAP represents a cancer type driven by non-genetic alterations, particularly mitochondrial dysfunction and metabolic shifts.
• The cytoplasmic clarity in CCPAP is likely due to glycogen, not lipid accumulation.
• Non-genetic profiling is a valuable approach for studying cancers with unknown drivers.