Genomic Study of Fumarate Hydratase-Deficient RCC

At the 2024 American Society of Clinical Oncology Annual Meeting, Xingming Zhang, MD, and colleagues presented results from their recent study, which investigated the molecular subtypes of fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC).

Researchers evaluated the tissue samples of 126 treatment-naïve patients collected from a multicenter database, including conducting whole-exome, RNA, and DNA-methylation sequencing. FH/2SC immunohistochemical staining and FH alterations analysis were used to confirm cases of FH-deficient RCC.

Using whole-exome sequencing, researchers discovered a connection between FH alteration patterns and tumor behavior and patient survival outcomes. Aggressive tumor behavior and poorer prognosis were found to be associated with tumors containing FH truncating alterations, including nonsense, frameshift, and splice site mutations and mutations close to hinge regions. Dr. Zhang and colleagues also created a CpG sites-specific methylation signature to conduct precise identification of FH-deficient RCC.

Transcriptomic analysis revealed 3 molecular subtypes characterized by enrichment of the immune/Angiogenic/Stromal (C1), WNT/Notch/MAPK (C2), and proliferation/stemness (C3) pathways.

For patients with C1 tumors, a combination of immune checkpoint blockade (ICB) and anti-angiogenic therapy provided the most significant survival benefit. Patients with C2 tumors experienced only a moderate response to ICB plus anti-angiogenic treatment. In contrast, those with C3 tumors demonstrated a negative reaction to both anti-angiogenic monotherapy and the combination therapy.

“These findings contribute to a profound understanding of the aggressive nature of FH-deficient RCC, offering insights into potential precision medicine approaches for disease management,” researchers wrote.