Characterizing the Genomic, Immune Landscape of TFE3-Rearranged Renal Cell Carcinoma

GU Oncology Now spoke with Shuanzeng Wei, MD, PhD, an associate professor in the Department of Pathology at Fox Chase Cancer Center, about his recent research that helped uncover genetic, transcriptional, and immune differences in TFE3-rearranged renal cell carcinoma (RCC) compared with papillary and clear cell RCC.

TFE3-rearranged RCC is a rare subtype of kidney cancer that is commonly misdiagnosed. The genetic markers uncovered by Dr. Wei and his team are an important step taken toward more accurately diagnosing this disease and providing the best treatment for diagnosed patients.

Can you detail what is already known about TFE3-rearranged RCC and why misdiagnosis is a common issue for these patients?

Dr. Wei: TFE3 translocation tumors differ from traditional papillary and clear cell RCC. They are a relatively new entity. Due to its rarity, we have limited knowledge. TFE3-rearranged RCC is more common in children, but it is increasingly being recognized in adults.

From a diagnostic standpoint, as a pathologist, it can be challenging to differentiate this tumor because it exhibits morphological features of both papillary and clear cell RCC. Without advanced technology, accurate diagnosis is difficult. For this reason, we aimed to identify molecular differences between tumors to aid in differential diagnosis and patient management.

How were patient tumor samples selected for this analysis, and what were your inclusion criteria for those samples?

Dr. Wei: Given the rarity of this tumor, we utilized Caris Life Sciences, a company conducting molecular testing nationwide. Caris provided 20 cases of TFE3-rearranged RCC from their database. Additionally, we randomly selected 20 cases of papillary and 392 cases of clear cell RCC for comparison, all sourced from the Caris database.

While acknowledging the relatively small sample size for TFE3-rearranged RCC, what were your findings regarding fusion partners and the tumor immune microenvironment?

Dr. Wei: The key differentiator for TFE3-rearranged RCC lies in the presence of TFE3 fusion and the absence of typical mutations found in papillary and clear cell carcinoma. Interestingly, translocation tumors often exhibit pTERT mutation.

Additionally, we identified a novel TFE3 fusion: SRRM2::TFE3 —which was present in 2 of our patient specimens. Furthermore, regarding PD-L1, almost 50% of cases showed expression, indicating a potential avenue for checkpoint inhibitor therapy.

These findings suggest significant advancements in our understanding of TFE3-rearranged RCC. How might they influence future research efforts in this rare disease setting?

Dr. Wei: Firstly, this research underscores the need for tailored treatment approaches distinct from those used for papillary and clear cell RCC since they different tumors.

Secondly, molecular testing could aid in accurate diagnosis.

Further studies with larger sample sizes are necessary to validate these findings and explore potential therapeutic avenues, particularly regarding checkpoint inhibitor therapy.