Professors Hailiang Zhang and Xiaolin Lu’s Team Unveils Multi-Omics Insights into TRCC – Mediamedic

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“Editor’s Note: Translocation renal cell carcinoma (TRCC), though rare, constitutes a significant proportion of kidney cancer cases among young and middle-aged patients. Analyzing its characteristics in depth can aid in accurate diagnosis, treatment planning, and prognosis evaluation. At the 2024 ESMO Asia Annual Meeting in Singapore, a study by the team from Fudan University Shanghai Cancer Center on TRCC was showcased in a poster presentation. Urology Frontier invited Professors Hailiang Zhang and Xiaolin Lu to share key findings from their research.

Urology Frontier: What is translocation renal cell carcinoma (TRCC), and what are its defining features?

Dr. Xiaolin Lu: TRCC primarily refers to renal cell carcinomas associated with TFE3 gene fusions or translocations. While these tumors represent only 1.5% to 5% of all kidney cancer cases, they are more prevalent among younger patients, particularly those under the age of 45, where they can constitute up to 15% of cases.

Compared to clear cell renal cell carcinoma, TRCC typically demonstrates more aggressive progression and a poorer prognosis. The variability in outcomes is influenced by differences in gene fusion targets, highlighting the need for precise molecular subtyping for accurate diagnosis and treatment planning.

Urology Frontier: Your team has been investigating TRCC for years. Could you share the latest advancements?

Dr. Xiaolin Lu:Through our research into the pathological features of TRCC, we’ve found that traditional HE-stained slides are insufficient for a definitive diagnosis because of their similarities to clear cell carcinoma in morphological appearance. Diagnosing TRCC requires fluorescence in situ hybridization (FISH) to detect specific gene fusions or translocations.

To delve deeper into molecular pathology, we conducted a multicenter study analyzing approximately 8,000 patient samples, identifying 80 TRCC cases and 80 clear cell carcinoma cases as controls. Using AI algorithms and machine learning, we analyzed over 1.5 million distinct HE-stained pathological features to discern subtle differences between TRCC and clear cell carcinoma.

This effort led to identifying unique pathological characteristics of TRCC, which not only help clinicians diagnose TRCC with greater accuracy but also provide pathologists with a more reliable diagnostic framework. These findings are crucial for understanding patient-specific pathological and physiological traits and guiding subsequent treatment strategies.

Urology Frontier: What are the implications of TRCC’s molecular characteristics for precision therapy and clinical practice?

Dr. Xiaolin Lu:Our research has focused on the TFE3 gene, exploring its various fusions and the downstream signaling pathway changes these fusions trigger. Through bioinformatics analysis and database mining, we identified several signaling pathways activated by TFE3 fusions, which provide potential therapeutic targets.

For example:

• TFE3-RBM10 fusion: Activates mTOR and ERK signaling pathways, suggesting that these patients may benefit from mTOR inhibitors.
• TFE3-PRCC fusion: Involves the JAK-STAT pathway.
• TFE3-MED15 fusion: Affects VEGF-mediated angiogenesis.
• TFE3-ASPSCR1 fusion: Activates multiple signaling pathways, indicating the potential need for combination therapies to effectively control disease progression.

These findings underline the complexity of TRCC, suggesting that a single therapeutic approach may not suffice. Instead, multi-modal and targeted treatment strategies could offer better outcomes for TRCC patients.

Urology Frontier: What are your team’s future research directions in kidney cancer?

Dr. Xiaolin Lu:Compared to prostate cancer and urothelial carcinoma, kidney cancer research has progressed more slowly in recent years, particularly concerning antibody-drug conjugates (ADC). However, emerging ADC therapies signal a new wave of innovation in this field.

1. Deepening molecular pathology research: Uncovering kidney cancer’s molecular pathology will further elucidate its biological mechanisms and identify new therapeutic targets.
2. Advancing drug therapies: Investigating ADCs and validating their potential applications in kidney cancer treatment is a priority. Additionally, ongoing studies into targeted combination immunotherapies hold promise.
3. Exploring novel agents: Research into innovative drugs, such as HIF-1α inhibitors, is gaining traction and could reshape kidney cancer management.

Future kidney cancer research will focus on these emerging therapeutic strategies, aiming for more effective disease management and improved patient outcomes.

Author Profiles

Professor Hailiang Zhang

• Position: Chief Physician and Deputy Director of Urology Department Administration, Fudan University Shanghai Cancer Center
• Expertise: Specialist in Urologic Oncology MDT and Ph.D. Supervisor
• Professional Affiliations: Deputy Chair, Minimally Invasive Surgery Group, Chinese Anti-Cancer Association Urologic Oncology Committee Member, Hereditary Cancer Collaboration Group, Chinese Anti-Cancer Association Member, Chinese Medical and Health International Exchange Promotion Association Director, Shanghai Anti-Cancer Association Editorial Board Member, Chinese Edition of Journal of Clinical Oncology, Urology Section
• Research and Publications: Published over 120 SCI-indexed articles as the first or corresponding author in journals such as Journal of Hematology & Oncology, Nature Communications, Clinical Cancer Research, and others, with the most cited article receiving over 400 citations. Additionally, published over 20 papers in authoritative domestic journals.
• Awards and Achievements: Recipient of the Best Paper Award at the 24th European Association of Urology Annual Meeting Delivered multiple invited presentations at EAU and American Urological Association meetings Principal investigator for one subproject of a national major special fund Lead researcher on several grants, including National Natural Science Foundation projects and Shanghai Science Foundation projects Co-recipient of numerous awards, including: Shanghai Science and Technology Progress First Prize Ministry of Education Science and Technology Progress First Prize National Science and Technology Progress First Prize.

Professor Xiaolin Lu

• Position: Attending Physician, Urology Department, Fudan University Shanghai Cancer Center
• Specialization: Surgery and comprehensive treatment of urologic cancers, clinical research on novel drugs
• Contributions: Participated in writing Translational Oncology and Oncological Surgery and contributed to science outreach content for Shanghai Medical Society’s centenary celebration Translator for the Chinese editions of Journal of Clinical Oncology and AJCC’s 8th Edition guidelines on prostate, testicular, penile, and urethral cancers Authored multiple academic papers.

Xi Tian

• Position: Ph.D. Candidate in Urology, Fudan University Shanghai Cancer Center, under Professor Dingwei Ye
• Research and Publications: Published over 20 SCI-indexed articles as the first or co-first author in journals such as Nature Communications, International Journal of Cancer, OncoImmunology, and International Journal of Biological Sciences Research frequently featured at major conferences, including EAU, ESMO Asia, CSCO, and CCO
• Achievements: Approved for two utility model patents and contributed to four invention patents Participated in multiple national key R&D projects, National Natural Science Foundation projects, and Shanghai Science Foundation initiatives Honored with the National Graduate Student Scholarship, Fudan University Outstanding Graduate, and Annual Excellent Graduate of Fudan University Shanghai Cancer Center.

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