ASCO GU 2021: Gene Expression Profiling to Identify Metabolic Gene Signature Predictive of Recurrence After Surgery In Stage III Clear-Cell RCC

(UroToday.com) Management of patients with localized or locally advanced renal cell carcinoma (RCC) involves surgical resection. However, 20-40% of all localized kidney cancer patients experience a recurrence. Adjuvant treatment in high-risk kidney cancer has not proven to successfully improve overall survival and the only drug approved so far in this setting is vascular endothelial growth factor (VEGF) inhibitor, sunitinib based on a modest disease-free survival benefit.1 As multiple trials are evaluating drugs including immune checkpoint inhibitors in patients with high risk localized clear cell RCC, there is an urgent need to identify biomarkers to help with therapeutic decisions as well as for risk stratification. At the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Shuchi Gulati and colleagues presented results of their analysis pertaining to genes involved in metabolic reprogramming in kidney cancer. The aim of the study was to analyze metabolic signatures in primary tumors from patients that remain disease free versus those that recur within 24 months of surgery.

This study comprised a deep transcriptomic analysis of patients with stage III clear cell RCC in the TCGA KIRC Firehose Legacy cohort. Caucasian males with stage III clear cell RCC in the TCGA cohort for whom recurrence data was available with a minimum follow-up of 2 years were identified for the analysis. Expression profiles of differentially expressed genes were clustered using the Bayesian infinite mixture model and samples clustered using average linkage hierarchical clustering based on pairwise Pearson’s correlations as the measure of similarity. Enrichment analysis of up- and down-regulated genes was performed using logistic regression. 

The cohort evaluated for this study included Caucasian male patients that remained disease free for at least 24 months after surgery (n = 22) and patients whose cancer recurred within 24 months (n = 20). Metabolic genes were identified, encoding subunits of mitochondrial electron transport chain as well as malate aspartate shuttle, where loss of coordinated co-expression between these genes identified patients at risk of recurrence after surgery. The gene signature stratified the 42 patients into three subtypes: significantly enriched for (i) recurrence (subtype 1), (ii) disease free status (subtype 2) and (iii) intermediate (subtype 3). Notably, a subset of 11 OxPhos genes was significantly increased in stage III recurrent tumors. This 11-gene signature stratifies stage III clear cell RCC: 

ASCOGU21_Gulati_1.png

Additionally, as follows is a figure depicting loss of coordinated expression of the 11 signature genes with other metabolic genes:

ASCOGU21_Gulati_2.png

Dr. Gulati concluded this presentation with several summary findings:

  • An 11-gene signature encoding members of mitochondrial respiratory complexes can stratify a training cohort of stage 3 clear cell RCC into disease free (good prognosis) versus recurrent (poor prognosis) disease
  • Loss of coordinated co-expression might indicate overall reprogramming of the OxPhos genes in patients with stage III recurrent disease
  • Further validation is in progress to include other races and female patients, as well as in real world samples 

Presented by: Shuchi Gulati, MD, University of Cincinnati Medical Center, Cincinnati, Ohio

Co-Authors: Vemuri Bhargav, Tom Cunningham, David Plas, Julio Alberto Landero, Jarek Meller, Maria Czyzyk-Krzeska; University of Cincinnati Medical Center, Cincinnati, OH; University of Cincinnati, Cincinnati, OH


Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021

References:

  1. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016;375(23):2246-2254.


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