Deciphering the genomic landscape of renal cell carcinoma brain metastases.
Abstract
4524 Background: Brain metastases from renal cell carcinoma (RCC) remain a major cause of morbidity and mortality, yet the drivers of metastatic dissemination remain poorly understood. Methods: Whole-exome sequencing was performed on 72 RCC brain metastasis samples with matched normal. To identify candidate metastatic drivers, the genetic alterations detected in the brain metastases were compared against alterations in extracranial metastases from the MSK-ECM cohort (n=137) and primary RCC tumors from TCGA (n=432) by case-control analyses. Candidate drivers were also identified by matched-pair analyses on the brain metastases vs. matched primary tumors or extracranial metastases from the same patient (n=25). A random survival forest model incorporating the candidate CNA events was developed to predict overall survival. The candidate metastatic drivers were further evaluated using functional experimental data from MetMap and DepMap. Survival analyses were conducted to assess the prognostic significance of the candidate drivers. Results: We identified metastatic drivers that were significantly enriched in RCC brain metastases, including 4q loss, 7p gain, 7q gain, 8p loss, 8q gain, 9p21.3 deletion, 12q15 amplification, and 14q loss. These driver events were associated with significantly poorer patient survival among RCC patients. A random survival forest model based on these CNA events stratified TCGA-KIRC patients into prognostically distinct risk groups (C-index = 0.64). Among the drivers, 8p loss, 8q gain, 9p21.3 deletion were associated with increased incidence of brain metastases across multiple primary cancer types in xenograft mouse models. These drivers were also strongly associated with metastatic progression and poor prognosis across RCC, lung adenocarcinoma, breast cancer, and melanoma. Conclusions: Somatic copy-number alterations represent key drivers of brain metastasis in RCC and other tumors that frequently metastasize to the brain. These findings indicate a shared genomic basis for brain tropism across cancers and highlight the potential utility of copy-number biomarkers for risk stratification and clinical decision-making.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (20)
Betul Gok Yavuz
The University of Chicago, Chicago, IL
Peng Li
Jose A. Ovando-Ricardez
Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
Alessandro La Ferlita
Jonathan W. T. Tse
The University of Hong Kong, Hong Kong, China
Sahin Hanalioglu
Hacettepe University Faculty of Medicine, Ankara, Turkey
Berrin Babaoglu
Hacettepe University Faculty of Medicine, Ankara, Turkey
Baylar Baylarov
Hacettepe University Faculty of Medicine, Ankara, Turkey
Lisa M. Norberg
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
Haidee Chancoco
The University of Texas MD Anderson Cancer Center, Houston, TX
Erika Thompson
7The University of Texas MD Anderson Cancer Center, Genetics, Houston, United States
Melike Mut
University of Virginia Health System, Charlottesville, VA
Figen Soylemezoglu
Hacettepe University Faculty of Medicine, Ankara, Turkey
Jason T. Huse
Adeboye O. Osunkoya
Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, GA
Mehmet Asim Bilen
From the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda (A.B.A., N.S., S.N., L.L., L.C.), the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (J.H.-C.), and the Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Rockville (H.S., E.S.) — all in Maryland; the Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN (K.V.B., M.O., C.M., G.P.B.); AdventHealth Cancer Institute and the University of Central Florida, Orlando (G.S.); Dana–Farber/Harvard Cancer Center, Boston (S.B., B.M.); UNC Lineberger Comprehensive Cancer Center, Chapel Hill (W.Y.K.), and Duke University Medical Center and Duke Cancer Institute, Durham (J.H., S.H.) — both in North Carolina; the University of Kansas Cancer Center, Westwood (R.P.); Memorial Sloan Kettering Cancer Center, New York (M.Y.T., M.J.M., J.E.R.), and Roswell Park Comprehensive Cancer Center, Buffalo (G.C.) — both in...
Merve Hasanov
Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
Eric Jonasch
Department of Genitourinary Medical Oncology The University of Texas MD Anderson Cancer Center Houston Texas USA
David J. H. Shih
School of Biomedical Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Elshad Hasanov
Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, The Ohio State University Comprehensive Cancer Center, Columbus, OH