ASCO GU 2022: Comprehensive Genomic Profiling of Chromophobe RCC Compared With Non-Chromophobe RCC: Impact of FLCN Genomic Alteration Status

(UroToday.com) The 2022 GU ASCO Annual meeting included a renal cell carcinoma (RCC) session featuring work from Dr. Joseph Jacob and colleagues presented results of comprehensive genomic profiling of chromophobe RCC compared with non-chromophobe RCC, specifically assessing the impact of FLCN genomic alteration status. FLCN is a tumor suppressor gene associated with cutaneous hair follicle development, and FLCN germline mutations are linked to inherited chromophobe RCC in the Birt-Hogg-Dube (BHD) syndrome. The FLCN gene is localized to chromosome 17p, associated with a variety of molecular pathways and is linked to multiple types of kidney tumors that feature granular eosinophilic cytoplasm. This study queried whether clinically sporadic chromophobe RCC featured FLCN mutations by comparing the genomic profiles of chromophobe RCC with non-chromophobe RCC.

 There were 109 chromophobe RCC and 5,862 non-chromophobe RCC that underwent hybrid-capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations. Tumor mutational burden was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3).

 Patients with chromophobe RCC were more frequently female and younger than patients with non-chromophobe RCC (p < .0001), and none of the submitted clinical records in the chromophobe RCC cases listed signs of BHD syndrome. A specific comparison between chromophobe RCC and non-chromophobe RCC is as follows:

 

ASCOGU22_Jacob_0 

 

FLCN genomic alterations were identified in only 1.1% of the non-chromophobe RCC cases, with 37% of the genomic alterations predicted to be germline. Chromophobe RCC had only 0.9% FLCN genomic alterations, with 100% of the genomic alterations predicted to be germline. Genomic alterations/tumor were slightly higher in non-chromophobe RCC vs chromophobe RCC (3.63 vs 2.44; p > 0.05). Genomic alterations more frequent in chromophobe RCC included TP53 (65.1% vs 19.6%)RB1 (13.8% vs 1.9%) and PTEN (22.0% vs 8.3%). Genomic alterations more frequent in the non-chromophobe RCC included VHLBAP1PBRM1SETD2CDKN2A/BARID1ANF2PIK3CA and TERT:

 

ASCOGU22_Jacob_1 

 

Putative biomarkers of immune checkpoint inhibitor response were infrequent in both groups with only a slightly higher, but still low, mean tumor mutational burden in non-chromophobe RCC vs chromophobe RCC cases. IHC revealed moderate PD-L1 expression at low and minimal PD-L1 expression at high staining level, which was slightly increased in the chromophobe RCC group.

 

Dr. Jacob concluded his presentation assessing comprehensive genomic profiling of chromophobe RCC compared with non-chromophobe RCC with the following take home messages:

  • FLCN mutations that are associated with the familial incidence of chromophobe RCC were not associated with sporadic chromophobe RCC
  • Sporadic chromophobe RCC has a substantially different genomic profile from non-chromophobe RCC and may harbor a few ‘targetable’ genomic alterations
  • Biomarkers of immune checkpoint inhibitors drug response revealed higher mean tumor mutational burden, tumor mutational burden >10 mutations/Mb and PBRM1 inactivating mutation frequencies in the non-chromophobe RCC tumors than the chromophobe RCC tumors, indicating possible lower response rates of chromophobe to immunotherapies

 

Presented By: Joseph M Jacob, MD, SUNY Upstate Medical University, Syracuse, NY

Co-Authors: Gennady Bratslavsky, Andrea Necchi, Philippe E. Spiess, Petros Grivas, Oleksandr Kravtsov, Richard S.P. Huang, Vamsi Parini, Brennan Decker, Douglas I. Lin, Dean C. Pavlick, Natalie Danziger, Jeffrey S. Ross

Affiliations: Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital, Milan, Italy, Moffitt Cancer Center & Research Institute, Tampa, FL, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, SUNY Upstate Medical University, Department of Urology, Syracuse, NY, Foundation Medicine, Inc, Cambridge, MA, Foundation Medicine, Cambridge, MA, Foundation Medicine, Inc., Cambridge, MA

Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022

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