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Folliculin mutations not associated with sporadic chromophobe RCC

Presented by
Dr Joseph Jacob, Upstate University Hospital, NY, USA
ASCO GU 2022
In contrast to inherited chromophobe renal cell carcinoma (RCC) in the Birt-Hogg-Dubé syndrome, clinically sporadic chromophobe RCC is not associated with mutations in folliculin.

Folliculin (FLCN) is a tumour suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chromophobe RCC in the Birt-Hogg-Dubé syndrome. Whether clinically sporadic chromophobe RCC also features FLCN mutations is not yet clear. Therefore, Dr Joseph Jacob (Upstate University Hospital, NY, USA) and colleagues evaluated genomic profiles of chromophobe RCC and compared them with genomic profiles of clear-cell RCC [1].

A total of 109 clinically sporadic chromophobe RCC and 5,862 clear-cell RCC samples were subjected to hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alterations. In addition, tumour mutational burden (TMB), microsatellite instability (MSI), and PD-L1 expression were determined.

Patients with chromophobe RCC were younger than patients with clear-cell RCC (median age 58 vs 62 years; P <0.0001). In both of these tumour subgroups, TMB was low (median 1.3 mut/Mb vs 2.6 mut/Mb). However, there was a lower incidence of high TMB (>10 mut/Mb) in the chromophobe RCC compared with the clear-cell RCC (0% vs 4.9%; P<0.01).

In chromophobe RCC, aberrations in TP53, RB1, and PTEN were more frequent, while in clear-cell RCC, aberrations in VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA, and TERT were more frequent (P<0.01). In addition, the frequency of FLCN alterations was not different in sporadic chromophobe RCCs compared to clear-cell RCC (0.9% vs 1.1%).

Based on these results, Dr Jabob concluded that “FLCN mutations that are associated with inherited chromophobe RCC are rarely associated with sporadic chromophobe RCC. In addition, sporadic chromophobe RCC is substantially different from clear-cell RCC at the genomic level and features few targetable genetic aberrations.”

  1. Bratslavsky G, et al. Comprehensive genomic profiling (CGP) of chromophobe renal cell carcinoma (chrRCC) compared with clear cell RCC (ccRCC): Impact of FLCN genomic alteration (GA) status. Abstract 292, ASCO GU 2022, 17–19 February.


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