Background: Birt-Hogg-Dubé (BHD) syndrome, stemming from germline alterations in the folliculin (FLCN) gene, is known to give rise to hybrid oncocytic/chromophobe tumors (HOCT) and chromophobe renal cell carcinoma (ChRCC). Interestingly, sporadic ChRCC cases do not typically exhibit FLCN alterations. Despite histological similarities between BHD-associated and sporadic renal tumors, a comprehensive molecular definition differentiating these tumor types has remained elusive. This study aims to comparatively define these tumor entities at the molecular level.
To gain a deeper comparative definition of renal tumorigenesis in both BHD-associated and sporadic renal tumors, we undertook whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) analyses. Our cohort included sixteen BHD-associated renal tumors from nine unrelated BHD patients, alongside twenty-one sporadic ChRCCs and seven sporadic oncocytomas. By comparing somatic mutation profiles in relation to FLCN variants, and contrasting RNA expression profiles, we sought to define the molecular distinctions between BHD-associated renal tumors and their sporadic counterparts.
Our RNA-seq analysis revealed a striking divergence in expression profiles between BHD-associated renal tumors and sporadic renal tumors, providing a clear comparative definition. Notably, sporadic ChRCCs segregated into two distinct clusters, characterized by the expression of L1CAM and FOXI1, which are recognized molecular markers for renal tubule subclasses. Furthermore, we observed an elevated mitochondrial DNA (mtDNA) copy number, coupled with fewer genetic variants, in BHD-associated renal tumors when compared to sporadic ChRCCs. Cell-of-origin analysis, leveraging WGS data, suggested that BHD-associated renal tumors and sporadic ChRCCs may originate from different cellular precursors. This analysis also indicated that second-hit FLCN alterations in BHD patients may occur relatively early in life, around the third decade.
In conclusion, these findings contribute to a more refined comparative definition of renal tumors, highlighting the distinct molecular landscapes of BHD-associated and sporadic renal tumors despite their histological similarities. This deeper understanding of their divergent renal tumourigenesis pathways is crucial for future diagnostic and therapeutic strategies.
