Fluorescent and Chromogenic in situ Hybridization of CEN17q as a Potent Useful Diagnostic Marker for Birt-Hogg-Dubé Syndrome-associated Chromophobe Renal Cell Carcinomas

Abstract Birt-Hogg-Dubé syndrome (BHD) is a familial disorder associated with a germline mutation of FLCN that is a tumor suppressor gene. Patients with BHD have high risks for developing multiple renal cell carcinomas (RCCs). The frequent histological types are hybrid oncocytic/chromophobe tumors (HOCTs) and chromophobe RCCs. The morphology of HOCTs could alert pathologists to the possibility of BHD. On the other hand, chromophobe RCCs occurring in BHD patients demonstrate positive immunostaining for cytokeratin-7, CD82 and Ksp-cadherin similar to their sporadic counterparts. Highly-reliable markers for BHD-associated chromophobe RCCs have not been identified. In the present study, we analyzed the state of chromosome 17 in 18 renal tumors composed of 8 chromophobe RCCs, 7 HOCTs and 3 papillary RCCs obtained from BHD patients using fluorescent and chromogenic in situ hybridization (FISH/CISH) probes for the centromeric region of chromosome 17 long arm (CEN17q). All chromophobe RCCs and HOCTs were disomic except for one chromophobe RCC that showed monosomy. On the other hand, 12 of 14 sporadic chromophobe RCCs were monosomic ( p = 0.0008). The state of chromosomes 2 and 6 were also statistically different ( p = 0.0074 and p = 0.0007, respectively). Three BHD-associated papillary RCCs demonstrated either trisomy (n = 2) or disomy (n = 1). Three of 5 sporadic papillary RCCs showed trisomy. The results indicate that FISH/CISH of CEN17q should be a potent useful marker for chromophobe RCCs in patients who have not been diagnosed with BHD and thereby help to determine whether the cases should be considered for genetic testing.