Maintained disomic chromosome 17 as a diagnostic marker for BHD-associated chromophobe RCC

Renal cell carcinomas (RCCs) can be life-threatening and although mostly sporadic, approximately 5% are associated with genetic conditions such as BHD. Early identification of families carrying cancer-predisposing mutations enables access to regular screening and earlier treatment. However, it can be difficult to distinguish between sporadic and inherited RCC based on standard immunohistological analysis. New research from Kato et al. (2016) assessed whether variability in the chromosomal status of chromosomes 17, 2, and 6 could be used to identify BHD-associated RCC.

The BHD gene FLCN is a tumour suppressor located on chromosome 17, with tumour growth associated with second hit mutations or loss of heterozygosity (Vocke et al., 2005). The most common tumour types in BHD patients are chromophobe RCC (chRCC) and hybrid oncocytoma/ chromophobe tumours (HOCTs) although other subtypes are seen. Sporadic chRCC tumours frequently exhibit variable chromosomal losses including loss of chromosome 17, whereas papillary (papRCC) tumours more often gain copies of chromosomes 7 and 17. Kato et al. decided to determine if these variations in the status of chromosome 17 could be used to help distinguish BHD-associated and sporadic tumours.

Kato et al. used CEN17q fluorescent and chromogenic in situ hybridisation (FISH and CISH respectively) to assess the status of chromosome 17 in BHD-associated tumours (8 chRCC, 7 HOCT and 3 papRCC) and sporadic tumours (14 chRCC and 5 papRCC). The BHD-tumours came from ten genetically confirmed BHD patients with additional somatic FLCN mutations identified in 9/13 samples available for genetic testing. The sporadic RCC patients were not tested for FLCN mutations but had no family history of BHD-associated pulmonary or dermatological pathologies. Where possible samples of normal renal tissue were assessed for comparison.

In each sample the FISH/CISH signal was counted in 100 nuclei with comparison to non-tumour samples used to establish if a tumour sample was monosomic, disomic and trisomic. All of the BHD-HOCT and 7/8 BHD-chRCC samples were disomic compared to 12/14 sporadic chRCC samples being monosomic (p=0.0008). The status of chromosome 17 could therefore be useful in distinguishing BHD-associated HOCTS and chRCC from sporadic chRCC. However, it was insufficient to distinguish between BHD-associated and sporadic forms of papRCC (1 disomic and 2 trisomic compared to 2 disomic and 3 trisomic) or clear cell RCC (ccRCC; data not shown but listed as disomic in all cases).

One BHD-chRCC was judged to be monosomic for CEN17q, but when reassessed with a second probe, CEP17, was found to be disomic. As false monosomy/polysomy could occur with any sample additional markers would be beneficial. Kato et al. found statistically significant differences in the FISH/CISH analysis of chRCC and HOCT samples with CEN2p and CEN6p probes; whilst the majority of sporadic chRCCs were monosomic at these loci the BHD-associated tumours retained disomy.

Previous work from this group has identified variations in sporadic chRCC marker expression (Iribe et al., 2015), as well as changes in FLCN and GPNMB expression (Fuyura et al., 2015) that can help distinguish between some sporadic and BHD-associated RCC subtypes. These markers, along with the findings from Kato et al., are summarised in the table below. Currently no diagnostic markers have been identified than can distinguish between sporadic and BHD-associated ccRCC nor oncocytomas. Although further work is needed to develop a robust marker panel for all RCC subtypes, the identification of distinguishing features of the most common BHD-tumour types is encouraging. Hopefully this and future work can be used by pathologists to identify new BHD patients and families.


Sporadic RCC subtype BHD-associated RCC subtype Distinguishing markers
Chromophobe RCC Chromophobe RCC ↓FLCN, ↑GPNMB, 17q/2p/6p disomy
Chromophobe RCC HOCT ↓CK7, ↓FLCN, ↑GPNMB, 17q/2p/6p disomy
Oncocytoma HOCT ↑Ksp-Cadherin, ↑CD82, ↓FLCN, ↑GPNMB
Papillary RCC Papillary RCC ↓FLCN, ↑GPNMB



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