Genome-wide genetic abnormalities in BHD-RCCs

Renal cell carcinoma (RCC) can be sporadic or associated with inherited mutations. These tumours frequently carry additional genetic abnormalities including copy number variations, deletions and amplifications. Although not all tumours have an altered genetic profile, sporadic RCC subtypes have common cytogenetic patterns. New research from Iribe et al. (2016) assessed several RCC subtypes from BHD patients to determine if they have similar or distinct patterns of genetic abnormalities.

In a previous study Klomp et al. (2010) found that six BHD-RCC tumours, which morphologically resembled sporadic chromophobe RCC (chRCC) and oncocytomas, did not share the typical gross chromosomal abnormalities seen in sporadic tumours. However, advances in technology make it possible to detect smaller deletions and amplifications across the genome. Iribe et al. assessed genomic alterations in BHD-associated chRCC, clear cell RCC (ccRCC), and hybrid oncocytotic/ chromophobe tumours (HOCTs).

Nineteen RCC samples were obtained from 10 genetically confirmed BHD patients; 9/19 tumours carried an identifiable additional FLCN mutation. Cytogenetic profiling was completed for 11 tumours including three HOCTs, six chRCC and two ccRCC samples. Sporadic chRCC, ccRCC and oncocytoma samples came from patients who, although not genetically tested for FLCN, had no clinical history of fibrofolliculomas, pulmonary cysts or pneumothoraces.

The common cytogenetic profiles for sporadic RCCs are varied: clear cell RCC (ccRCC) tumours often show loss of chromosome 3q and 19q, and gain of 5q (as discussed in last week’s blog); chRCC tumours contain a wider range of losses in chromosomes 1, 2, 6, 10, 13, 17 and 21 (Davis et al., 2014); and, although less frequently seen, renal oncocytomas can have losses of chromosomes 1 and Y (Lindgren et al., 2004). All of the BHD patient HOCT samples (n=3) and 4/6 BHD-chRCC had a broadly balanced chromosome number, but the remaining two BHD-chRCC samples (from different patients) showed gain of chromosome 3q. The two BHD-ccRCC samples were more unbalanced with gains and losses of several chromosomes – a wider range than sporadic ccRCC samples – and neither carried a VHL mutation. This supports BHD tumours having distinct cytogenetic profiles compared to sporadic tumours.

Loss of heterogeneity (LOH) analysis in the BHD-RCC samples detected numerous LOH regions in all tumour types across all chromosomes – excluding Y as only one sample was male. Allele-specific analysis revealed that most of the LOH regions were the result of uniparental disomy (UPD), with several common UPD regions on chromosomes 3, 8, 16 and X. Although UPD has been reported in other malignancies, levels are not usually very high. Therefore a series of UPD regions, common across BHD-RCC subtypes, could be a cytogenetic marker for tumours associated with BHD.

UPD in cancer cells can lead to altered gene expression; NETO2 at 16q11.2 is up-regulated in sporadic ccRCC samples (Zaravinos et al., 2014) and is in a common UPD region in BHD-RCCs. Iribe et al. compared NETO2 expression in BHD-RCC, sporadic-RCC and normal kidney tissue samples. NETO2 was upregulated in sporadic samples and BHD-RCC compared to normal kidney controls – although expression was variable. In addition, comparison of BHD-patient and control normal kidney tissue identified increased NETO2 expression in BHD tissue. It is unknown whether this could contribute to BHD tumourigenesis or if the same increased expression is seen in BHD patients that do not develop renal tumours.

Further research is required to establish whether BHD-RCCs acquire these chromosomal abnormalities during the progressive stages of tumourigenesis or if the same abnormalities would be identified in BHD patient normal kidney tissue. Either way BHD-RCC tumours have a distinct cytogenetic profile to sporadic RCC, although the similarities in BHD-RCC subtypes suggest that they could share common therapeutic targets.

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  • Iribe Y, Yao M, Tanaka R, Kuroda N, Nagashima Y, Nakatani Y, & Furuya M (2016). Genome-Wide Uniparental Disomy and Copy Number Variations in Renal Cell Carcinomas Associated with Birt-Hogg-Dubé Syndrome. The American journal of pathology, 186 (2), 337-46 PMID: 26776076.
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