NF2 Tumor Suppressor Gene Inactivation in Advanced Papillary Renal Cell Carcinoma.

To the Editor: In a recent issue of this journal, Argani et al1 described a distinctive biphasic hyalinizing psammomatous renal cell carcinoma (RCC) associated with somatic neurofibromatosis type 2 (NF2) gene mutations. We would like to support the observation of Argani and colleagues by providing molecular evidence of NF2 mutation-associated renal neoplasia in a large cohort of clinically advanced papillary renal cell carcinomas (pRCCs) and highlight the importance of this finding for the application of targeted therapies. The NF2 gene on chromosome 22q encodes the tumor suppressor protein merlin involved in a wide range of mitogenic signaling pathways, including receptor tyrosine kinases, Rac/p21-activated kinase, mammalian/ mechanistic target of rapamycin (mTOR), and the Hippo pathway. Heterozygous germline NF2 loss or inactivation is associated with neurofibromatosis type 2 syndrome, which results in the development of vestibular schwannomas, meningiomas, ependymomas, and ocular disturbances. Somatic genomic alterations (GAs) in NF2 have recently been described in a spectrum of kidney tumors including aggressive variants such as collecting duct carcinoma, sarcomatoid RCC, and unclassified RCC as well as in more indolent mucinous and spindle cell carcinoma of the kidney.2–5 We analyzed NF2 GA by comprehensive genomic profiling (CGP) in a large cohort of 414 clinically advanced pRCCs to evaluate (1) the frequencies and type of NF2 GA; and (2) cooccurring GA in other genes and biomarkers to support the driving role of NF2. Formalin-fixed paraffin-embedded tissues underwent hybrid-capture based CGP using the FoundationOne platform which interrogates the coding exons of up to 395 cancer-related genes and introns from up to 34 genes commonly rearranged in cancer (Cambridge, MA) to evaluate all classes of GA, variant-level loss of heterozygosity (LOH), tumor mutational burden (TMB), and microsatellite instability. Programmed death-ligand 1 (PD-L1) (Dako 22C3) and NF2 (1:100, D3S3W; Cell Signalling Technology) expression in tumor cells was measured by immunohistochemistry (IHC). Forty-eight (12%) pRCC cases featured NF2 GA. All NF2 mutant (NF2mut) cases were stage IV; 21 NF2mut samples used for CGP were biopsies of metastases and 27 were primary kidney tumors. The age and sex were not statistically different between NF2mut and NF2 wild-type (NF2wt) pRCCs (Table 1). Notable differences of our cohort from the TCGA pRCC dataset include a higher incidence of NF2 GA (12% vs. 3.2%). In contrast to the limited number of patients with confirmed stage IV disease in the TCGA cohort, the majority of patients in our cohort had stage IV disease. Thus, higher frequencies of NF2 GA in our cohort suggest an association ofNF2GA with more aggressive pRCC and may suggest its role in disease progression. The distribution of GA in pRCC is shown in the Table 1 and Supplementary Figure 1 (Supplemental Digital Content 1, http://links.lww.com/PAS/B12). Within NF2muts, short variant (SV) mutations were the predominant type of GA (76.4%). Less common GA were copy number alterations (homozygous deletions and amplifications) (12.7% and TABLE 1. Clinicopathologic Features and GAs in NF2 Mutated Versus NF2 Wildtype pRCC