Abstract
In BAP1 tumor predisposition syndrome, clear cell renal cell carcinoma (RCC) is frequently associated with melanoma and/or mesothelioma, while germline MITF p.E318K alterations are being increasingly reported in melanoma/RCC. Limited data exist on the co-occurrence of melanoma and/or mesothelioma with renal neoplasia and the prevalence of associated germline alterations. To assess the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia using our institutional nephrectomy registry and to determine the prevalence of BAP1 and MITF alterations within this cohort. In this genetic association study, medical records from 8295 patients from 1970 to 2018, renal neoplasia co-occurring with melanoma and/or mesothelioma within a single institutional nephrectomy registry was reevaluated based on contemporary histopathologic criteria and the medical records were reviewed. Data were analyzed from September 2019 to May 2021. Identified cases were screened for BAP1 loss using immunohistochemistry; while patients with melanoma and clear cell RCC were screened for MITF p.E318K alterations. Tumors from patients with potential germline alterations were analyzed with comprehensive molecular profiling using a 514-gene next generation sequencing panel. Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia (cutaneous melanoma, n = 76; uveal melanoma, n = 11; mesothelioma, n = 6). A total of 69 (74.2%) were male; 24 (25.8%) were female; median age at diagnosis of renal neoplasia was 63 years (IQR, 58-70 years) and the median duration of follow-up was 8.5 years (IQR, 5.0-14.6 years). Two patients with clear cell RCC had germline BAP1 alterations in the setting of cutaneous melanoma and mesothelioma. Two patients with hybrid oncocytic tumors had biallelic inactivation of FLCN in a setting of Birt-Hogg-Dubé (BHD) syndrome associated with uveal melanoma and mesothelioma. Tumor-only screening of clear cell RCC associated with cutaneous (n = 53) and uveal melanoma (n = 6) led to the identification of 1 patient with a likely germline MITF p.E318K alteration. After excluding benign renal neoplasia (such as oncocytoma and angiomyolipoma), alterations of BAP1, FLCN, and MITF were identified in 5 of 81 patients (6.2%) with melanoma and/or mesothelioma and renal neoplasia. In contrast to hybrid oncocytic tumors in BHD, no unique genotype-phenotype correlations were seen for clear cell RCC with pathogenic BAP1/ MITF alterations and VHL loss of function variants. Four of 5 cases (80%) met current National Comprehensive Cancer Network criteria for germline testing based on a combination of age, multifocality, histologic findings, and family history. In this genetic association study, findings support the continued use of these National Comprehensive Cancer Network criteria and suggest more stringent screening may be warranted in this patient population.
Highlights
Hereditary predisposition syndromes associated with the co-occurrence of melanoma and/or mesothelioma and renal cell carcinoma (RCC) include BAP1 tumor predisposition syndrome and tumors associated with MITF p.E318K alterations.[1,2]The spectrum of tumor associations in BAP1 tumor predisposition syndrome has gradually expanded from uveal melanoma and mesothelioma to include early-onset clear cell RCC.[3,4] For instance, in 1 study,[5 13] RCC-affected individuals from 7 families were found to have pathogenic germline alterations involving BAP1
Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia
The clear cell RCCs identified in this study had likely somatic alterations involving the VHL gene, and they exhibited some unusual morphologic features, such as the presence of nuclear pseudo-inclusions, our results suggest a lack of unique genotype-phenotype associations for renal neoplasia in BAP1 tumor predisposition syndrome
Summary
Hereditary predisposition syndromes associated with the co-occurrence of melanoma and/or mesothelioma and renal cell carcinoma (RCC) include BAP1 tumor predisposition syndrome and tumors associated with MITF p.E318K alterations.[1,2]The spectrum of tumor associations in BAP1 tumor predisposition syndrome has gradually expanded from uveal melanoma and mesothelioma to include early-onset clear cell RCC.[3,4] For instance, in 1 study,[5 13] RCC-affected individuals from 7 families were found to have pathogenic germline alterations involving BAP1. Hereditary predisposition syndromes associated with the co-occurrence of melanoma and/or mesothelioma and renal cell carcinoma (RCC) include BAP1 tumor predisposition syndrome and tumors associated with MITF p.E318K alterations.[1,2]. In a review of 181 patients with germline BAP1 variants, the combined frequency of BAP1 null and missense variants among probands was the highest in uveal melanoma (60 of 181 [33%]), followed by cutaneous melanoma (51 of 181 [28%]) and mesothelioma (41 of 181 [23%]).[1] In contrast, the incidence of RCC in this cohort was lower (12 of 181 [7%]; 4 of 40, and 8 of 121 probands with missense and null variants, respectively).[1]. The MITF p.E318K alteration leads to impaired sumoylation and transcriptional dysregulation and has been associated with both a high nevi count (>200) and increased risk of melanoma.[6,7] A separate study[2] showed an odds ratio of 4.78 for melanoma, while the odds ratio for combined melanoma and RCC among carriers of this alteration was as high as 14.46
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