Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD.
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Urology. 2023 Sep;179:58-70. doi: 10.1016/j.urology.2023.04.035. Epub 2023 Jun 16.
To characterize the clinical manifestations and genetic basis of a familial cancer syndrome in patients with lipomas and Birt-Hogg-Dubé-like clinical manifestations including fibrofolliculomas and trichodiscomas and kidney cancer.
Genomic analysis of blood and renal tumor DNA was performed. Inheritance pattern, phenotypic manifestations, and clinical and surgical management were documented. Cutaneous, subcutaneous, and renal tumor pathologic features were characterized.
Affected individuals were found to be at risk for a highly penetrant and lethal form of bilateral, multifocal papillary renal cell carcinoma. Whole genome sequencing identified a germline pathogenic variant in PRDM10 (c.2029 T>C, p.Cys677Arg), which cosegregated with disease. PRDM10 loss of heterozygosity was identified in kidney tumors. PRDM10 was predicted to abrogate expression of FLCN, a transcriptional target of PRDM10, which was confirmed by tumor expression of GPNMB, a TFE3/TFEB target and downstream biomarker of FLCN loss. In addition, a sporadic papillary RCC from the TCGA cohort was identified with a somatic PRDM10 mutation.
We identified a germline PRDM10 pathogenic variant in association with a highly penetrant, aggressive form of familial papillary RCC, lipomas, and fibrofolliculomas/trichodiscomas. PRDM10 loss of heterozygosity and elevated GPNMB expression in renal tumors indicate that PRDM10 alteration leads to reduced FLCN expression, driving TFE3-induced tumor formation. These findings suggest that individuals with Birt-Hogg-Dubé-like manifestations and subcutaneous lipomas, but without a germline pathogenic FLCN variant, should be screened for germline PRDM10 variants. Importantly, kidney tumors identified in patients with a pathogenic PRDM10 variant should be managed with surgical resection instead of active surveillance.
描述具有脂肪瘤和 Birt-Hogg-Dubé 样临床表现（包括纤维毛囊瘤和毛发角化病）和肾癌的家族性癌症综合征患者的临床表现和遗传基础。
对血液和肾肿瘤 DNA 进行基因组分析。记录遗传模式、表型表现以及临床和手术管理。对皮肤、皮下和肾肿瘤的病理特征进行了描述。
发现受影响的个体有罹患双侧、多灶性乳头状肾细胞癌的高外显率和致死性风险。全基因组测序鉴定出 PRDM10 中的种系致病性变异（c.2029 T>C，p.Cys677Arg），该变异与疾病共分离。在肾肿瘤中鉴定到 PRDM10 杂合性丢失。PRDM10 被预测会使 FLCN 的表达缺失，而 FLCN 是 PRDM10 的转录靶标，这通过肿瘤中 GPNMB 的表达得到证实，GPNMB 是 TFE3/TFEB 的靶标，也是 FLCN 缺失的下游生物标志物。此外，从 TCGA 队列中鉴定出了一个散发性乳头状 RCC，存在体细胞 PRDM10 突变。
我们在一个家族性乳头状肾细胞癌、脂肪瘤和纤维毛囊瘤/毛发角化病具有高度外显率和侵袭性的病例中发现了种系 PRDM10 致病性变异。肾肿瘤中存在 PRDM10 杂合性丢失和 GPNMB 表达升高，表明 PRDM10 改变导致 FLCN 表达降低，从而驱动 TFE3 诱导的肿瘤形成。这些发现表明，具有 Birt-Hogg-Dubé 样表现和皮下脂肪瘤但无种系致病性 FLCN 变异的个体应筛查种系 PRDM10 变异。重要的是，患有致病性 PRDM10 变异的患者的肾肿瘤应通过手术切除而不是主动监测进行治疗。
