PDF(Pubmed)
Abstract：
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.
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.
摘要：
目的：描述脂肪瘤患者家族性癌综合征的临床表现和遗传基础，包括纤维囊瘤、毛状肉瘤和肾癌。
方法：进行血液和肾肿瘤DNA的基因组分析。继承模式,表型表现，并记录了临床和手术管理.皮肤,皮下和肾脏肿瘤的病理特征进行了表征。
结果：发现受影响的个体有高度渗透和致命形式的双侧，多灶性乳头状肾细胞癌。全基因组测序确定了PRDM10中的种系致病性变异(c.2029T>C，p.Cys677Arg),与疾病分离。在肾肿瘤中鉴定出PRDM10杂合性丢失(LOH)。预计PRDM10将废除FLCN的表达，PRDM10的转录靶标，通过GPNMB的肿瘤表达证实，TFE3/TFEB靶标和FLCN损失的下游生物标志物。此外,来自TCGA队列的散发性乳头状RCC被鉴定为体细胞PRDM10突变.
结论：我们确定了与高渗透剂相关的种系PRDM10致病变异体，家族性乳头状RCC的侵袭性形式，脂肪瘤和纤维囊瘤/毛眼肉瘤。肾肿瘤中PRDM10LOH和GPNMB表达升高表明PRDM10改变导致FLCN表达降低,驱动TFE3诱导的肿瘤形成。这些结果表明，患有BHD样表现和皮下脂肪瘤的个体，但是没有种系致病性FLCN变体，应筛选种系PRDM10变体。重要的是,在具有致病性PRDM10变异体的患者中发现的肾肿瘤应通过手术切除治疗,而不是主动监测.
方法：进行血液和肾肿瘤DNA的基因组分析。继承模式,表型表现，并记录了临床和手术管理.皮肤,皮下和肾脏肿瘤的病理特征进行了表征。
结果：发现受影响的个体有高度渗透和致命形式的双侧，多灶性乳头状肾细胞癌。全基因组测序确定了PRDM10中的种系致病性变异(c.2029T>C，p.Cys677Arg),与疾病分离。在肾肿瘤中鉴定出PRDM10杂合性丢失(LOH)。预计PRDM10将废除FLCN的表达，PRDM10的转录靶标，通过GPNMB的肿瘤表达证实，TFE3/TFEB靶标和FLCN损失的下游生物标志物。此外,来自TCGA队列的散发性乳头状RCC被鉴定为体细胞PRDM10突变.
结论：我们确定了与高渗透剂相关的种系PRDM10致病变异体，家族性乳头状RCC的侵袭性形式，脂肪瘤和纤维囊瘤/毛眼肉瘤。肾肿瘤中PRDM10LOH和GPNMB表达升高表明PRDM10改变导致FLCN表达降低,驱动TFE3诱导的肿瘤形成。这些结果表明，患有BHD样表现和皮下脂肪瘤的个体，但是没有种系致病性FLCN变体，应筛选种系PRDM10变体。重要的是,在具有致病性PRDM10变异体的患者中发现的肾肿瘤应通过手术切除治疗,而不是主动监测.
