Zhang Wanying, Tan Adrian Y, Blumenfeld Jon, Liu Genyan, Michaeel Alber, Zhang Tuo, Robinson Brian D, Salvatore Steven P, Kapur Sandip, Donahue Stephanie, Bobb Warren O, Rennert Hanna
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA; Department of Microbiology, Weill Cornell Medical College, New York, NY, USA.
Cancer Genet. 2016 Jan-Feb;209(1-2):11-20. doi: 10.1016/j.cancergen.2015.11.002. Epub 2015 Dec 1.
Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 and is characterized by proliferation of renal tubular epithelium and progressive chronic kidney disease. Derangements in similar cellular signaling pathways occur in ADPKD and renal malignancies, although an association of these disorders has not been established. Herein, we present a case of papillary RCC (pRCC) incidentally discovered in a patient with ADPKD following bilateral native nephrectomy during renal transplantation. Whole exome sequencing of the pRCC found a somatic missense mutation in MET proto-oncogene, p.Val1110Ile, not present in kidney cyst epithelium or non-cystic tissue. RNA sequencing demonstrated increased mRNA expression of MET and pathway-related genes, but no significant copy number variation of MET was detected. Genetic analysis of PKD genes from peripheral blood lymphocytes and renal cyst epithelium identified a constitutional PKD1 germline mutation, p.Trp1582Ser, predicted to be pathogenic. Unique somatic mutations in PKD1 were also detected in 80% of the renal cysts analyzed, but not in the pRCC. These results suggest that, in this patient, the pRCC utilized a signaling pathway involving MET that was distinct from the pathogenesis of ADPKD. This is the first report of PKD1 mutations and a somatic mutation of the MET oncogene in a pRCC in ADPKD.
常染色体显性多囊肾病（ADPKD）由PKD1和PKD2基因突变引起，其特征为肾小管上皮细胞增殖和进行性慢性肾病。尽管尚未证实这些疾病之间存在关联，但ADPKD和肾恶性肿瘤中存在相似的细胞信号通路紊乱。在此，我们报告一例在肾移植期间双侧肾切除术后于ADPKD患者中偶然发现的乳头状肾细胞癌（pRCC）病例。对pRCC进行全外显子组测序发现，MET原癌基因存在体细胞错义突变p.Val1110Ile，肾囊肿上皮或非囊肿组织中未发现该突变。RNA测序显示MET及相关通路基因的mRNA表达增加，但未检测到MET的显著拷贝数变异。对外周血淋巴细胞和肾囊肿上皮的PKD基因进行遗传分析，发现一个推测为致病性的PKD1种系突变p.Trp1582Ser。在80%分析的肾囊肿中也检测到PKD1的独特体细胞突变，但在pRCC中未检测到。这些结果表明，在该患者中，pRCC利用了一条涉及MET的信号通路，该通路与ADPKD的发病机制不同。这是关于ADPKD患者pRCC中PKD1突变和MET癌基因体细胞突变的首例报告。
