title: Independent Tumor Origin in Two Cases of Synchronous Bilateral Clear Cell Renal Cell Carcinoma.
abstract: Bilateral renal cell carcinomas (RCCs) pose a challenge for clinical treatment and management. Most bilateral RCCs are sporadic, and do not show a hereditary pattern indicative of VHL syndrome or other inherited cancers. The origin and evolution of these sporadic bilateral RCCs remains elusive. We obtained normal and tumor samples from two male patients suffering from early stage synchronous bilateral clear cell RCC (ccRCC), and analyzed genomic DNA using whole exome sequencing and bisulfite pyrosequencing. We detected distinct 3p loss of heterozygosity (LOH) in both tumors in each patient. Two tumors within the same patient harbored distinct driver mutations and different CpG hypermethylation sites in the VHL promoter. Moreover, tumors exhibit independent evolutionary trajectories. Therefore, distinct 3p LOH, combined with contingent driver gene mutations and independent VHL hypermethylation, led to independent tumor origin and parallel evolution of bilateral ccRCC in these two patients. Our results indicate that tumors in these two cases were not due to common germline oncogenic mutations. They were results of multiple de novo mutations in each kidney, rather than primary ccRCC with contralateral renal metastasis. Therefore, histopathologic and genetic profiling from single tumor specimen may underestimate the mutational burden and somatic heterogeneity of bilateral ccRCCs.
authors.affiliation: Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Capital medical University, Beijing, China.|Department of Urology, Beijing Friendship Hospital, Capital medical University, Beijing, China.
authors.forename: Zhengguo
authors.initials: Z
authors.lastname: Ji
authors.affiliation: Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Capital medical University, Beijing, China.
authors.forename: Jialu
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Capital medical University, Beijing, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Capital medical University, Beijing, China.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Institute of Chinese Materia Medica, Chinese Academy of Chinese Medical Science, Beijing 100700, China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Capital medical University, Beijing, China.|Beijing Institute for Brain Disorders, Center of Schizophrenia, Capital Medical University, Beijing 100069, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Ye
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000473:pathology
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein