Cancer Medicine | |
The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling | |
Alexander Sankin4  Abraham A. Hakimi4  Nina Mikkilineni2  Irina Ostrovnaya1  Mikhail T. Silk3  Yupu Liang2  Roy Mano2  Michael Chevinsky2  Robert J. Motzer5  Stephen B. Solomon3  Emily H. Cheng2  Jeremy C. Durack3  Jonathan A. Coleman4  Paul Russo4  | |
[1] Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York City, New York;Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York City, New York;Interventional Radiology Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York City, New York;Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York City, New York;Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York City, New York | |
关键词: Biomarker; genetic heterogeneity; kidney cancer; renal biopsy; renal cell carcinoma; | |
DOI : 10.1002/cam4.293 | |
来源: Wiley | |
【 摘 要 】
Primary clear cell renal cell carcinoma (ccRCC) genetic heterogeneity may lead to an underestimation of the mutational burden detected from a single site evaluation. We sought to characterize the extent of clonal branching involving key tumor suppressor mutations in primary ccRCC and determine if genetic heterogeneity could limit the mutation profiling from a single region assessment. Ex vivo core needle biopsies were obtained from three to five different regions of resected renal tumors at a single institution from 2012 to 2013. DNA was extracted and targeted sequencing was performed on five genes associated with ccRCC (von-Hippel Lindau [VHL], PBRM1, SETD2, BAP1, and KDM5C). We constructed phylogenetic trees by inferring clonal evolution based on the mutations present within each core and estimated the predictive power of detecting a mutation for each successive tumor region sampled. We obtained 47 ex vivo biopsy cores from 14 primary ccRCC's (median tumor size 4.5 cm, IQR 4.0–5.9 cm). Branching patterns of various complexities were observed in tumors with three or more mutations. A VHL mutation was detected in nine tumors (64%), each time being present ubiquitously throughout the tumor. Other genes had various degrees of regional mutational variation. Based on the mutations' prevalence we estimated that three different tumor regions should be sampled to detect mutations in PBRM1, SETD2, BAP1, and/or KDM5C with 90% certainty. The mutational burden of renal tumors varies by region sampled. Single site assessment of key tumor suppressor mutations in primary ccRCC may not adequately capture the genetic predictors of tumor behavior.Abstract
【 授权许可】
CC BY
© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
【 预 览 】
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