Copy number alterations in urothelial carcinomas: their clinicopathological significance and correlation with DNA methylation alterations.
Copy number alterations in urothelial carcinomas: their clinicopathological significance and correlation with DNA methylation alterations.
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DOI：
10.1093/carcin/bgq274
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发表时间：
2011-04
期刊：
影响因子：
4.7
通讯作者：
Kanai Y
中科院分区：
文献类型：
--
作者：
Nishiyama N;Arai E;Nagashio R;Fujimoto H;Hosoda F;Shibata T;Tsukamoto T;Yokoi S;Imoto I;Inazawa J;Kanai Y
本研究的目的是阐明尿路上皮癌（UC）的临床病理特征的遗传背景。使用244 K寡核苷酸阵列对49个UC组织样品进行阵列比较基因组杂交分析。2q33.3-q37.3、4p15.2-q13.1和5q13.3-q35.3的丢失以及7p11.2-q11.23和20q13.12-q13.2的增加与较高的组织学分级相关，而7p21.2-p21.12的增加与较深的浸润相关。6q14.1-q27和17p13.3-q11.1的丢失以及19q13.12-q13.2和20q13.12-q13.33的增加与淋巴管受累相关。16p12.2-p12.1缺失和3q26.32-q29增加与血管受累相关。5q14.1-q23.1、6q14.1-q27、8 p22-p21.3、11q13.5-q14.1和15q11.2-q22.2的丢失以及7p11.2-q11.22和19q13.12-q13.2的增加与侵袭性非乳头状UC的发展相关。1p32.2-p31.3、10q11.23-q21.1和15q21.3缺失与肿瘤复发相关。基于拷贝数改变的无监督层次聚类分析将UC分为三个亚类：与全基因组DNA低甲基化相关的拷贝数改变、C型CpG岛上的区域DNA高甲基化以及全基因组DNA低甲基化和高甲基化分别聚集在簇A、B1和B2中。应在上述区域探索可能编码用于UC诊断和鉴别的治疗靶点和/或指标的肿瘤相关基因。遗传和表观遗传事件似乎在尿路上皮癌发生过程中积累，反映了UC的临床病理多样性。
The aim of this study was to clarify the genetic backgrounds underlying the clinicopathological characteristics of urothelial carcinomas (UCs). Array comparative genomic hybridization analysis using a 244K oligonucleotide array was performed on 49 samples of UC tissue. Losses of 2q33.3–q37.3, 4p15.2–q13.1 and 5q13.3–q35.3 and gains of 7p11.2–q11.23 and 20q13.12–q13.2 were correlated with higher histological grade, and gain of 7p21.2–p21.12 was correlated with deeper invasion. Losses of 6q14.1–q27 and 17p13.3–q11.1 and gains of 19q13.12–q13.2 and 20q13.12–q13.33 were correlated with lymph vessel involvement. Loss of 16p12.2–p12.1 and gain of 3q26.32–q29 were correlated with vascular involvement. Losses of 5q14.1–q23.1, 6q14.1–q27, 8p22–p21.3, 11q13.5–q14.1 and 15q11.2–q22.2 and gains of 7p11.2–q11.22 and 19q13.12–q13.2 were correlated with the development of aggressive non-papillary UCs. Losses of 1p32.2–p31.3, 10q11.23–q21.1 and 15q21.3 were correlated with tumor recurrence. Unsupervised hierarchical clustering analysis based on copy number alterations clustered UCs into three subclasses: copy number alterations associated with genome-wide DNA hypomethylation, regional DNA hypermethylation on C-type CpG islands and genome-wide DNA hypo- and hypermethylation were accumulated in clusters A, B1 and B2, respectively. Tumor-related genes that may encode therapeutic targets and/or indicators useful for the diagnosis and prognostication of UCs should be explored in the above regions. Both genetic and epigenetic events appear to accumulate during urothelial carcinogenesis, reflecting the clinicopathological diversity of UCs.
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