比较基因组杂交技术分析肾细胞癌中染色体基因组的变化及意义
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摘要
目的:运用比较基因组杂交技术(CGH)分析肾细胞癌的染色体基因组变化特征,并比较不同组织学亚型、分级以及不同临床分期的肾细胞癌之间的基因组变化差异及意义。
方法:选用外科手术切除并经病理组织学证实的46例原发性肾细胞癌(其中透明细胞癌10例,乳头状肾细胞癌13例,嫌色细胞癌12例,Xp11.2易位/TFE3基因融合相关性肾癌9例,未分化癌2例)石蜡包埋组织,应用CGH技术分析肾细胞癌基因组的变化;并比较不同组织学亚型、分级和临床分期的肾细胞癌之间基因组变化差异。所有数据资料均运用SPSS 13.0软件包进行统计学分析。
结果:CGH分析结果显示:1. 46例肾细胞癌染色体基因组均存在不同程度的变化,其中扩增最常见于7q(47.8%),16p(39.1%),20q(34.8%) ,最常累及的染色体区段为7q22-31(39.1%)16p 12-13(21.7%),20q12-13(21.7%) ;而缺失最常见的是1p(45.7%),3p(45.7%),13q(37.0%),14q(30.4), 8p(30.4%),最常累及的染色体区段为3p22(21.7%), 8p16-23(26.1%),14q22-32(26.1%)。2.不同亚型肾细胞癌染色体基因组的变化各具特点:(1) 10例透明细胞癌中,扩增最常见的是7q(90%),16p(80%),5q (60%),缺失最常见的是3p(90%),8p(80%),1p(70%),4p(60%),4q(60%),9p(60%);(2) 13例乳头状癌中,扩增最常见的是7p(61.5%),7q(61.5%),12q(61.5%),16q(53.8%), 20p(53.8%),20q(53.8%),缺失最常见的是14q(61.5%),18q(61.5%),13q(53.8%),3p(46.2%),4p(46.2%),6q(46.2%);(3) 12例嫌色细胞癌中,扩增最常见的是1q(58.3%),3q(50%),1p(41.7%),缺失最常见的是1p(66.7%),17p(66.7%),10p(58.3%),13p(5 8.3%),2q(50%),8p(50%)。1q21-23扩增多见于嫌色细胞癌肉瘤样变,与非肉瘤样变嫌色细胞癌具有显著差异(P=0.010);(4) 9例Xp11.2易位/TFE3基因融合相关性肾癌中,扩增最常见的是Xp (66.7%),7q(55.6%),12q(55.6%),8p(44.4%),8q(44.4%),16q(44.4%),17p(44.4%),17q(44.4%),20q(44.4%) ,缺失最常见的是3p(44.4%),9q(44.4%),14q(44.4%);(5) 2例未分化癌中,扩增最常见1p,1q,3q,8p,16q,缺失最常见的是2p,2q,3p, 5p,6p,11q,17p,17q,20p。3.在不同临床TNM分期中,5q及7q扩增多见于Ⅰ～Ⅱ期患者,与Ⅲ～Ⅳ期肾细胞癌患者间有显著差异(P=0.002和P=0.007);20q扩增及9q缺失多见于Ⅲ～Ⅳ期患者,与Ⅰ～Ⅱ期肾细胞癌患者间有显著差异(P=0.002和P=0.001)。4. 7q扩增在透明细胞癌与乳头状癌1-2级(Fuhrman核型分级系统)中高频发生,与3-4级者差异显著(P=0.045)。
结论:(1)染色体7q,16p,20q扩增及1p,3p,13q,14q,8p缺失与肾细胞癌发生有相关性。(2)5q和7q扩增可能提示肾细胞癌预后较好,20q扩增与9q缺失可能提示肾细胞癌预后较差。(3)7q扩增与低级别透明细胞癌及乳头肾癌相关,提示与预后有关。
Objective: To characterize the profiles of chromosome imbalance of renal cell carcinoma by Comparative Genomic Hybridization (CGH).And compare the different alterations among the histological subtypes , grading and clinical staging.
Methods: Forty-six primary renal cell carcinoma for which formalin-fixed, paraffin-embedded samples were available were collected from the archives of the Department of Pathology. Including10 clear cell renal cell carcinoma cases, 13 papillary renal cell carcinoma cases, 12 chromophobe renal cell carcinoma cases, 9 renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions cases, and 2 undifferentiated renal carcinoma cases were collected for the study. A set of representative hematoxylin and eosin stained slides were marked with identifying numbers and reviewed individually by two pathologists blinded to all clinical information according to 2004 WHO Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs.We screened DNA copy number changes in whole genomes by CGH in 46 primary renal cell carcinoma. Analyse according to histological type, grading,clinical staging, respectively. All data were analyzed using the SPSS 13.0 software package.
Results: 1. 46 cases with renal cell carcinoma showed evidence of increased or decreased DNA sequence copy numbers involving one or more regions of the genome. The frequently gained chromosome arms of RCC were 7q,16p,20q, and the frequently lost chromosome arms of RCC were 1p,3p,13q,14q,8p. 2. Different histological type of RCC showed different abnormality of DNA copy number. (1) The frequently gained chromosome arms of CCRCC were 7q,16p,5q; the frequently lost chromosome arms were 3p,8p,1p, 4p,4q,9p. (2) The frequently gained chromosome arms of PRCC were 7p,7q,12q,16q,20p,20q; the frequently lost chromosome arms were 14q,18q,13q,3p,4p,6q. (3) The frequently gained chromosome arms of ChrRCC were 1q,3q,1p; the frequently lost chromosome arms were1p,17p,10p,13p,2q,8p. Gains of 1q21-23 significantly correlated with ChrRCC and sarcomatoid variants ChrRCC type (P=0.010). (4) The frequently gained chromosome arms of Xp11.2RCC were Xp,7q,12q,8p,8q,16q,17p,17q,20q; the frequently lost chromosome arms were3p, 9q,14q. (5) The frequently gained chromosome arms of UnRCC were 1p,1q,3q,8p,16q; the frequently lost chromosome arms were2p,2q,3p,5p,6p,11q,17p,17q,20p. 3. Gains of 5q,7q,20q and losses of 9q were significantly correlated with clinical staging (P=0.002, P=0.007). 4. 7q was frequently gained in grade 1-2 than 3-4 (nuclear grade of Fuhrman system) of CCRCC and PRCC (P=0.045).
Conclusions:(1)7q,16p,2Qq gained and 1 p,3p,13q,14q,8p losses are correlated with RCC. (2) gains of Sq and 7q may indicated prognosis of RCC be favourable; gains of 20q and losses of 9q Enay indicated poor prognosis of RCC.(3)gains of 7q is correkated with low grade of CCRCC and PRCC,and indicated be correlated with prognosis.
方法:选用外科手术切除并经病理组织学证实的46例原发性肾细胞癌(其中透明细胞癌10例,乳头状肾细胞癌13例,嫌色细胞癌12例,Xp11.2易位/TFE3基因融合相关性肾癌9例,未分化癌2例)石蜡包埋组织,应用CGH技术分析肾细胞癌基因组的变化;并比较不同组织学亚型、分级和临床分期的肾细胞癌之间基因组变化差异。所有数据资料均运用SPSS 13.0软件包进行统计学分析。
结果:CGH分析结果显示:1. 46例肾细胞癌染色体基因组均存在不同程度的变化,其中扩增最常见于7q(47.8%),16p(39.1%),20q(34.8%) ,最常累及的染色体区段为7q22-31(39.1%)16p 12-13(21.7%),20q12-13(21.7%) ;而缺失最常见的是1p(45.7%),3p(45.7%),13q(37.0%),14q(30.4), 8p(30.4%),最常累及的染色体区段为3p22(21.7%), 8p16-23(26.1%),14q22-32(26.1%)。2.不同亚型肾细胞癌染色体基因组的变化各具特点:(1) 10例透明细胞癌中,扩增最常见的是7q(90%),16p(80%),5q (60%),缺失最常见的是3p(90%),8p(80%),1p(70%),4p(60%),4q(60%),9p(60%);(2) 13例乳头状癌中,扩增最常见的是7p(61.5%),7q(61.5%),12q(61.5%),16q(53.8%), 20p(53.8%),20q(53.8%),缺失最常见的是14q(61.5%),18q(61.5%),13q(53.8%),3p(46.2%),4p(46.2%),6q(46.2%);(3) 12例嫌色细胞癌中,扩增最常见的是1q(58.3%),3q(50%),1p(41.7%),缺失最常见的是1p(66.7%),17p(66.7%),10p(58.3%),13p(5 8.3%),2q(50%),8p(50%)。1q21-23扩增多见于嫌色细胞癌肉瘤样变,与非肉瘤样变嫌色细胞癌具有显著差异(P=0.010);(4) 9例Xp11.2易位/TFE3基因融合相关性肾癌中,扩增最常见的是Xp (66.7%),7q(55.6%),12q(55.6%),8p(44.4%),8q(44.4%),16q(44.4%),17p(44.4%),17q(44.4%),20q(44.4%) ,缺失最常见的是3p(44.4%),9q(44.4%),14q(44.4%);(5) 2例未分化癌中,扩增最常见1p,1q,3q,8p,16q,缺失最常见的是2p,2q,3p, 5p,6p,11q,17p,17q,20p。3.在不同临床TNM分期中,5q及7q扩增多见于Ⅰ～Ⅱ期患者,与Ⅲ～Ⅳ期肾细胞癌患者间有显著差异(P=0.002和P=0.007);20q扩增及9q缺失多见于Ⅲ～Ⅳ期患者,与Ⅰ～Ⅱ期肾细胞癌患者间有显著差异(P=0.002和P=0.001)。4. 7q扩增在透明细胞癌与乳头状癌1-2级(Fuhrman核型分级系统)中高频发生,与3-4级者差异显著(P=0.045)。
结论:(1)染色体7q,16p,20q扩增及1p,3p,13q,14q,8p缺失与肾细胞癌发生有相关性。(2)5q和7q扩增可能提示肾细胞癌预后较好,20q扩增与9q缺失可能提示肾细胞癌预后较差。(3)7q扩增与低级别透明细胞癌及乳头肾癌相关,提示与预后有关。
Objective: To characterize the profiles of chromosome imbalance of renal cell carcinoma by Comparative Genomic Hybridization (CGH).And compare the different alterations among the histological subtypes , grading and clinical staging.
Methods: Forty-six primary renal cell carcinoma for which formalin-fixed, paraffin-embedded samples were available were collected from the archives of the Department of Pathology. Including10 clear cell renal cell carcinoma cases, 13 papillary renal cell carcinoma cases, 12 chromophobe renal cell carcinoma cases, 9 renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions cases, and 2 undifferentiated renal carcinoma cases were collected for the study. A set of representative hematoxylin and eosin stained slides were marked with identifying numbers and reviewed individually by two pathologists blinded to all clinical information according to 2004 WHO Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs.We screened DNA copy number changes in whole genomes by CGH in 46 primary renal cell carcinoma. Analyse according to histological type, grading,clinical staging, respectively. All data were analyzed using the SPSS 13.0 software package.
Results: 1. 46 cases with renal cell carcinoma showed evidence of increased or decreased DNA sequence copy numbers involving one or more regions of the genome. The frequently gained chromosome arms of RCC were 7q,16p,20q, and the frequently lost chromosome arms of RCC were 1p,3p,13q,14q,8p. 2. Different histological type of RCC showed different abnormality of DNA copy number. (1) The frequently gained chromosome arms of CCRCC were 7q,16p,5q; the frequently lost chromosome arms were 3p,8p,1p, 4p,4q,9p. (2) The frequently gained chromosome arms of PRCC were 7p,7q,12q,16q,20p,20q; the frequently lost chromosome arms were 14q,18q,13q,3p,4p,6q. (3) The frequently gained chromosome arms of ChrRCC were 1q,3q,1p; the frequently lost chromosome arms were1p,17p,10p,13p,2q,8p. Gains of 1q21-23 significantly correlated with ChrRCC and sarcomatoid variants ChrRCC type (P=0.010). (4) The frequently gained chromosome arms of Xp11.2RCC were Xp,7q,12q,8p,8q,16q,17p,17q,20q; the frequently lost chromosome arms were3p, 9q,14q. (5) The frequently gained chromosome arms of UnRCC were 1p,1q,3q,8p,16q; the frequently lost chromosome arms were2p,2q,3p,5p,6p,11q,17p,17q,20p. 3. Gains of 5q,7q,20q and losses of 9q were significantly correlated with clinical staging (P=0.002, P=0.007). 4. 7q was frequently gained in grade 1-2 than 3-4 (nuclear grade of Fuhrman system) of CCRCC and PRCC (P=0.045).
Conclusions:(1)7q,16p,2Qq gained and 1 p,3p,13q,14q,8p losses are correlated with RCC. (2) gains of Sq and 7q may indicated prognosis of RCC be favourable; gains of 20q and losses of 9q Enay indicated poor prognosis of RCC.(3)gains of 7q is correkated with low grade of CCRCC and PRCC,and indicated be correlated with prognosis.
引文
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23 Brennan C, Zhang Y, Leo C, et al.High-resolution global profiling of genomic alterations with long oligonucleotide microarray. Cancer Res, 2004, 64 (14) : 4744-4748
24 Conrad D F, Andrews T D, Carter N P, et al.A high-resolution survey of deletion polymer- phism in the human genome. Nat Genet, 2006, 38 (1) : 75-81
25 Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in the human genome. Science, 2004, 305(5683) : 525-528
26 Dhami P, Coffey A J, Abbs S, et al. Exon array CGH: detection of copy2number changes at the resolution of individual exons in the human genome. Am J Hum Genet, 2005, 76 (5) :750-762
27 Egeland R D, Southern E M. Electrochemically directed synthesis of oligonucleotides forDNA microarray fabrication. Nucleic Acids Res, 2005, 33 (14) : e125
28 Baldocchi R A, Glynne R J, Chin K, et al. Design considerations for array CGH to oligonucleotide arrays.Cytometry A, 2005, 67 (2) : 129-136
29 Tsubosa Y, Sugihara H, Mukaisho K, et al. Effects of degenerate oligonucleotide-primed polymerase chain reaction amplification and labeling methods on the sensitivity and specificity of metaphase and array2based comparative genomic hybridization. Cancer Genet Cytogenet, 2005, 158 (2) : 156-166
30 Devries S, Nyante S, Korkola J, et al. Array2based comparative genomic hybridization from formalin-fixed, paraffin-embedded breast tumors. J Mol Diagn, 2005, 7 (1) : 65-71
31 Natrajan R, Williams R D, Grigoriadis A , et al.Delineation of a 1Mb breakpoint region at
1p13 in Wilms tumors by fine-tiling oligonucleotide array CGH.Genes Chromosomes Can- cer, 2007,46(6): 607-615
32 Tyybakinoja A, Vilpo J, Knuutila S. High-resolution oligonucleotide array-CGH pinpoints genes involved in cryptic losses in chronic lymphocytic leukemia.Cytogenet Genome Res, 2007,118(1): 8-12
33 Vekony H, Leemans C R, Ylstra B, et al.Salivary gland carcinosarcoma: Oligonucleotide array CGH reveals similar genomic profiles in epithelial and mesenchymal components. Oral Oncol, 2009,45(3):259-265
34 Arai E, Ushijima S, Tsuda H, et al. Genetic Clustering of Clear Cell Renal Cell Carcinoma Based on Array-Comparative Genomic Hybridization: Its Association with DNA Methylation Alteration and Patient Outcome. Clin Cancer Res, 2008, 14: 5531-5539
35 Altinok G, Kattar MM, Mohamed A, et al. Pediatric Renal Carcinoma Associated With Xp11.2 Translocations/TFE3 Gene Fusions and Clinicopathologic Associations. Pediatr Dev Pathol. 2005 8(2):168-180
36 Parast MM, Eudy G, Gow KW, et al. A unique case of renal carcinoma with Xp11.2 translocations/ TFE3 gene fusions in a 3-year-old child, with coexistent von Hippel-Lindau gene mutation.Pediatr Dev Pathol. 2004;7(4):403-6. Epub 2004 Jul 15
37 Brunelli M, Gobbo S, Cossu R P, et al.Chromosomal gains in the sarcomatoid transform- ation of chromophobe renal cell carcinoma. Mod Pathol, 2007 ,20(3): 303-309
38 Ramaswamy S, Ken N, Eric S, et al. A molecular signature of metastasis in primary solid tumors. Nat Genet, 2003, 33: 49-54
39 van de Wiel M A, Costa J L, Smid K, et al.Expression microarray analysis and oligo array comparative genomic hybridization of acquired gemcitabine resistance in mouse colon rev- eals selection for chromosomal aberrations. Cancer Res,2005, 65 (22) : 10208-10213
40 Lazar V, AndréF, Liedtke C, et al.High resolution oligonucleotide array-CGH to identify therapeutic targets in breast cancer.ASCO Meeting Abstracts, 2008,26: 547
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22 Selzer R R, Richmond T A, Pofahl N J, et al.Analysis of chromosome breakpoints in neur- oblastoma at subkilobase resolution using fine-tiling oligonucleotide array CGH. Genes Chromosomes Cancer, 2005, 44 (3) : 305-319
23 Brennan C, Zhang Y, Leo C, et al.High-resolution global profiling of genomic alterations with long oligonucleotide microarray. Cancer Res, 2004, 64 (14) : 4744-4748
24 Conrad D F, Andrews T D, Carter N P, et al.A high-resolution survey of deletion polymer- phism in the human genome. Nat Genet, 2006, 38 (1) : 75-81
25 Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in the human genome. Science, 2004, 305(5683) : 525-528
26 Dhami P, Coffey A J, Abbs S, et al. Exon array CGH: detection of copy2number changes at the resolution of individual exons in the human genome. Am J Hum Genet, 2005, 76 (5) :750-762
27 Egeland R D, Southern E M. Electrochemically directed synthesis of oligonucleotides forDNA microarray fabrication. Nucleic Acids Res, 2005, 33 (14) : e125
28 Baldocchi R A, Glynne R J, Chin K, et al. Design considerations for array CGH to oligonucleotide arrays.Cytometry A, 2005, 67 (2) : 129-136
29 Tsubosa Y, Sugihara H, Mukaisho K, et al. Effects of degenerate oligonucleotide-primed polymerase chain reaction amplification and labeling methods on the sensitivity and specificity of metaphase and array2based comparative genomic hybridization. Cancer Genet Cytogenet, 2005, 158 (2) : 156-166
30 Devries S, Nyante S, Korkola J, et al. Array2based comparative genomic hybridization from formalin-fixed, paraffin-embedded breast tumors. J Mol Diagn, 2005, 7 (1) : 65-71
31 Natrajan R, Williams R D, Grigoriadis A , et al.Delineation of a 1Mb breakpoint region at
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32 Tyybakinoja A, Vilpo J, Knuutila S. High-resolution oligonucleotide array-CGH pinpoints genes involved in cryptic losses in chronic lymphocytic leukemia.Cytogenet Genome Res, 2007,118(1): 8-12
33 Vekony H, Leemans C R, Ylstra B, et al.Salivary gland carcinosarcoma: Oligonucleotide array CGH reveals similar genomic profiles in epithelial and mesenchymal components. Oral Oncol, 2009,45(3):259-265
34 Arai E, Ushijima S, Tsuda H, et al. Genetic Clustering of Clear Cell Renal Cell Carcinoma Based on Array-Comparative Genomic Hybridization: Its Association with DNA Methylation Alteration and Patient Outcome. Clin Cancer Res, 2008, 14: 5531-5539
35 Altinok G, Kattar MM, Mohamed A, et al. Pediatric Renal Carcinoma Associated With Xp11.2 Translocations/TFE3 Gene Fusions and Clinicopathologic Associations. Pediatr Dev Pathol. 2005 8(2):168-180
36 Parast MM, Eudy G, Gow KW, et al. A unique case of renal carcinoma with Xp11.2 translocations/ TFE3 gene fusions in a 3-year-old child, with coexistent von Hippel-Lindau gene mutation.Pediatr Dev Pathol. 2004;7(4):403-6. Epub 2004 Jul 15
37 Brunelli M, Gobbo S, Cossu R P, et al.Chromosomal gains in the sarcomatoid transform- ation of chromophobe renal cell carcinoma. Mod Pathol, 2007 ,20(3): 303-309
38 Ramaswamy S, Ken N, Eric S, et al. A molecular signature of metastasis in primary solid tumors. Nat Genet, 2003, 33: 49-54
39 van de Wiel M A, Costa J L, Smid K, et al.Expression microarray analysis and oligo array comparative genomic hybridization of acquired gemcitabine resistance in mouse colon rev- eals selection for chromosomal aberrations. Cancer Res,2005, 65 (22) : 10208-10213
40 Lazar V, AndréF, Liedtke C, et al.High resolution oligonucleotide array-CGH to identify therapeutic targets in breast cancer.ASCO Meeting Abstracts, 2008,26: 547