SILENCING OF THE VHL TUMOR-SUPPRESSOR GENE BY DNA METHYLATION IN RENAL-CARCINOMA

被引:1311
作者
HERMAN, JG
LATIF, F
WENG, YK
LERMAN, MI
ZBAR, B
LIU, S
SAMID, D
DUAN, DSR
GNARRA, JR
LINEHAN, WM
BAYLIN, SB
机构
[1] JOHNS HOPKINS MED INST, DEPT MED, BALTIMORE, MD 21231 USA
[2] NCI, FREDERICK CANC RES & DEV CTR, IMMUNOBIOL LAB, FREDERICK, MD 21702 USA
[3] NCI, SURG BRANCH, UROL ONCOL SECT, BETHESDA, MD 20892 USA
[4] NCI, DIV CANC TREATMENT, CLIN PHARMACOL BRANCH, BETHESDA, MD 20892 USA
关键词
D O I
10.1073/pnas.91.21.9700
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mutational inactivation and allelic loss of the von Hippel-Lindan (VHL) gene appear to be causal events for the majority of spontaneous clear-cell renal carcinomas. We now show that hypermethylation of a normally unmethylated CPG island in the 5' region provides another potentially important mechanism for inactivation of the VHL gene in a significant portion of these cancers. This hypermethylation was found in 5 of 26 (19%) tumors examined. Four of these had lost one copy of VHL while one retained two heavily methylated alleles. Four of the tumors with VHL hypermethylation had no detectable mutations, whereas one had a missense mutation in addition to hypermethylation of the single retained allele. As would be predicted for the consequence of methylation in this 5' CpG island, none of the 5 tumors expressed the VHL gene. In contrast, normal kidney and all tumors examined with inactivating VHL gene mutations but no CpG island methylation had expression. In a renal cell culture line, treatment with 5-aza-2'-deoxycytidine resulted in reexpression of the VHL gene. These findings suggest that aberrant methylation of CpG islands may participate in the tumor-suppressor gene inactivations which initiate or cause progression of common human cancers.
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页码:9700 / 9704
页数:5
相关论文
共 36 条
[11]  
FEINBERG AP, 1988, CANCER RES, V48, P1159
[12]   PARENTAL-ORIGIN-SPECIFIC EPIGENETIC MODIFICATION OF THE MOUSE H19 GENE [J].
FERGUSONSMITH, AC ;
SASAKI, H ;
CATTANACH, BM ;
SURANI, MA .
NATURE, 1993, 362 (6422) :751-755
[13]   MUTATIONS OF THE VHL TUMOR-SUPPRESSOR GENE IN RENAL-CARCINOMA [J].
GNARRA, JR ;
TORY, K ;
WENG, Y ;
SCHMIDT, L ;
WEI, MH ;
LI, H ;
LATIF, F ;
LIU, S ;
CHEN, F ;
DUH, FM ;
LUBENSKY, I ;
DUAN, DR ;
FLORENCE, C ;
POZZATTI, R ;
WALTHER, MM ;
BANDER, NH ;
GROSSMAN, HB ;
BRAUCH, H ;
POMER, S ;
BROOKS, JD ;
ISAACS, WB ;
LERMAN, MI ;
ZBAR, B ;
LINEHAN, WM .
NATURE GENETICS, 1994, 7 (01) :85-90
[14]   HYPOMETHYLATION OF DNA FROM BENIGN AND MALIGNANT HUMAN-COLON NEOPLASMS [J].
GOELZ, SE ;
VOGELSTEIN, B ;
HAMILTON, SR ;
FEINBERG, AP .
SCIENCE, 1985, 228 (4696) :187-190
[15]  
GREGOR V, 1988, HUM GENET, V83, P155
[16]   INCREASED CYTOSINE DNA-METHYLTRANSFERASE ACTIVITY DURING COLON-CANCER PROGRESSION [J].
ISSA, JPJ ;
VERTINO, PM ;
WU, JJ ;
SAZAWAL, S ;
CELANO, P ;
NELKIN, BD ;
HAMILTON, SR ;
BAYLIN, SB .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1993, 85 (15) :1235-1240
[17]   DENOVO METHYLATION OF THE MYOD1 CPG ISLAND DURING THE ESTABLISHMENT OF IMMORTAL CELL-LINES [J].
JONES, PA ;
WOLKOWICZ, MJ ;
RIDEOUT, WM ;
GONZALES, FA ;
MARZIASZ, CM ;
COETZEE, GA ;
TAPSCOTT, SJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (16) :6117-6121
[18]  
KAUTIAINEN TL, 1986, J BIOL CHEM, V261, P1594
[19]   IDENTIFICATION OF THE VONHIPPEL-LINDAU DISEASE TUMOR-SUPPRESSOR GENE [J].
LATIF, F ;
TORY, K ;
GNARRA, J ;
YAO, M ;
DUH, FM ;
ORCUTT, ML ;
STACKHOUSE, T ;
KUZMIN, I ;
MODI, W ;
GEIL, L ;
SCHMIDT, L ;
ZHOU, FW ;
LI, H ;
WEI, MH ;
CHEN, F ;
GLENN, G ;
CHOYKE, P ;
WALTHER, MM ;
WENG, YK ;
DUAN, DSR ;
DEAN, M ;
GLAVAC, D ;
RICHARDS, FM ;
CROSSEY, PA ;
FERGUSONSMITH, MA ;
LEPASLIER, D ;
CHUMAKOV, I ;
COHEN, D ;
CHINAULT, AC ;
MAHER, ER ;
LINEHAN, WM ;
ZBAR, B ;
LERMAN, MI .
SCIENCE, 1993, 260 (5112) :1317-1320
[20]   ROLE FOR DNA METHYLATION IN GENOMIC IMPRINTING [J].
LI, E ;
BEARD, C ;
JAENISCH, R .
NATURE, 1993, 366 (6453) :362-365