BRCA1 promoter methylation predicts adverse ovarian cancer prognosis

被引:95
作者
Chiang, Jing Wang
Karlan, Beth Y.
Cass, Ilana
Baldwin, Rae Lynn
机构
[1] Cedars Sinai Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Los Angeles, CA 90048 USA
[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA
关键词
DNA methylation; ovarian cancer; survival;
D O I
10.1016/j.ygyno.2005.10.034
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Objective. To compare the clinical outcome of ovarian cancer patients whose tumors contain BRCA1 genes silenced by promoter hypermethylation to patients with germline BRCA1 mutations and to patients with wild-type BRCA genes. Methods. Ovarian cancers from a hospital-based honor bank were characterized as having a BRCA1 mutation; or a methylated BRCA1, BRCA1 pseudogene or MLH1 promotor; or a wild-type BRCA gene. Survival of patients with methylated BRCA1 promoters (N = 11) was compared to that of patients with wild-type BRCA genes (N = 30) and BRCA1 mutations (N = 22). A methylator phenotype was defined to include tumors with hypermethylation of BRCA1, hMLH1 and/or dBRCA1 pseudogene promoters (N = 23). Results. All cohorts had comparable clinical factors except for age at diagnosis. Median age of methylated BRCA1 and wild-type BRCA patients was older than BRCA1 mutation carriers (60 and 63 versus 48 years; P = 0.04). The median disease-free interval was significantly shorter for patients with a methylated BRCA1 promoter (9.8 months) than for BRCA1 mutation carriers (39.5 months; P = 0.04). Median overall survival was also significantly shorter for patients with a methylated BRCA1 promoter (35.6 months) than BRCA1 mutation carriers (78.6 months: P = 0.02). The combined methylator phenotype cohort had significantly shorter survival (36.1 months) compared to wild-type BRCA patients (63.3 months: P = 0.02). Conclusion. These data suggest that methylation of the BRCA1 promoter is associated with poor patient outcome. BRCA1 may be part of a global panel of methylated genes associated with aggressive disease. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:403 / 410
页数:8
相关论文
共 35 条
[1]   DNA methylation and ovarian cancer [J].
Ahluwalia, A ;
Yan, P ;
Hurteau, JA ;
Bigsby, RM ;
Jung, SH ;
Huang, THM ;
Nephew, KP .
GYNECOLOGIC ONCOLOGY, 2001, 82 (02) :261-268
[2]  
Baldwin RL, 2000, CANCER RES, V60, P5329
[3]   Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis [J].
Belinsky, SA ;
Nikula, KJ ;
Palmisano, WA ;
Michels, R ;
Saccomanno, G ;
Gabrielson, E ;
Baylin, SB ;
Herman, JG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (20) :11891-11896
[4]   CPG-RICH ISLANDS AND THE FUNCTION OF DNA METHYLATION [J].
BIRD, AP .
NATURE, 1986, 321 (6067) :209-213
[5]   Clinicopathologic features of BRCA-linked and sporadic ovarian cancer [J].
Boyd, J ;
Sonoda, Y ;
Federici, MG ;
Bogomolniy, F ;
Rhei, E ;
Maresco, DL ;
Saigo, PE ;
Almadrones, LA ;
Barakat, RR ;
Brown, CL ;
Chi, DS ;
Curtin, JP ;
Poynor, EA ;
Hoskins, WJ .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2000, 283 (17) :2260-2265
[6]  
Buller RE, 2002, CLIN CANCER RES, V8, P1196
[7]  
Buller RE, 2001, CLIN CANCER RES, V7, P831
[8]   Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer [J].
Cameron, EE ;
Bachman, KE ;
Myöhänen, S ;
Herman, JG ;
Baylin, SB .
NATURE GENETICS, 1999, 21 (01) :103-107
[9]   Improved survival in women with BRCA-associated ovarian carcinoma [J].
Cass, I ;
Baldwin, RL ;
Varkey, T ;
Moslehi, R ;
Narod, SA ;
Karlan, BY .
CANCER, 2003, 97 (09) :2187-2195
[10]  
Claus EB, 1996, CANCER, V77, P2318, DOI 10.1002/(SICI)1097-0142(19960601)77:11<2318::AID-CNCR21>3.0.CO