Introduction: DNA methylation plays an important role in the carcinogenesis, progression, and prognosis of various human cancers. RASSF1A, BRCA1, APC, and p16 are the frequently methylated genes among patients with ovarian cancer. Therefore, our study aimed to better determine the prognostic and cancer characteristics effects of RASSF1A, BRCA1, APC, and p16 promoter methylation in ovarian cancer patients. Methods: Databases such as PubMed, Web of Science, EMBASE, CNKI, and WanFang were searched for published studies up to March 4, 2024. The outcomes are shown as OR and HR with their 95% CIs. Then, the random or fixed-effect model was performed to evaluate the effect sizes. Results: Finally, 27 articles were included in this meta-analysis. No significant relationships were observed between RASSF1A, BRCA1, and APC promoter methylation and the clinical prognostic (including overall survival and progression-free survival) and cancer characteristics (including ascites, lymph node metastasis, and pelvic peritoneal metastasis) in ovarian cancer. p16 promoter methylation was significantly related to poor progression-free survival (PFS) (HR = 1.52, 95% CI = 1.14–2.04) and overall survival (OS) (HR = 1.39, 95% CI = 1.06, to 1.83) in univariate and poor PFS in multivariate Cox regression models (HR = 1.42, 95% CI = 1.05–1.92). Besides, our results indicated that the clinical stage was associated with inferior OS while there was no significant association between tumor grade and OS. Conclusion: RASSF1A, BRCA1, and APC promoter methylation were not significantly associated with clinical prognostic and cancer characteristics. p16 may be a useful biomarker for predicting PFS in ovarian cancer. Furthermore, the clinical stage was significantly associated with OS. In further research, more prospective and multicenter validation studies remain needed.

1.
Sung
H
,
Ferlay
J
,
Siegel
RL
,
Laversanne
M
,
Soerjomataram
I
,
Jemal
A
, et al
.
Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
.
CA Cancer J Clin
.
2021
;
71
(
3
):
209
49
.
2.
Vang
R
,
Shih
IM
,
Kurman
RJ
.
Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems
.
Adv Anat Pathol
.
2009
;
16
(
5
):
267
82
.
3.
Jemal
A
,
Siegel
R
,
Xu
J
,
Ward
E
.
Cancer statistics, 2010
.
CA Cancer J Clin
.
2010
;
60
(
5
):
277
300
.
4.
Ye
M
,
Huang
T
,
Ni
C
,
Yang
P
,
Chen
S
.
Diagnostic capacity of RASSF1A promoter methylation as a biomarker in tissue, brushing, and blood samples of nasopharyngeal carcinoma
.
EBioMedicine
.
2017
;
18
:
32
40
.
5.
Khan
SA
,
Reddy
D
,
Gupta
S
.
Global histone post-translational modifications and cancer: biomarkers for diagnosis, prognosis and treatment
.
World J Biol Chem
.
2015
;
6
(
4
):
333
45
.
6.
Chmelarova
M
,
Dvorakova
E
,
Spacek
J
,
Laco
J
,
Palicka
V
.
Importance of promoter methylation of GATA4 gene in epithelial ovarian cancer
.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub
.
2013
;
157
(
4
):
294
7
.
7.
Baylin
SB
,
Jones
PA
.
A decade of exploring the cancer epigenome - biological and translational implications
.
Nat Rev Cancer
.
2011
;
11
(
10
):
726
34
.
8.
Issa
JP
.
DNA methylation as a therapeutic target in cancer
.
Clin Cancer Res
.
2007
;
13
(
6
):
1634
7
.
9.
Rezk
NA
,
Mohamed
RH
,
Alnemr
AA
,
Harira
M
.
Promoter methylation of RASSF1A gene in Egyptian patients with ovarian cancer
.
Appl Biochem Biotechnol
.
2018
;
185
(
1
):
153
62
.
10.
Zhu
X
,
Yang
H
,
Lang
J
,
Zhang
Y
.
Ras association domain family protein 1a hypermethylation and PD-L1 expression in ovarian cancer: a retrospective study of 112 cases
.
Eur J Obstet Gynecol Reprod Biol
.
2019
;
240
:
103
8
.
11.
Bhagat
R
,
Kumar
SS
,
Vaderhobli
S
,
Premalata
CS
,
Pallavi
VR
,
Ramesh
G
, et al
.
Epigenetic alteration of p16 and retinoic acid receptor beta genes in the development of epithelial ovarian carcinoma
.
Tumour Biol
.
2014
;
35
(
9
):
9069
78
.
12.
Kalachand
RD
,
O’Riain
C
,
Toomey
S
,
Carr
A
,
Timms
KM
,
O’Toole
S
, et al
.
Prevalence of tumor BRCA1 and BRCA2 dysfunction in unselected patients with ovarian cancer
.
Obstet Gynecol Sci
.
2020
;
63
(
5
):
643
54
.
13.
Shen
WJ
,
Dai
DQ
,
Guo
KJ
,
Li
XM
.
RASSF1A and BRCA1 and p16 gene aberrant methylation detection and its clinical significance in epithelial ovarian cancer
.
Chin J Cancer Prev Treat
.
2008
;
15
(
7
).
14.
Raos
D
,
Ulamec
M
,
Katusic Bojanac
A
,
Bulic-Jakus
F
,
Jezek
D
,
Sincic
N
.
Epigenetically inactivated RASSF1A as a tumor biomarker
.
Bosn J Basic Med Sci
.
2021
;
21
(
4
):
386
97
.
15.
Agathanggelou
A
,
Cooper
WN
,
Latif
F
.
Role of the Ras-association domain family 1 tumor suppressor gene in human cancers
.
Cancer Res
.
2005
;
65
(
9
):
3497
508
.
16.
Xiao
X
,
Cai
F
,
Niu
X
,
Shi
H
,
Zhong
Y
.
Association between P16INK4a promoter methylation and ovarian cancer: a meta-analysis of 12 published studies
.
PLoS One
.
2016
;
11
(
9
):
e0163257
.
17.
Shen
C
,
Sheng
Q
,
Zhang
X
,
Fu
Y
,
Zhu
K
.
Hypermethylated APC in serous carcinoma based on a meta-analysis of ovarian cancer
.
J Ovarian Res
.
2016
;
9
(
1
):
60
.
18.
Ruan
J
,
Xu
P
,
Fan
W
,
Deng
Q
,
Yu
M
.
Quantitative assessment of aberrant P16INK4a methylation in ovarian cancer: a meta-analysis based on literature and TCGA datasets
.
Cancer Manag Res
.
2018
;
10
:
3033
46
.
19.
Si
JG
,
Su
YY
,
Han
YH
,
Chen
RH
.
Role of RASSF1A promoter methylation in the pathogenesis of ovarian cancer: a meta-analysis
.
Genet Test Mol Biomarkers
.
2014
;
18
(
6
):
394
402
.
20.
Wang
H
,
Cui
M
,
Zhang
S
,
He
J
,
Song
L
,
Chen
Y
.
Relationship between RAS association domain family protein 1A promoter methylation and the clinicopathological characteristics in patients with ovarian cancer: a systematic meta-analysis
.
Gynecol Obstet Invest
.
2018
;
83
(
4
):
349
57
.
21.
Kalachand
RD
,
Stordal
B
,
Madden
S
,
Chandler
B
,
Cunningham
J
,
Goode
EL
, et al
.
BRCA1 promoter methylation and clinical outcomes in ovarian cancer: an individual patient data meta-analysis
.
J Natl Cancer Inst
.
2020
;
112
(
12
):
1190
203
.
22.
Page
MJ
,
McKenzie
JE
,
Bossuyt
PM
,
Boutron
I
,
Hoffmann
TC
,
Mulrow
CD
, et al
.
The PRISMA 2020 statement: an updated guideline for reporting systematic reviews
.
Bmj
.
2021
;
372
:
n71
.
23.
Wells
G
, editor.
The newcastle-ottawa scale (NOS) for assessing the quality of non-randomised studies in meta-analyses
.
Symposium on systematic reviews: beyond the basics
;
2014
.
24.
Wiley
A
,
Katsaros
D
,
Chen
H
,
Rigault de la Longrais
IA
,
Beeghly
A
,
Puopolo
M
, et al
.
Aberrant promoter methylation of multiple genes in malignant ovarian tumors and in ovarian tumors with low malignant potential
.
Cancer
.
2006
;
107
(
2
):
299
308
.
25.
Swisher
EM
,
Gonzalez
RM
,
Taniguchi
T
,
Garcia
RL
,
Walsh
T
,
Goff
BA
, et al
.
Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas
.
Mol Cancer
.
2009
;
8
:
48
.
26.
How
JA
,
Jazaeri
AA
,
Fellman
B
,
Daniels
MS
,
Penn
S
,
Solimeno
C
, et al
.
Modification of homologous recombination deficiency score threshold and association with long-term survival in epithelial ovarian cancer
.
Cancers
.
2021
;
13
(
5
):
946
.
27.
Montavon
C
,
Gloss
BS
,
Warton
K
,
Barton
CA
,
Statham
AL
,
Scurry
JP
, et al
.
Prognostic and diagnostic significance of DNA methylation patterns in high grade serous ovarian cancer
.
Gynecol Oncol
.
2012
;
124
(
3
):
582
8
.
28.
Chaudhry
P
,
Srinivasan
R
,
Patel
FD
.
Utility of gene promoter methylation in prediction of response to platinum-based chemotherapy in epithelial ovarian cancer (EOC)
.
Cancer Invest
.
2009
;
27
(
8
):
877
84
.
29.
Patch
AM
,
Christie
EL
,
Etemadmoghadam
D
,
Garsed
DW
,
George
J
,
Fereday
S
, et al
.
Whole-genome characterization of chemoresistant ovarian cancer
.
Nature
.
2015
;
521
(
7553
):
489
94
.
30.
Choi
YL
,
Kang
SY
,
Shin
YK
,
Choi
JS
,
Kim
SH
,
Lee
SJ
, et al
.
Aberrant hypermethylation of RASSF1A promoter in ovarian borderline tumors and carcinomas
.
Virchows Arch
.
2006
;
448
(
3
):
331
6
.
31.
Bhagat
R
,
Chadaga
S
,
Premalata
CS
,
Ramesh
G
,
Ramesh
C
,
Pallavi
VR
, et al
.
Aberrant promoter methylation of the RASSF1A and APC genes in epithelial ovarian carcinoma development
.
Cell Oncol
.
2012
;
35
(
6
):
473
9
.
32.
Xing
BL
,
Li
T
,
Tang
ZH
,
Jiao
L
,
Ge
SM
,
Qiang
X
, et al
.
Cumulative methylation alternations of gene promoters and protein markers for diagnosis of epithelial ovarian cancer
.
Genet Mol Res
.
2015
;
14
(
2
):
4532
40
.
33.
McAlpine
JN
,
Porter
H
,
Kobel
M
,
Nelson
BH
,
Prentice
LM
,
Kalloger
SE
, et al
.
BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma
.
Mod Pathol
.
2012
;
25
(
5
):
740
50
.
34.
He
Y
,
Jin
MS
,
Du
DS
,
Wang
CZ
.
Study on promoter methylation of RASSF1A gene in ovarian cancer and peritoneal fluid
.
J Bengbu Med Coll
.
2011
;
36
(
1
):
35
41
.
35.
Li
QR
,
Liu
PS
,
Feng
JB
.
Detection of aberrant methylation of RASSF1A gene in the tissue and the serum from ovarian tumor patients and its clinical significance
.
Chin J Cancer Prev Treat
.
2008
;
15
(
05
):
374
7
.
36.
Katsaros
D
,
Cho
W
,
Singal
R
,
Fracchioli
S
,
Rigault De La Longrais
IA
,
Arisio
R
, et al
.
Methylation of tumor suppressor gene p16 and prognosis of epithelial ovarian cancer
.
Gynecol Oncol
.
2004
;
94
(
3
):
685
92
.
37.
Shen
WJ
,
Guo
KJ
,
Song
S
,
Dai
DQ
.
Clinical value of promoter hypermethylation of APC gene in epithelia ovarian carcinoma
.
J Shandong Med
.
2007
;
47
(
32
):
38
9
.
38.
Sun
J
,
Lu
J
,
Zou
DF
,
Wu
GP
.
Hypermethylation of APC gene promoter in epithelial ovarian carcinoma
.
J Bethune Mil Med Coll
.
2008
;
6
(
5
):
257
9+4
.
39.
Ruscito
I
,
Dimitrova
D
,
Vasconcelos
I
,
Gellhaus
K
,
Schwachula
T
,
Bellati
F
, et al
.
BRCA1 gene promoter methylation status in high-grade serous ovarian cancer patients--a study of the tumour Bank ovarian cancer (TOC) and ovarian cancer diagnosis consortium (OVCAD)
.
Eur J Cancer
.
2014
;
50
(
12
):
2090
8
.
40.
Ignatov
T
,
Eggemann
H
,
Costa
SD
,
Roessner
A
,
Kalinski
T
,
Ignatov
A
.
BRCA1 promoter methylation is a marker of better response to platinum-taxane-based therapy in sporadic epithelial ovarian cancer
.
J Cancer Res Clin Oncol
.
2014
;
140
(
9
):
1457
63
.
41.
Cunningham
JM
,
Cicek
MS
,
Larson
NB
,
Davila
J
,
Wang
C
,
Larson
MC
, et al
.
Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status
.
Sci Rep
.
2014
;
4
:
4026
.
42.
Rzepecka
IK
,
Szafron
L
,
Stys
A
,
Bujko
M
,
Plisiecka-Halasa
J
,
Madry
R
, et al
.
High frequency of allelic loss at the BRCA1 locus in ovarian cancers: clinicopathologic and molecular associations
.
Cancer Genet
.
2012
;
205
(
3
):
94
100
.
43.
Radosa
MP
,
Hafner
N
,
Camara
O
,
Diebolder
H
,
Mothes
A
,
Winzer
H
, et al
.
Loss of BRCA1 protein expression as indicator of the BRCAness phenotype is associated with favorable overall survival after complete resection of sporadic ovarian cancer
.
Int J Gynecol Cancer
.
2011
;
21
(
8
):
1399
406
.
44.
Prieske
K
,
Prieske
S
,
Joosse
SA
,
Trillsch
F
,
Grimm
D
,
Burandt
E
, et al
.
Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer
.
Oncotarget
.
2017
;
8
(
47
):
83063
74
.
45.
Giannopoulou
L
,
Chebouti
I
,
Pavlakis
K
,
Kasimir-Bauer
S
,
Lianidou
ES
.
RASSF1A promoter methylation in high-grade serous ovarian cancer: a direct comparison study in primary tumors, adjacent morphologically tumor cell-free tissues and paired circulating tumor DNA
.
Oncotarget
.
2017
;
8
(
13
):
21429
43
.
46.
Hu
F
,
Chen
L
,
Bi
MY
,
Zheng
L
,
He
JX
,
Huang
YZ
, et al
.
Potential of RASSF1A promoter methylation as a biomarker for colorectal cancer: meta-analysis and TCGA analysis
.
Pathol Res Pract
.
2020
;
216
(
8
):
153009
.
47.
Bai
ZJ
,
Liu
Q
,
Wang
XS
,
Liu
WY
.
APC promoter methylation is correlated with development and progression of bladder cancer, but not linked to overall survival: a meta-analysis
.
Neoplasma
.
2019
;
66
(
3
):
470
80
.
48.
Guo
T
,
Ren
Y
,
Wang
B
,
Huang
Y
,
Jia
S
,
Tang
W
, et al
.
Promoter methylation of BRCA1 is associated with estrogen, progesterone and human epidermal growth factor receptor-negative tumors and the prognosis of breast cancer: a meta-analysis
.
Mol Clin Oncol
.
2015
;
3
(
6
):
1353
60
.
49.
Gerdes
B
,
Ramaswamy
A
,
Ziegler
A
,
Lang
SA
,
Kersting
M
,
Baumann
R
, et al
.
p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb
.
Ann Surg
.
2002
;
235
(
1
):
51
9
.
You do not currently have access to this content.