ONCOLOGY LETTERS 12: 2001-2007, 2016

c‑met is overexpressed in type I ovarian cancer:

Results of an investigative analysis in a cohort
of consecutive ovarian cancer patients
MARCO JOHANNES BATTISTA1, MARCUS SCHMIDT1, SINA JAKOBI1, CRISTINA COTARELO2,
KATRIN ALMSTEDT1, ANNE‑SOPHIE HEIMES1, GEORGIOS‑MARIOS MAKRIS1, VERONIKA WEYER3,
ANTJE LEBRECHT1, GERALD HOFFMANN1 and MICHAEL EICHBAUM4

Departments of 1Gynecology and Obstetrics, and 2Pathology; 3Institute of Medical Biostatistics, Epidemiology and Informatics,
University Medical Center Mainz, Mainz D‑55131; 4Department of Gynecology and Obstetrics,
Marienkrankenhaus Frankfurt, Frankfurt D‑60318, Germany

Received July 9, 2015; Accepted April 22, 2016

DOI: 10.3892/ol.2016.4895

Abstract. The tyrosine kinase c‑met alters signaling associated with type I but not type II OC, and that overex-
cascades such as the BRAF‑MAPK and PI3K‑PKB path- pression of c‑met does not affect the prognosis of OC.
ways. These alterations are involved in the carcinogenesis of
type I but not type II ovarian cancer (OC). Therefore, the Introduction
present study investigated the patterns of c‑met expression
in a cohort of consecutive patients with OC. c‑met expres- Ovarian cancer (OC) has the worst prognosis among the
sion was determined by immunohistochemical analysis. gynecological malignancies (1). Each year, ~21,980 new
Differences in c‑met overexpression among subgroups of cases are diagnosed in the United States and ~14,270 women
established clinicopathological features, including age, succumb to OC (1). During the last decade, novel insights
histological subtype, tumor stage, histological grading, have led to a dualistic model of the carcinogenesis of
post‑operative tumor burden and completeness of chemo- OC (2‑5). This model assists in the grouping of various
therapy, were determined by χ2 test. Cox regression analyses different histological subtypes into two broad catego-
were performed to determine the prognostic effect of c‑met. ries (3,4). Low‑grade serous OC, endometrioid OC, clear
Survival rates were estimated using the Kaplan‑Meier cell OC and mucinous OC represent type I OC (3‑5).
method. A total of 106 patients were enrolled into the study. These conditions generally present as a large tumor that
c‑met was overexpressed in 20.8% of the entire cohort; 35.7% is confined to a single ovary. Mutations in isoform b of
of patients with type I OC and 8.6% of patients with type rapidly accelerated fibrosarcoma protein (BRAF), phospha-
II OC showed overexpression (P=0.001). However, c‑met tidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α
overexpression was not associated with any other established (PI3KCA), catenin β ‑1 (CTNNB1), phosphatase and tensin
clinicopathological features (all P‑values >0.05). Univariate homolog, Kirsten rat sarcoma viral oncogene homolog,
Cox regression analysis showed that overexpression of c‑met and AT‑rich interactive domain‑containing protein 1A are
was associated neither with progression‑free survival (PFS) responsible for a step‑wise progression from normal epithe-
nor with disease‑specific survival (DSS) (P=0.835 and lium through differing degrees of atypia to non‑invasive and
P=0.414, respectively). Kaplan‑Meier plots also failed to then invasive type I carcinoma (3‑5). Type II OC mainly
demonstrate an effect of c‑met on the 5‑year PFS and DSS consists of high‑grade serous OC and presents as advanced
rates (P= 0.938 and P= 0.412, respectively). These findings disease with a poor prognosis (3‑5). In the majority of
support the hypotheses that the overexpression of c‑met is type II OCs, alterations in p53 are responsible for genetic
instability, with marked chromosomal aberrations (6).
Hepatocyte growth factor/scatter factor (HGF/SF) and
its receptor tyrosine kinase, c‑met, the product of the c‑met
proto‑oncogene, provide vital signals for survival and
Correspondence to: Dr Marco Johannes Battista, Department
long‑distance epithelial and myogenic precursor cell migra-
of Gynecology and Obstetrics, University Medical Center Mainz,
Langenbeckstraße 1, Mainz D‑55131, Germany tion during embryogenesis (7). Cancer cells are able to use
E‑mail: battist@uni‑mainz.de HGF/SF‑c‑met for invasion and metastasis (7). Aberrant c‑met
activation results from various mechanisms and occurs in a
Key words: ovarian cancer, c‑met, type I ovarian cancer, type II variety of different types of cancer, including renal cancer,
ovarian cancer, prognosis hepatocellular cancer, basal‑like breast cancer, lung cancer
and OC (8). The intracellular signaling cascades activated by
c‑met include the phosphoinositide 3‑kinase‑protein kinase B
2002 BATTISTA et al: c-MET IS OVEREXPRESSED IN TYPE I OVARIAN CANCER

(PI3K‑PKB) and the RAS‑mitogen‑activated protein kinase A

(MAPK) pathways (7,9). A complex cross‑signaling network
involving the c‑met epidermal growth factor receptor,
c‑met‑vascular endothelial growth factor receptor (VEGFR)
and c‑met‑Wingless‑related integration site‑CTNBB1 path-
ways has also emerged (10,11). According to the results
of a phase II trial, cabozantinib, a potent inhibitor of
c‑met and VEGFR‑2, exhibited clinical activity in 68 OC
patients, as suggested by the recorded response rates (12).
However, the prognostic impact of c‑met in OC remains B
controversial (13‑15).
Therefore, the present study examined the expression of
c‑met and its prognostic effect in an unselected, consecutive
cohort of patients with OC.

Materials and methods

Patients and tissue samples. The archives were searched

for all patients with OC who underwent primary surgery C
at University Medical Center Mainz between 2004 and
2011. Patients entered the study only if formalin‑fixed,
paraffin‑embedded (FFPE) tissue samples were available.
Follow‑up was performed by writing letters to patients or
their physicians and by checking the patient records until
May 2013. Mortality from OC or other reasons unrelated
to cancer, and recurrence of disease, which included metas-
tasis and local relapse, was documented. Patient charts
were reviewed to collect data regarding age at diagnosis, D
histological grade, tumor stage of disease in accordance to
the International Federation of Gynecology and Obstetrics
guidelines, as previously reported (16,17). Briefly, the amount
of residual disease subsequent to primary surgery was regis-
tered as no tumor burden (R0), or as residual disease <2 cm
(R1) or >2 cm (R2). Completed chemotherapy was defined
as 6 courses of platinum‑based monotherapy in early OC
or as platinum‑based combination therapy with paclitaxel
for patients with advanced OC. Pathological review of all
cases was performed by one individual in order to deter- Figure 1. Representative examples of immunostaining (original magnifica-
mine the histological type: In accordance with the current tion, x50; inset, x400). (A) No staining against c‑met in a case of high‑grade
FIGO classification from 2014, all serous OC were classi- serous OC, histological grade 3. (B) Weak staining of c‑met in a case of
high‑grade serous OC, histological grade 3. (C) Moderate staining of c‑met
fied as high‑grade or low‑grade serous OC as suggested by in a case of low‑grade serous OC, histological grade 1. (D) Strong staining of
Malpica et al (18). In contrast, the current FIGO classifica- c‑met in a case of low‑grade serous OC. OC, ovarian cancer.
tion relies on the traditional three‑tier grading system from
1971 for the mucinous, endometrioid, clear‑cell and mixed
subtypes (3‑5). The study was approved by the Research
Ethics Committee of the University Medical Centre Mainz manufacturer's protocols. All series included appropriate
(Mainz, Germany). Informed consent was obtained from all positive (human liver tissues) and negative (distilled water
patients. All specimens were handled according to the ethical used as a substitute for anti-HGF-R antibodies in human
and legal standards. liver tissues) controls with adequate results.
c‑met was assessed using a four‑tier system, as previ-
Immunohistochemistry and evaluation of c‑met staining. ously described by Yamamoto et al for c‑met in OC (13).
Immunohistochemical analyses were performed on 4‑µm Briefly, no discernible staining or background type staining
thick sections according to standard procedures. Serial was considered as negative (score of 0); definite cytoplasmic
sections of FFPE tumor tissues were stained with polyclonal staining and/or equivocal discontinuous membrane staining
anti‑HGF R/c‑met goat anti‑human antibodies (catalog scored 1+; unequivocal membrane staining with mild to
no. AF276; R&D Systems GmbH, Wiesbaden, Germany). moderate intensity scored 2+; and strong and complete
The immunoreaction was visualized using Histofine ® membrane staining scored 3+ (Fig. 1). c‑met was assessed
Simple Stain MAX peroxidase anti‑goat antibody (catalog as 2+ or 3+ only if at least 10% of the tumor cells showed
no. 414162F; Medac, Tornesch, Germany). Immunohisto- complete membrane staining (13). A score of 2+ or 3+ was
chemistry assays were performed in accordance with the defined as c‑met overexpression in accordance to the criteria
 ONCOLOGY LETTERS 12: 2001-2007, 2016 2003

Table I. Patient characteristics (n=106).

Parameter Value

Age, years
Mean (±SD) 59.08 (±12.60)
Interquartile range 51.44‑70.36
Tumor stage (FIGO), n (%)
I 22 (20.8)
II 6 (5.7)
III 63 (59.4)
IV 15 (14.2)
Histological grade, n (%)a
G1 3 (12.5)
G2 11 (45.8)
G3 10 (41.7)
Histological type, n (%) Figure 2. Overexpression of c‑met with regard to clinicopathological factors.
Age is categorized by the mean; tumor stage is classified in accordance to
Type I 48 (45.3) FIGO criteria and is categorized into stage I, II, III and IV; histological grade
Type II 58 (54.7) is categorized into grade I, II and III and is provided only for non‑serous
Serous 82 (77.4) OC (n=24); histological type is categorized into type I and type II OC;
post‑operative residual tumor burden is categorized into R0 (defined as no
High‑grade serous 58 (54.7)
post‑operative tumor burden), R1 (defined as tumor burden <2 cm) and R2
Low‑grade serous 24 (22.6) (defined as tumor burden >2 cm); and completeness of chemotherapy is
Mucinous 14 (13.2) categorized into completed and not completed. Table III contains the values
of c‑met overexpression. FIGO, International Federation of Gynecology and
Endometrioid 5 (4.7)
Obstetrics.
Clear cell 2 (1.9)
Mixed 3 (2.8)
Post‑operative residual tumor burden, n (%)
R0 62 (58.5) presented in absolute and relative numbers or as the median
R1 33 (31.1) and quartiles. Comparison between clinicopathological
R2 11 (10.4) factors and the overexpression of c‑met was calculated using
the χ2 test. The Cox proportional hazard regression model
Chemotherapy, n (%)
was used to evaluate the effect of investigative variables on
Complete 82 (77.4) progression‑free survival (PFS) and disease‑specific survival
Incomplete 13 (12.3) (DSS). PFS was defined as the time‑frame between the date
Missing data 11 (10.4) of the first histological proof of OC and the date of the first
Events, n (%) progression. DSS was defined as the time‑frame between the
Relapse 69 (65.1) date of the first histological proof of OC and the date of death
Mortality due to OC 44 (41.5) due to OC. Univariate Cox‑regression analysis was performed
c‑met‑positive 22 (20.8) for every single variable. Variables with a P‑value of <0.05
entered the multivariate Cox‑regression analysis with a vari-
a
n=24, the histological grading is given only for mucinous, endome- able selection via backward elimination. All associations
trioid, clear‑cell and mixed cases in accordance to the current FIGO were reported as hazard ratios (HRs) with 95% confidence
classification. SD, standard deviation; FIGO, International Federation interval (CIs) and P‑values. Kaplan‑Meier estimations were
of Gynecology and Obstetrics; R0, no tumor burden; R1, residual performed to describe survival rates. As this was an investi-
disease <2 cm; R2, residual disease >2 cm; OC, ovarian cancer. gative study, no adjustments for multiple testing were made.
The statistical tests were performed for illustrative purposes
only. P‑values were awarded for descriptive reasons only and
should be interpreted with caution and in connection with
reported by Yamamoto et al (13). The immunohistochemical effect estimates.
evaluation was performed independently by two individuals
trained in histological and immunohistochemical diagnos- Results
tics, who were unaware of the clinical outcome. Slides with
a different assessment were discussed until a consensus was A total of 146 patients were screened. Of these, 8 and
reached. 29 patients were excluded due to missing tissue samples and
incomplete follow‑up information, respectively. A further
Statistical analysis. Statistical analyses were performed 3 patients suffered from an ovarian borderline tumor. There-
using the SPSS statistical software program, version 23.0 fore, 106 patients were enrolled in the study. The median
(IMB SPSS, Armonk, NY, USA). Patient characteristics are follow‑up time was 28.2 months. In this time, 69 (65.1%) cases
2004 BATTISTA et al: c-MET IS OVEREXPRESSED IN TYPE I OVARIAN CANCER

Table II. Patients' characteristics with c‑met positive ovarian cancer.

Post‑operative Completeness Follow‑up + time

Case Expression Age, tumor of after diagnosis,
no. of c‑met years Histotype Grading Stage burden, cm chemotherapy years

1 2+ 47 HGS ‑ I 0 Yes ALI, +6.9

2 2+ 72 HGS ‑ III <2 Yes DOD, +1.2
3 2+ 75 HGS ‑ IV <2 No DOD, +2.4
4 2+ 63 HGS ‑ III <2 Yes AWD, +3.5
5 2+ 66 HGS ‑ III <2 Yes DOD, +8.5
6 2+ 55 LGS ‑ I 0 Yes ALI, +1.4
7 2+ 54 LGS ‑ III >2 Yes DOD, +5.0
8 2+ 65 LGS ‑ III >2 N/A DOD, +4.1
9 2+ 68 LGS ‑ III 0 Yes DOD, +0.4
10 2+ 77 Mucinous 1 III 0 Yes AWD, +1.4
11 2+ 69 Mucinous 2 III 0 Yes DOD, +7.6
12 2+ 48 Mucinous 2 IV <2 Yes ALI, +0.5
13 2+ 36 Mucinous 2 I 0 Yes ALI, +4.1
14 2+ 73 Mucinous 2 I 0 Yes DOD, +1.2
15 2+ 24 Mucinous 2 III 0 Yes AWD, +1.0
16 2+ 40 Mucinous 3 III <2 Yes DOD, +0.5
17 2+ 65 Endometrioid 2 IV <2 N/A DOD, +0.5
18 2+ 40 Endometrioid 2 I 0 Yes ALI, +4.0
19 2+ 48 Clear cell 3 III 0 Yes ALI, +4.0
20 2+ 71 Mixed 3 III >2 Yes DOD, +4.0
21 3+ 52 LGS ‑ I 0 Yes DOD, +4.9
22 3+ 57 Mucinous 2 I 0 Yes ALI, +5.7

HGS, high‑grade serous; LGS, low‑grade serous; ALI, alive; DOD, died of disease; N/A, not available.

A B

Figure 3. Kaplan‑Meier plots of c‑met with regard to (A) progression‑free survival and (B) disease‑specific survival for the entire cohort. The dashed lines
represent the c‑met‑negative patients, whereas the continued lines represent the c‑met‑positive patients.

of recurrence and 44 (41.5%) mortalities due to OC occurred. of 24 (20.8%) cases with low‑grade serous OC showed
A total of 58 (54.7%) patients exhibited high‑grade serous OC, overexpression of c‑met. In total, 17 out of 48 (35.4%) cases
and 48 (45.3%) patients exhibited type I OC. The characteris- displayed overexpression of c‑met among the patients with
tics of the patients are presented in Table I. type I OC, whereas only 5 out of 58 (8.6%) of the cases
Overexpression of c‑met was observed in 22 (20.8%) with type II OC displayed c‑met overexpression (P=0.001)
cases. The characteristics of the patients with overexpres- (Table III and Fig. 2). Overexpression of c‑met was not
sion of c‑met are presented in Table II. It became evident associated with any other clinicopathological features
that 8 out of 14 (57.1%) cases with mucinous OC and 5 out (Table III and Fig. 2).
 ONCOLOGY LETTERS 12: 2001-2007, 2016 2005

Table III. Clinicopathological factors with regard to the overexpression of c‑met.

Clinicopathological factor Negative, n Positive, n (%) P‑valuea

Ageb 0.406
<59.08 41 12 (22.6)
>59.08 43 10 (18.9)
Tumor stage (FIGO) 0.344
I 15 7 (31.8)
II 6 0 (0.0)
III 51 12 (19.0)
IV 12 3 (20.0)
Histological grade (n=24)c 0.122
1 2 1 (33.3)
2 3 8 (72.7)
3 7 3 (30.0)
Histological type 0.001d
b

Type I 31 17 (35.4)
Type II 53 5 (8.6)
Post‑operative residual tumor burden 0.834
R0 50 12 (19.4)
R1 26 7 (21.2)
R2 8 3 (27.3)
Completeness of chemotherapy (n=105) 0.186
b

Yes 12 1 (7.7)
No 63 19 (23.2)
a
Using Pearson's chi‑squared test. bUsing Fisher's Exact test. cn=24, the histological grading is given only for mucinous, endometrioid, clear‑cell
and mixed cases in accordance to the current FIGO classification dP<0.05. FIGO, International Federation of Gynecology and Obstetrics; R0,
no tumor burden; R1, residual disease <2 cm; R2, residual disease >2 cm.

According to univariate Cox‑regression analysis, c‑met was The study results support the hypothesis that the overex-
not associated with PFS or DSS (P=0.835 and 0.414, respec- pression of c‑met is involved in the carcinogenesis of type
tively) (Table IV). According to multivariate Cox‑regression I OC. This may be due to the fact that c‑met is involved in
analysis, only tumor stage and post‑operative tumor burden cross‑talks with several pathways, such as RAS‑MAPK and
retained significance in terms of PFS (P= 0.001 and P<0.001, PI3K‑AKT (7,9), known to impact the development of type I
respectively), with HRs of 1.608 (95% CI, 1.210‑2.138) and OC subtypes (3‑5).
1.915 (95% CI, 1.345‑2.728), respectively. In terms of DSS, Results of studies by Yamamoto et al (13) and
post‑operative tumor burden and completeness of chemo- Sawada et al (14) are in agreement with the present study obser-
therapy retained their significance (P= 0.003 and P= 0.012, vations. To the best of our knowledge, Yamamoto et al (13)
respectively), with HRs of 2.077 (95% CI, 1.284‑3.360) and reported the largest study of c‑met overexpression in
0.321 (95% CI, 0.133‑0.776), respectively (Table IV). Accord- non‑serous OC: In a consecutive cohort of 201 OC patients, a
ingly, Kaplan‑Meier plots failed to demonstrate an effect of large subset of 90 patients exhibited clear‑cell OC. Not unex-
c‑met, with no significant difference between c‑met‑positive pectedly, the reported c‑met protein levels were comparable
and c‑met‑negative cases, respectively, in terms of 5‑year with the present study results: C‑met overexpression was
PFS rate (24.2 vs. 32.5%, P=0.938) and 5‑year DSS rate detected in 22% of clear‑cell OC but not in any non‑clear
(54.8 vs. 29.9%, P=0.412) (Fig. 3A and B). Furthermore, cell OC, and copy number alterations were detectable in
c‑met expression did not alter the 5‑year PFS and DSS rates 24% of the clear cell OC and in 3% of the non‑clear cell
among any subgroups, including the high‑grade serous OC OC, respectively (13). In 2007, Sawada et al (14) published
or non‑high‑grade serous OC groups (data not shown). the results of c‑met overexpression in a cohort of 138 OC
patients. Within this cohort, 82.6% patients exhibited
Discussion serous OC and 69.6% exhibited poorly‑differentiated OC.
Comparable with the present results, the study reported
To the best of our knowledge, the present study reports for c‑met overexpression in only 11% of cases (15/138). Notably,
the first time that the overexpression of c‑met is significantly a higher proportion of patients with mucinous and clear
associated with type I OC in comparison with type II OC. cell OC showed overexpression of c‑met (3/10 and 1/3,
2006 BATTISTA et al: c-MET IS OVEREXPRESSED IN TYPE I OVARIAN CANCER

Table IV. Univariate and multivariate Cox‑regression analysis for progression‑free and disease‑specific survival.

A, Progression‑free survival

Univariate Multivariate
‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
Parameter HR (95% CI) P‑value HR (95% CI) P‑value

Age, years 0.730 (0.455‑1.172) 0.192 ‑

Tumor stage (FIGO) 1.825 (1.406‑2.368) <0.001a 1.608 (1.210‑2.138) 0.001a
Histological grade 1.518 (0.482‑4.782) 0.476 ‑
Histological type 0.692 (0.423‑1.132) 0.142 ‑
Post‑operative residual tumor burden 2.420 (1.744‑3.358) <0.001a 1.915 (1.345‑2.728) <0.001a
Completeness of chemotherapy 0.547 (0.278‑1.077) 0.081 ‑
c‑met 0.938 (0.511‑1.719) 0.835 ‑

B, Disease‑specific survival

Univariate Multivariate
‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
Parameter HR (95% CI) P‑value HR (95% CI) P‑value

Age, years 0.569 (0.311‑1.040) 0.067 ‑

Tumor stage (FIGO) 1.986 (1.387‑2.843) <0.001a 1.396 (0.898‑2.170) 0.138
Histological grade 1.251 (0.329‑4.764) 0.742 ‑
Histological type 1.002 (0.551‑1.821) 0.996 ‑
Post‑operative residual tumor burden 2.135 (1.440‑3.168) <0.001a 2.077 (1.284‑3.360) 0.003a
Completeness of chemotherapy 0.312 (0.141‑0.688) 0.004a 0.321 (0.133‑0.776) 0.012a
c‑met 1.330 (0671‑2.637) 0.414 ‑

P<0.05. FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; CI, confidence interval.
a

respectively) (14). However, potential limitations of these of c‑met in the entire cohort or in the subset of non‑clear cell
two studies result from the fact that no further differentiation OC in terms of PFS (13). Sawada et al (14) showed an inde-
between high‑grade and low‑grade serous OC was performed. pendent impaired effect of c‑met overexpression in terms of
Furthermore, the latter study had only a small proportion of overall survival (P=0.005), but not in terms of PFS. Within
patients with non‑serous OC. By contrast, Goode et al (15) this cohort, a notably high rate of 82.6% of serous OC cases
reported a notably high rate of 97.8% for c‑met overexpres- and a high rate of 69.6% of histological poorly‑differentiated
sion in a cohort of >320 consecutive OC patients (moderate OC patients were included (14). Arguably, potential limita-
staining in 38.9% and strong staining in 58.9% of the entire tions of these two studies arise from the fact that no further
cohort). However, no further differentiation into the various differentiation between high‑grade and low‑grade serous OC
histological subtypes of OC was provided. In summary, the was performed and that the number of patients presenting
available literature on the pattern of expression of c‑met in with non‑serous OC was notably low or was not reported.
OC is partially contradictory (13‑15). Overall, in the present study, the prognostic effect of
The present study performed Cox‑regression analyses the post‑operative tumor burden, the tumor stage and the
and Kaplan‑Meier estimations to investigate the potential completeness of chemotherapy, as well as the low rate of
prognostic impact of c‑met. According to the data, overex- c‑met positive cases, are in line with the published literature.
pression of c‑met failed to exhibit any prognostic impact in However, limitations result from the retrospective design of
the entire cohort, as well as in the subsets of type I or type II the study. In order to reduce a bias resulting from incomplete
OC, respectively. In line with this analysis, Goode et al (15) follow‑up, patients with incomplete follow‑up were excluded
were not able to detect an association of genotype, protein from the study.
expression and mortality within a consecutive cohort of In conclusion, to the best of our knowledge, the present
>320 patients. Conversely, Yamamoto et al (13) reported an study shows for the first time that c‑met was predominantly
independent negative prognostic effect of c‑met, as evaluated overexpressed in type I OC, supporting the hypothesis that
by immunohistochemistry, on overall survival in the subset of c‑met has a role in the development of type I OC. However,
clear cell carcinoma (P=0.018). Supporting the present results, c‑met overexpression was not associated with prognosis in this
the study failed to demonstrate any further prognostic impact disease.
 ONCOLOGY LETTERS 12: 2001-2007, 2016 2007

Acknowledgements  9. Birchmeier C, Birchmeier W, Gherardi E and Vande Woude GF:

Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:
915‑925, 2003.
The abstract was presented at the Annual Meeting of 10. Lai  AZ, Abella  JV and Park  M: Crosstalk in Met receptor
Deutsche Krebsgesellschaft Feb 2016 in Berlin and published oncogenesis. Trends Cell Biol 19: 542‑551, 2009.
11. Trusolino L, Bertotti A and Comoglio PM: MET signalling:
as abstract no. 0194 in Oncol Res Treat (Suppl 1): 2016. This Principles and functions in development, organ regeneration
study was supported in part by a grant from the University and cancer. Nat Rev Mol Cell Biol 11: 834‑848, 2010.
of Heidelberg (Heidelberg, Germany; grant no. 20080715). 12. Buckanovich R, Berger R, Sella A, Sikic B, Shen X, Ramies D,
Smith DC and Vergote IB: Activity of cabozantinib (XL184)
The authors would like to thank Ms. Susanne Gebhard and in advanced ovarian cancer patients (pts): Results from a phase
Ms. Martina Seehase (Department of Gynecology and Obstet- II randomized discontinuation trial (RDT). J Clin Oncol 29
rics, University Medical Center Mainz, Mainz, Germany) for (suppl): abstract 5008, 2011.
13. Yamamoto  S, Tsuda  H, Miyai  K, Takano  M, Tamai  S and
providing technical assistance and support in data manage- Matsubara O: Gene amplification and protein overexpression
ment. of MET are common events in ovarian clear‑cell adenocar-
cinoma: Their roles in tumor progression and prognostication
References of the patient. Mod Pathol 24: 1146‑1155, 2011.
14. Sawada K, Radjabi AR, Shinomiya N, Kistner E, Kenny H,
Becker  AR, Turkyilmaz MA, Salgia R, Yamada SD, Vande
 1. Siegel R, Ma J, Zou Z and Jemal A: Cancer Statistics, 2014. CA Woude GF, et al: c‑Met overexpression is a prognostic factor
Cancer J Clin 64: 9‑29, 2014. in ovarian cancer and an effective target for inhibition of peri-
 2. Piek JM, Kenemans P and Verheijen RH: Intraperitoneal serous toneal dissemination and invasion. Cancer Res 67: 1670‑1679,
adenocarcinoma: A critical appraisal of three hypotheses on its 2007.
cause. Am J Obstet Gynecol 191: 718‑732, 2004. 15. Goode  EL, Chenevix‑Trench  G, Hartmann  LC, Fridley  BL,
 3. Levanon K, Crum C and Drapkin R: New insights into the patho- Kalli KR, Vierkant RA, Larson MC, White KL, Keeney GL,
genesis of serous ovarian cancer and its clinical impact. J Clin Oberg TN, et al: Assessment of hepatocyte growth factor
Oncol 26: 5284‑5293, 2008. in ovarian cancer mortality. Cancer Epidemiol Biomarkers
 4. Kurman RJ: Origin and molecular pathogenesis of ovarian high‑grade Prev 20: 1638‑1648, 2011.
serous carcinoma. Ann Oncol 24 (Suppl 10): x16‑x21, 2013. 16. Battista  MJ, Mantai  N, Sicking  I, Cotarelo  C, Weyer  V,
 5. Landen  CN Jr, Birrer  MJ and Sood  AK: Early events in the Lebrecht  A, Solbach C and Schmidt M: Ki‑67 as an inde-
pathogenesis of epithelial ovarian cancer. J Clin Oncol  26: pendent prognostic factor in an unselected cohort of patients
995‑1005, 2008. with ovarian cancer: Results of an explorative, retrospective
 6. Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, study. Oncol Rep 31: 2213‑2219, 2014.
Sharma R, Stewart C, Fereday S, Caldas C, Defazio A, et al: 17. Battista MJ, Cotarelo C, Jakobi S, Steetskamp J, Makris G,
Driver mutations in TP53 are ubiquitous in high grade serous Sicking I, Weyer V and Schmidt M: Overexpression of epithelial
carcinoma of the ovary. J Pathol 221: 49‑56, 2010. cell adhesion molecule protein is associated with favorable
 7. Gherardi E, Birchmeier W, Birchmeier C and Vande Woude G: prognosis in an unselected cohort of ovarian cancer patients.
Targeting MET in cancer: Rationale and progress. Nat Rev J Cancer Res Clin Oncol 140: 1097‑1102, 2014.
Cancer 12: 89‑103, 2012. 18. Malpica A, Deavers MT, Lu K, Bodurka DC, Atkinson EN,
 8. Ma PC, Tretiakova MS, Mackinnon AC, Ramnath N, Johnson C, Gershenson  DM and Silva EG: Grading ovarian serous
Dietrich  S, Seiwert  T, Christensen JG, Jagadeeswaran R, carcinoma using a two‑tier system. Am J Surg Pathol  28:
Krausz T, et al: Expression and mutational analysis of MET in human 496‑504, 2004.
solid cancers. Genes Chromosomes Cancer 47: 1025‑1037, 2008.