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Abramson Cancer CenterNCI CANCERLIT® Search: Hereditary Ovarian Cancer - March 2002
National Cancer Institute®
Last Modified: March 1, 2002
Table of Contents
1
UI - 11805588
AU - Vachon CM; Mink PJ; Janney CA; Sellers TA; Cerhan JR; Hartmann L; Folsom
TI -
AR
Association of parity and ovarian cancer risk by family history of
breast or ovarian cancer in a population-based study of postmenopausal
women.
SO - Epidemiology 2002 Jan;13(1):66-71
AD - Department of Health Sciences Research, Mayo Clinic and Mayo Foundation,
Rochester, MN 55905, USA. vachon@mayo.edu
Although parity is associated with a decreased risk of ovarian cancer in
the general population, this association among women with a family
history is less clear. We examined this question in a prospective cohort
of 31,377 Iowa women 55-69 years of age at baseline. Relative risks
(RRs) and 95% confidence intervals (CIs) were estimated through Cox
regression. We identified 181 incident epithelial ovarian cancers
through 13 years of follow-up. At baseline, 14% of the women reported
breast or ovarian cancer in a first-degree relative, and an additional
12% reported a family history in a second-degree relative. Among women
without a family history of breast or ovarian cancer in a first-degree
relative, nulliparous women were at slightly increased risk of ovarian
cancer (RR = 1.4, 95% CI = 0.9-2.4) compared with parous women, whereas
among women with a family history, nulliparous women were at a much
higher risk (RR = 2.7, 95% CI = 1.1-6.6) than parous women. Similar
results were seen when family history included first- or second-degree
relatives with breast or ovarian cancer or a first- or second-degree
relative with ovarian cancer only. Nulliparity may be more strongly
associated with an increased risk of ovarian cancer among women with a
family history of breast or ovarian cancer, compared with women who do
not have a family history of those cancers.
2
UI - 11793480
AU - Tereschenko IV; Basham VM; Ponder BA; Pharoah PD
TI -
BRCA1 and BRCA2 mutations in Russian familial breast cancer.
SO - Hum Mutat 2002 Feb;19(2):184
AD - Department of Prevention, Cancer Research Institute, Tomsk Scientific
Centre, Tomsk, Russia. tivru@yahoo.com
We have screened index cases from 25 Russian breast/ovarian cancer
families for germ-line mutations in all coding exons of the BRCA1 and
BRCA2 genes, using multiplex heteroduplex analysis. In addition we
tested 22 patients with breast cancer diagnosed before age 40 without
family history and 6 patients with bilateral breast cancer. The
frequency of families with germline mutations in BRCA was 16% (4/25).
One BRCA1 mutation, 5382insC, was found in three families. The results
of present study, and those of a separate study of 19 breast-ovarian
cancer families, suggest that BRCA1 5382insC is a founder mutation in
the Russian population. Three BRCA2 mutations were found in patients
with breast cancer without family history: two in young patients and one
in patients with bilateral breast cancer. Four novel BRCA2 mutations
were identified: three frameshift (695insT, 1528del4, 9318del4) and one
nonsense (S1099X). Copyright 2002 Wiley-Liss, Inc.
3
UI - 11748848
AU - Machackova E; Damborsky J; Valik D; Foretova L
TI -
Novel germline BRCA1 and BRCA2 mutations in breast and breast/ovarian
cancer families from the Czech Republic.
SO - Hum Mutat 2001 Dec;18(6):545
AD - Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer
Institute, Zluty kopec 7, Brno 656 53, Czech Republic.
Germline mutations in breast cancer susceptibility genes, BRCA1 and
BRCA2, are responsible for a substantial proportion of high-risk breast
and breast/ovarian cancer families. To characterize the spectrum of
BRCA1 and BRCA2 mutations, we screened Czech families with
breast/ovarian cancer using the non-radioactive protein truncation test,
heteroduplex analysis and direct sequencing. In a group of 100 high-risk
breast and breast/ovarian cancer families, four novel frame shift
mutations were identified in BRCA1 and BRCA2 genes. In BRCA1, two novel
frame shift mutations were identified as 3761-3762delGA and
2616-2617ins10; in BRCA2, two novel frame shift mutations were
identified as 5073-5074delCT and 6866delC. Furthermore, a novel missense
substitution M18K in BRCA1 gene in a breast/ovarian cancer family was
identified which lies adjacent just upstream of the most highly
conserved C3HC4 RING zinc finger motif. To examine the tertiary
structure of the RING zinc finger domain and possible effects of M18K
substitution on its stability, we used threading techniques according to
the crystal structure of RAG1 dimerization domain of the DNA-binding
protein. Copyright 2000 Wiley-Liss, Inc.
4
UI - 11773283
AU - Geisler JP; Hatterman-Zogg MA; Rathe JA; Buller RE
TI -
Frequency of BRCA1 dysfunction in ovarian cancer.
SO - J Natl Cancer Inst 2002 Jan 2;94(1):61-7
AD - Division of Gynecologic Oncology, Department of Obstetrics and
Gynecology, Holden Comprehensive Cancer Center, University of Iowa, Iowa
City 52242, USA.
BACKGROUND: Ovarian cancer is one of the most common hereditary cancers
in women. Mutations in the BRCA1 gene increase a woman's risk of ovarian
cancer. Testing for BRCA1 mutations is cumbersome and impractical for
large populations. Therefore, we developed an efficient strategy to
detect various types of BRCA1 dysfunction and also determined the
relative frequency of BRCA1 dysfunction in ovarian cancer. METHODS:
Tumors from 221 patients with epithelial ovarian cancer were screened
for loss of heterozygosity (LOH) at the BRCA1 locus. BRCA1 complementary
DNA (cDNA) and genomic DNA from all cancers with BRCA1 LOH (106 tumors)
or noninformative status (15 tumors) were polymerase chain reaction
(PCR) amplified and analyzed for protein truncation in a coupled
transcription/translation test. When truncated BRCA1 protein was
detected, the BRCA1 gene from both the tumor and a paired blood sample
was sequenced. When BRCA1 expression in tumor cDNA was not detected with
a protein truncation test, a methylation-specific PCR was used to
determine whether the promoter region of BRCA1 was methylated and thus
inactivated. All statistical tests were two-sided. RESULTS: Fifty-one
(23.1%) of 221 tumors had BRCA1 dysfunction, including 18 with germline
mutations, 15 with somatic mutations, and 18 with monoallelic or
biallelic hypermethylated promoters. By the consideration of only tumors
with LOH or that were noninformative, the efficiency for detecting BRCA1
dysfunction improved to 45 (37.2%) of 121 tumors. Therefore,
LOH/noninformative was a strong predictor of mutation status (Fisher's
exact test, P<.001). However, this subset of tumors did not include
those with BRCA1 missense mutations (estimated at six [2.7%] of 221 not
detected by our method) or biallelic promoter methylation (estimated at
six [2.7%] of 221). CONCLUSIONS: BRCA1 dysfunction in ovarian cancer is
common and occurs via multiple mechanisms. The use of LOH, rather than a
family history of ovarian cancer, as a first step in a screening
strategy, followed by protein truncation testing, appears to increase
the chance of identifying tumors with BRCA1 dysfunction.
5
UI - 11832208
AU - Venkitaraman AR
TI -
Cancer susceptibility and the functions of BRCA1 and BRCA2.
SO - Cell 2002 Jan 25;108(2):171-82
AD - University of Cambridge, CRC Department of Oncology, Hutchison/MRC
Research Centre, Hills Road, Cambridge CB2 2XZ, United Kingdom.
arv22@cam.ac.uk
Inherited mutations in BRCA1 or BRCA2 predispose to breast, ovarian, and
other cancers. Their ubiquitously expressed protein products are
implicated in processes fundamental to all cells, including DNA repair
and recombination, checkpoint control of cell cycle, and transcription.
Here, I examine what is known about the biological functions of the BRCA
proteins and ask how their disruption can induce susceptibility to
specific types of cancer.
6
UI - 11857010
AU - Bish A; Sutton S; Jacobs C; Levene S; Ramirez A; Hodgson S
TI -
Changes in psychological distress after cancer genetic counselling: a
comparison of affected and unaffected women.
SO - Br J Cancer 2002 Jan 7;86(1):43-50
AD - Department of Clinical Genetics, Guy's Hospital, St Thomas's Street,
London SE1 9RT, UK. alison.bish@kcl.ac.uk
This study sought to examine changes in psychological distress following
cancer genetic counselling. Women attending a family cancer clinic
completed questionnaires before their appointment and at 2 weeks, 6
months and 12 months after their appointment. Twenty-six women were at
low risk of developing breast or ovarian cancer, 76 were at moderate
risk, 46 were at high risk and 46 women had previously had breast or
ovarian cancer. All groups were compared with regard to measures of
anxiety, depression, general psychological distress, worry about
developing breast and ovarian cancer, and perceived risk of developing
breast/ovarian cancer and perceived likelihood of carrying a genetic
mutation. General psychological distress did not change over the course
of the study and the groups did not differ on these measures. Worry
about developing breast cancer and perceptions of the likelihood of
carrying a genetic mutation significantly reduced following genetic
counselling. On the whole women who had already had breast/ovarian
cancer showed more concerns about ovarian cancer and raised perceptions
of risk in comparison with the other groups, indicating the need for
sensitive counselling of such women.
7
UI - 11852993
AU - Pieretti M; Hopenhayn-Rich C; Khattar NH; Cao Y; Huang B; Tucker TC
TI -
Heterogeneity of ovarian cancer: relationships among histological group,
stage of disease, tumor markers, patient characteristics, and survival.
SO - Cancer Invest 2002;20(1):11-23
AD - Department of Pathology and Laboratory Medicine, University of Kentucky
Medical Center, Lexington, USA. mpieretti@usouthal.edu
Epidemiological studies have established associations between various
reproductive factors and risk of ovarian cancer; it has also been
observed that some of these risk factors are only associated with
specific histological subgroups. To investigate the correlation of
genetic alterations with these risk factors, we examined a consecutive
series of 158 ovarian cancer cases treated at the University of Kentucky
(1990-96). Common molecular genetic alterations (LOH on chromosome 17,
P53 alterations, K-RAS mutations), histological and clinical
characteristics of the disease, demographic patient information and
survival were evaluated. These latter data were from the Kentucky Cancer
Registry. Univariate analysis showed higher frequencies of chromosome 17
loss and P53 mutations in tumors of advanced stage and grade, and in
older and post-menopausal women. Non-mucinous tumors were more likely to
be classified as late stage, high-grade cancers, and to have chromosome
17 loss and P53 mutations. Survival analysis indicated that stage was
the only independent significant variable. When stage was the outcome
variable in multiple logistic regression analysis, histology and
chromosome 17 loss were significantly associated with poor survival.
This case-case study provides evidence that ovarian cancers of mucinous
and non-mucinous histology are significantly different with respect to
clinical characteristics, survival and molecular alterations. It also
lends support to the hypothesis that ovarian cancer is a heterogeneous
disease with distinct etiological factors and clinical outcomes, which
may require different approaches to treatment.
8
UI - 11812076
AU - Kigawa J; Sato S; Shimada M; Kanamori Y; Itamochi H; Terakawa N
TI -
Effect of p53 gene transfer and cisplatin in a peritonitis carcinomatosa
model with p53-deficient ovarian cancer cells.
SO - Gynecol Oncol 2002 Feb;84(2):210-5
AD - Department of Obstetrics and Gynecology, Tottori University School of
Medicine, Yonago 683-8504, Japan. kigawa@grape.med.tottori-u.ac.jp
OBJECTIVE: To determine whether combination treatment consisting of p53
gene transfer and cisplatin (CDDP) improves prognosis of ovarian cancer
patients with peritonitis carcinomatosa, we tried this therapy in a
peritonitis carcinomatosa model that we developed. METHODS: A human
ovarian adenocarcinoma cell line, HRA, which has homozygous deletion of
the p53 gene, was used. For p53 gene transfection, we used a recombinant
adenovirus carrying a wild-type p53 gene (AxCAp53). To determine the
efficiency of the recombinant adenovirus to transduce HRA cells, the
cells were infected with AxCALacZ, and the transduced cells were
detected by beta-galactosidase staining. The expression of the p53
protein was monitored by Western blot analysis up to 15 days after
infection of 50 MOI AxCAp53. The combination effect of AxCAp53 and CDDP
was evaluated by 3-(4, 5-dimethelthiazol-2-yl)-2, 5-diphenyltetrazolium
bromide assay. Apoptotic cells were assessed morphologically by staining
with Hoechst 33258. For the peritonitis carcinomatosa model in this
study, we used severe combined immunodeficiency mice with an
intraperitoneal injection of HRA cells. RESULTS: The p53 protein was
expressed at 24 h after infection with AxCAp53 and disappeared on the
14th day. The present in vitro study showed that wild-type p53 gene
transduction significantly enhanced sensitivity to CDDP and the
apoptotic index in HRA cells. A significant survival advantage was
observed in the combination treatment of AxCAp53 and CDDP compared with
single treatments. However, the repetitious treatment did not show
significant survival advantage in the long term. CONCLUSION: The present
study suggests that intraperitoneal treatment with AxCAp53 and CDDP is
potentially useful as an adjuvant therapeutic modality for peritonitis
carcinomatosa, although further study is needed to improve the long-term
survival for those patients. B)2001 Elsevier Science.
9
UI - 11812079
AU - Bao R; Selvakumaran M; Hamilton TC
TI -
Targeted gene therapy of ovarian cancer using an ovarian-specific
promoter.
SO - Gynecol Oncol 2002 Feb;84(2):228-34
AD - Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia,
Pennsylvania 19111, USA.
OBJECTIVES: The "suicide" gene therapy of cancer using promoters such as
cytomegalovirus could cause severe toxicity to normal tissues due to a
lack of specificity of prodrug activation. Therefore, we investigated
gene therapy of ovarian cancer using ovarian-specific promoter (OSP1) to
limit the synthesis of the prodrug activating enzyme HSVtk to ovarian
cancer cells. METHODS: The HSVtk expressing plasmid pOSP1-HSVtk was
created and transfected into an ovarian cancer cell line OVCAR3. The
ganciclovir (GCV) sensitivity of the stable transfectants was evaluated
with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
method. Tissue specificity of this promoter was evaluated by comparing
the sensitivity to GCV between ovarian and nonovarian cancer cell lines
after they were transfected with pOSP1-HSVtk. One transfectant sensitive
to GCV was implanted intraperitoneally to immunocompromised mice which
were treated subsequently with GCV. Furthermore, this ovarian cancer
survival model was used to evaluate the in vivo efficacy of cationic
lipid mediated pOSP1-HSVtk gene delivery followed by GCV treatment.
RESULTS: Stable transfectants of OVCAR3 cells bearing OSP1-HSVtk became
more sensitive to GCV treatment compared to the parental cell line and
vector transfected OVCAR3 cell line. OSP1-HSVtk could specifically
sensitize the OVCAR3 ovarian cancer cell line to GCV. SCID mice
transplanted with the OVCAR3 transfectant and treated with GCV survived
longer than the mice without GCV treatment (P = 0.032). In vivo gene
delivery mediated by a cationic lipid (GL67) followed by GCV treatment
yielded a longer survival in the OVCAR3 survival model (P = 0.016).
CONCLUSIONS: The OSP1 promoter can selectively direct suicide gene
therapy of ovarian cancer and the in vivo efficacy is improved by using
a cationic lipid GL67 as delivery vehicle as opposed to the direct
injection of plasmid. B)2001 Elsevier Science.
10
UI - 11848480
AU - Walt H; Hornung R; Fink D; Dobler-Girdziunaite D; Stallmach T; Spycher
TI -
MA; Maly F; Haller U; Burki N
Hypercalcemic-type of small cell carcinoma of the ovary:
characterization of a new tumor line.
SO - Anticancer Res 2001 Sep-Oct;21(5):3253-9
AD - Department of Obstetrics and Gynecology, University Hospital, Zurich,
Switzerland. heinrich.walt@fhk.usz.ch
BACKGROUND: The aim of this study was to develop and characterize a
mouse xenograft model for the hypercalcemic-type of small cell carcinoma
of the ovary (HTSCCO). PATIENTS AND METHODS: Tumor fragments were
removed from a patient and cultured in six subsequent generations of
nude mice. Histology, comparative genomic hybridization (CGH), electron
microscopy and serum calcium levels were investigated. RESULTS:
Morphology remained the same from the primary tumor of the patient
through the 6th passage in the mouse. Serum calcium levels were
significantly higher in the tumor-bearing mice compared to controls. CGH
of the HTSCCO did not show evidence of a close relationship to either a
germ cell tumor or an epithelial ovarian cancer. CONCLUSION: Some
evidence was provided that the HTSCCO is an inhomogeneous tumor that is
neither related to a germ cell tumor nor to an epithelial ovarian
cancer, but is a distinct tumor entity.
11
UI - 11848511
AU - Szary J; Kalita K; Przybyszewska M; Dus D; Kieda C; Janik P; Szala S
TI -
KDR promoter can transcriptionally target cytosine deaminase suicide
gene to cancer cells of nonendothelial origin.
SO - Anticancer Res 2001 Sep-Oct;21(5):3471-5
AD - Department of Molecular Biology, Center of Oncology, Maria
Sklodowska-Curie Memorial Institute, Gliwice, Poland.
The KDR/flk-1 gene promoter is considered to be endothelial
cell-specific. We show its activity in two cancer cell lines of
non-endothelial origin: in murine L1 sarcoma and OVP-10 human ovarian
carcinoma cell lines. KDR promoter-driven cytosine deaminase gene can be
efficiently expressed in these cells leading to sensitization to
5-fluorocytosine, as demonstrated both in vitro and in vivo. Our results
indicated that KDR promoter activity is not endothelial cell-exclusive
and that this promoter can also be used to obtain specific expression of
therapeutic genes in certain cancer cells.
12
UI - 11870520
AU - O'Doherty AM; Church SW; Russell SE; Nelson J; Hickey I
TI -
Methylation status of oestrogen receptor-alpha gene promoter sequences
in human ovarian epithelial cell lines.
SO - Br J Cancer 2002 Jan 21;86(2):282-4
AD - School of Biology and Biochemistry, The Queen's University of Belfast,
Lisburn Road, Belfast, Northern Ireland, UK.
We have determined the methylation status of the CpG island of the
oestrogen receptor alpha gene in seven human ovarian cell lines. Cell
lines expressing oestrogen receptor alpha showed no evidence of
hypermethylation. In three of four cell lines that produced no
detectable oestrogen receptor alpha protein, hypermethylation was
observed at the NotI site of the CpG island. These results indicate that
aberrant hypermethylation may be responsible for a significant
proportion of epithelial ovarian tumours in which oestrogen receptor
alpha expression is lost. Copyright 2002 The Cancer Research Campaign
13
UI - 11815406
AU - Bonadona V; Saltel P; Desseigne F; Mignotte H; Saurin JC; Wang Q;
TI -
Sinilnikova O; Giraud S; Freyer G; Plauchu H; Puisieux A; Lasset C
Cancer patients who experienced diagnostic genetic testing for cancer
susceptibility: reactions and behavior after the disclosure of a
positive test result.
SO - Cancer Epidemiol Biomarkers Prev 2002 Jan;11(1):97-104
AD - Unit of Prevention and Genetic Epidemiology, Comprehensive Cancer Center
Leon Berard, 28 rue Laennec, 69008 Lyon, France.
The aim of this prospective study was to evaluate the consequences of
the disclosure of a positive genetic test result to patients affected
with cancer. Personal repercussions and patients' behavior with the
transmission of their results to relatives were considered. We conducted
semistructured interviews with 23 cancer patients identified as carriers
of a cancer-predisposing mutation for hereditary breast ovarian or
nonpolyposis colorectal cancers, 1 month after the disclosure of the
test result. Eight patients spontaneously expressed distressed reactions
("you no longer feel cured"), and 14 patients reported at least one
negative feeling (dissatisfied, discouraged, unhappy, or worried),
despite expecting to be a carrier. Sixteen patients expressed concerns
about the risk of developing another cancer, and 18 were concerned for
their children's future, in that they may carry the mutation and develop
a cancer. Although 8 patients found that disadvantages of knowing their
genetic status outweighed the advantages, all but 1 did not regret
having undergone genetic testing. All of the patients transmitted their
results to at least one close relative. Although 6 of them expressed
difficulties in being the only person who could transmit the information
and 9 said it was a heavy responsibility, all except 1 did not want
someone else to have to inform their families. Our results illustrate
the potential negative impact of diagnostic genetic testing in patients
with cancer. This includes distressed reactions and difficulties in
transmitting their results to relatives. Future large-scale studies are
warranted to confirm our findings.
14
UI - 11772280
AU - Harries M; Kaye SB
TI -
Recent advances in the treatment of epithelial ovarian cancer.
SO - Expert Opin Investig Drugs 2001 Sep;10(9):1715-24
AD - CRC Department of Medical Oncology, The Royal Marsden Hospital, Downs
Road, Sutton, Surrey, SM2 5PT, UK. mark.harries@rmh.nthames.nhs.uk
Ovarian cancer leads to more fatalities than any other form of
gynaecological cancer in North America and Europe. Over the last 30
years survival figures have improved somewhat due to improvements in
diagnosis, surgery and chemotherapy. Despite these advances, the
majority of patients will die from their disease, with the overall
5-year survival being just 30%. The majority of patients with this
disease will require treatment with cytotoxic chemotherapy. It is now
well established that the platinum agents (cisplatin or carboplatin) are
the most important drugs to be included in first-line regimens. More
recently, randomised trials have confirmed the benefit of the addition
of taxanes to platinum-containing regimens and the standard of care has
become the combination of carboplatin and paclitaxel. Several unanswered
questions remain regarding the optimal schedule, the optimum duration of
treatment, possible benefits to be gained from the addition of other
drugs and whether paclitaxel the best taxane. Despite high response
rates to first line chemotherapy, the majority of patients with advanced
ovarian cancer will relapse and will be candidates for further
chemotherapy, which can palliate symptoms and improve survival even in
recurrent disease. For a patient relapsing within six months of
first-line treatment, studies have shown that there is little point in
rechallenge with the same drugs. However, for patients who have a longer
treatment-free interval the response rates to rechallenge with platinum
is significant. A number of drugs have been shown to have activity in
platinum- and taxane-refractory disease and are approved for this and/or
other applications. These include topotecan, etoposide, pegylated
liposomal doxorubicin, epirubicin, gemcitabine, altretamine, oxaliplatin
and vinorelbine. Anti-oestrogens such as tamoxifen have a small but
significant response rate. Recurrent ovarian cancer is a good setting to
test investigational agents and compounds with promising activity
including new platinums and taxoids, as well as a range of new
compounds. Non-cytotoxic approaches that are showing promise include
therapies designed to overcome drug resistance, signal transduction
inhibitors, immunotherapy and gene therapy.
15
UI - 11857368
AU - Rogers PM; Beale PJ; Al-Moundhri M; Boxall F; Patterson L; Valenti M;
TI -
Raynaud F; Hobbs S; Johnston S; Kelland LR
Overexpression of BclXL in a human ovarian carcinoma cell line:
paradoxic effects on chemosensitivity in vitro versus in vivo.
SO - Int J Cancer 2002 Feb 20;97(6):858-63
AD - CRC Centre for Cancer Therapeutics, The Institute of Cancer Research,
Sutton, Surrey, United Kingdom.
The effect of overexpressing the antiapoptotic protein BclXL in a human
ovarian carcinoma cell line has been investigated in terms of
sensitivity to the 2 major drugs used to treat this disease, paclitaxel
and cisplatin. Stable transfection of BclXL into CH1 cells, which are
relatively sensitive to cisplatin, resulted in around 2.7-fold higher
expression in comparison with empty vector controls. However, this level
of overexpression did not result in significant resistance in vitro to
paclitaxel or cisplatin at the 50% inhibition level, using either
short-term (4-day) growth inhibition or longer term colony-forming
assays. By contrast, parallel subcutaneous xenograft models of these
isogenic ovarian carcinoma cells in vivo, differing only in BclXL
status, showed that this low-level BclXL overexpression conferred
significant resistance to both paclitaxel and cisplatin in comparison
with parent, nontransfected tumours. Whereas parent non-BclXL
transfected tumours were highly responsive, with the disappearance of
tumours for at least 50 days post treatment, tumours overexpressing
BclXL grew back after 30 and 20 days after treatment with paclitaxel and
cisplatin, respectively. These differences in responsiveness to
paclitaxel in vivo were not attributable to any significant changes in
the delivery of drug to the tumour. These data suggest that the
responsiveness of ovarian cancer to paclitaxel and cisplatin in vivo,
and therefore perhaps clinically, is influenced by levels of the
antiapoptotic protein BclXL. Such effects may be missed in vitro when
using short-term growth inhibition or clonogenic assays. Copyright 2001
Wiley-Liss, Inc.
16
UI - 11786575
AU - Ben David Y; Chetrit A; Hirsh-Yechezkel G; Friedman E; Beck BD; Beller
TI -
U; Ben-Baruch G; Fishman A; Levavi H; Lubin F; Menczer J; Piura B;
Struewing JP; Modan B; National Israeli Study of Ovarian Cancer
Effect of BRCA mutations on the length of survival in epithelial ovarian
tumors.
SO - J Clin Oncol 2002 Jan 15;20(2):463-6
AD - Department of Gynecology, Haemek Medical Center, Afula.
PURPOSE: To study the role of BRCA mutations in ovarian cancer survival.
PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors
(whenever blood samples were not available) at the time of the primary
surgery were obtained in the course of a nationwide case-control study
of women with ovarian cancer in Israel. The three common BRCA mutations
in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a
multiplex polymerase chain reaction to amplify the exons containing the
three mutations using fluor-labeled primers in a single reaction.
Because each mutation is a small insertion or deletion, they can be
detected as length polymorphisms. Patients were followed for up to 5
years (range, 20 to 64 months). Statistical analysis was performed using
the Kaplan-Meier method and the log-rank test. Stepwise Cox regression
analysis was used for determination of independent prognostic factors.
RESULTS: This report is based on 896 blood or tumor specimens analyzed
for the presence of the BRCA mutations. Of these, 234 women (26.1%) were
found to be positive. A significant difference in survival pattern was
found between BRCA1/BRCA2 carriers and noncarriers among the women with
invasive ovarian cancer (median survival, 53.4 months v. 37.8 months;
3-year survival, 65.8% v. 51.9%, respectively). These differences were
independent of age at diagnosis or stage of the disease. CONCLUSION: Our
data indicate that the survival of patients with ovarian cancer is
affected by BRCA germline mutation, at least in the early years after
diagnosis.
17
UI - 11829379
AU - Leeson S; Iredale R; Stansfield K; Evans A; Gray J
TI -
Developing a cancer genetics service in Wales: opinions of
gynaecologists on the management of women at risk of familial ovarian
cancer.
SO - Eur J Cancer Care (Engl) 2001 Sep;10(3):172-8
AD - Department of Obstetrics and Gynaecology, Ysbyty Gwynedd, North Wales,
UK.
In Wales, a cancer genetics service has been developing since 1998.
Gynaecologists play an integral role in the management of women with a
family history of ovarian cancer and we were interested in investigating
referral practice and management for relatives of patients with ovarian
cancer among gynaecologists in Wales. In 1999, a postal questionnaire
was sent to all gynaecologists. The response rate was 51%. The
questionnaire contained structured questions about current provision and
a number of hypothetical scenarios to explore referral patterns to the
cancer genetics service. The results of this study showed that referrals
varied widely among specialists, as did the numbers who required onward
referral to cancer genetics. The offer of screening to women at high
risk of ovarian cancer was consistent, although there were variations in
how often it was offered and the age at which it was offered. Most
gynaecologists were easily able to establish when it was appropriate to
refer onwards to cancer genetics, differentiating between women at high
or low risk. There was some confusion about women at moderate risk of
ovarian cancer. This study demonstrated the need for clear referral
guidelines in Wales. Guidelines have since been distributed to all
general practitioners and specialists; however, continued monitoring and
further evaluation of referral practices will be necessary.
18
UI - 11844822
AU - Shih HA; Couch FJ; Nathanson KL; Blackwood MA; Rebbeck TR; Armstrong KA;
TI -
Calzone K; Stopfer J; Seal S; Stratton MR; Weber BL
BRCA1 and BRCA2 mutation frequency in women evaluated in a breast cancer
risk evaluation clinic.
SO - J Clin Oncol 2002 Feb 15;20(4):994-9
AD - Abramson Family Cancer Research Institute and Department of
Biostatistics, University of Pennsylvania School of Medicine,
Philadelphia, PA, USA.
PURPOSE: To determine the prevalence of BRCA1 and BRCA2 mutations in
families identified in a breast cancer risk evaluation clinic. PATIENTS
AND METHODS: One hundred sixty-four families seeking breast cancer risk
evaluation were screened for coding region mutations in BRCA1 and BRCA2
by conformation-sensitive gel electrophoresis and DNA sequencing.
RESULTS: Mutations were identified in 37 families (22.6%); 28 (17.1%)
had BRCA1 mutations and nine (5.5%) had BRCA2 mutations. The Ashkenazi
Jewish founder mutations 185delAG and 5382insC (BRCA1) were found in 10
families (6.1%). However, 6174delT (BRCA2) was found in only one family
(0.6%) despite estimates of equal frequency in the Ashkenazi population.
In contrast to other series, the average age of breast cancer diagnosis
was earlier in BRCA2 mutation carriers (32.1 years) than in women with
BRCA1 mutations (37.6 years, P =.028). BRCA1 mutations were detected in
20 (45.5%) of 44 families with ovarian cancer and 12 (75%) of 16
families with both breast and ovarian cancer in a single individual.
Significantly fewer BRCA2 mutations (two [4.5%] of 44) were detected in
families with ovarian cancer (P =.01). Eight families had male breast
cancer; one had a BRCA1 mutation and three had BRCA2 mutations.
CONCLUSION: BRCA1 mutations were three times more prevalent than BRCA2
mutations. Breast cancer diagnosis before 50 years of age, ovarian
cancer, breast and ovarian cancer in a single individual, and male
breast cancer were all significantly more common in families with BRCA1
and BRCA2 mutations, but none of these factors distinguished between
BRCA1 and BRCA2 mutations. Evidence for reduced breast cancer penetrance
associated with the BRCA2 mutation 6174delT was noted.
19
UI - 11855879
AU - Leitao M; Boyd J
TI -
Preoperative CA-125 levels in patients with hereditary compared to
sporadic epithelial ovarian carcinoma.
SO - Gynecol Oncol 2002 Mar;84(3):413-5
AD - Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York,
New York 10021, USA.
OBJECTIVE: The aim of this study was to determine whether a significant
difference in preoperative CA-125 levels exists between patients with
BRCA-associated hereditary ovarian carcinoma and those with sporadic
ovarian carcinoma and whether the CA-125 level predicts the probability
of optimal cytoreductive surgery. METHODS: From a retrospective cohort
of 189 consecutive ovarian cancer patients genotyped for BRCA mutation
status, data on preoperative CA-125 levels were available for 49/88
(56%) hereditary cases and 43/101 (43%) sporadic cases. Data on the
extent of surgical cytoreduction were obtained for all 92 patients with
available CA-125 data. Comparison of preoperative CA-125 levels between
hereditary and sporadic groups was assessed using the Kruskal-Wallis
chi(2) test. Correlation of surgical cytoreduction with preoperative
CA-125 level was assessed using Fisher's exact test. RESULTS: Mean
preoperative CA-125 levels were not significantly different among BRCA1
(2289 U/ml), BRCA2 (2586 U/ml), and sporadic (3307 U/ml) cases (P =
0.5). For hereditary cases, optimal cytoreduction was achieved in 59% of
patients with preoperative CA-125 levels of <500 U/ml and in 52% of
patients with preoperative levels >500 U/ml. For sporadic cases, optimal
cytoreduction was achieved in 62% of patients with CA-125 levels of <500
U/ml and in 20% of patients with levels >500 U/ml (P = 0.01).
CONCLUSIONS: Preoperative CA-125 levels are not significantly different
for patients with hereditary compared to sporadic ovarian carcinoma. The
probability of optimal cytoreduction is independent of the preoperative
CA-125 level for hereditary cases, but optimal cytoreduction is
significantly less likely for sporadic cases with CA-125 levels of >500
U/ml.
20
UI - 11850083
AU - Schmid-Braz AT; Cavalli LR; Cornelio DA; Wuicik L; Ribeiro EM;
TI -
Bleggi-Torres LF; Lima RS; de Andrade Urban C; Haddad BR; Cavalli IJ
Comprehensive cytogenetic evaluation of a mature ovarian teratoma case.
SO - Cancer Genet Cytogenet 2002 Jan 15;132(2):165-8
AD - Departamento de Genetica, Universidade Federal do Parana, Caixa Postal
19071, CEP 81531-970, Curitiba, Parana, Brazil.
Mature ovarian teratomas are benign ovarian germ cell tumors that
usually present with a normal karyotype. There are very few reports
describing chromosomal abnormalities in these tumors, none of which are
recurrent. In this study we report on a mature teratoma case with clonal
chromosomal alterations which include monosomies of chromosomes 6, 14,
16, and 21; trisomies of chromosomes 14 and 21; and deletions of Xq, 5p,
16p, and 17p. Comparative genomic hybridization evaluation of the sample
revealed a normal profile. These findings are discussed together with
the cytogenetic reports on other cases of ovarian teratomas described in
the literature.
21
UI - 11857748
AU - Llort G; Munoz CY; Tuser MP; Guillermo IB; Lluch JR; Bale AE; Franco MA
TI -
Low frequency of recurrent BRCA1 and BRCA2 mutations in Spain.
SO - Hum Mutat 2002 Mar;19(3):307
AD - Unidad de Consejo Genetico. Servicio de Prevencion y Control del Cancer,
Instituto Catalonian National Cancer Institute, Barcelona, Spain.
BRCA1 and BRCA2 mutations underlie a substantial proportion of all
hereditary breast cancer. The mutational spectrum in these genes is very
broad, with hundreds of different BRCA mutations reported worldwide.
However, high frequency founder mutations make up a substantial fraction
of all mutations in some ethnic groups. We directly sequenced BRCA1 and
BRCA2 in 35 Spanish breast/ovarian cancer families and found 13
mutations of which 3 had been reported previously in Spain. The ten
novel mutations are: IVS5+1 G>A, 1491delA, Leu1086Ter, and Gln895Ter in
BRCA1; Glu49Ter, 5373delGTAT, 5947delCTCT, 6672delTA, 8281insA, and
Pro3039Leu (which also involves a splice site) in BRCA2. Our data, in
combination with previous reports, indicate that 14 mutations have been
seen recurrently in Spanish families. Analyzing these 14 mutations in 42
previously untested breast/ovarian cancer families revealed only two
families testing positive, one for BRCA1 185delAG and one for BRCA2
9254delATCAT. While several mutations have been found recurrently in
Spain, none appear to be high frequency founder mutations based on
studies of breast and ovarian cancer families. Copyright 2002
Wiley-Liss, Inc.
22
UI - 11857749
AU - Khoo US; Chan KY; Cheung AN; Xue WC; Shen DH; Fung KY; Ngan HY; Choy KW;
TI -
Pang CP; Poon CS; Poon AY; Ozcelik H
Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: a
founder mutation of BRCA1 identified in the Chinese population.
SO - Hum Mutat 2002 Mar;19(3):307-8
AD - Department of Pathology, Queen Mary Hospital, The University of Hong
Kong, Hong Kong.
Previous mutational analysis for BRCA gene mutations in sporadic ovarian
cancer occurring in Chinese patients in Hong Kong identified six
germline BRCA1 mutations and one germline BRCA2 mutation, six of which
were novel (Khoo et al., 2000). Knowledge of BRCA gene mutations in the
Chinese population is relatively scant. In this study, we focussed on
whether any of these mutations could be recurrent in our Chinese
population, making use of archival paraffin embedded tissue. A
consecutive series of 214 ovarian cancer cases, half of Southern Chinese
origin from Hong Kong whilst the other half of Northern Chinese origin
from Beijing were used for the study. We identified one further novel
mutation, 1081delG, in BRCA1. This was found to occur in two unrelated
individuals with shared haplotype as revealed by allelotype analysis,
thus demonstrating founder effect. Two other recurrent mutations were
also identified, the 2371-2372delTG mutation in BRCA1 and the 3337C>T
mutation in BRCA2 recurring in two and three unrelated individuals
respectively, giving an overall prevalence 4.7% of recurrent BRCA
mutations in ovarian cancer in the Southern Chinese population. Most
importantly, all our recurrent mutation carriers were identified from
Southern Chinese patients from Hong Kong whilst such mutations were
absent in samples from the Northern Chinese. Our findings indicate
possible heterogeneity in the BRCA genotype between Northern and
Southern Chinese. The identification of a founder mutation and two
recurrent mutations moreover, has important implications towards
screening strategies for breast and ovarian cancer among Chinese of
southern ancestral origin who are now dispersed throughout the world.
Copyright 2002 Wiley-Liss, Inc.
23
UI - 11867510
AU - Baxter SW; Choong DY; Eccles DM; Campbell IG
TI -
Transforming growth factor beta receptor 1 polyalanine polymorphism and
exon 5 mutation analysis in breast and ovarian cancer.
SO - Cancer Epidemiol Biomarkers Prev 2002 Feb;11(2):211-4
AD - Cancer Genetics Laboratory, Victorian Breast Cancer Research Consortium,
Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne,
Victoria 3002, Australia.
24
UI - 11715007
AU - Kauff ND; Scheuer L; Robson ME; Glogowski E; Kelly B; Barakat R; Heerdt
TI -
A; Borgen PI; Davis JG; Offit K
Insurance reimbursement for risk-reducing mastectomy and oophorectomy in
women with BRCA1 or BRCA2 mutations.
SO - Genet Med 2001 Nov-Dec;3(6):422-5
AD - Clinical Genetics Service, Department of Medicine, Memorial
Sloan-Kettering Cancer Center, New York, NY 10021, USA.
PURPOSE: Risk-reducing surgery is an important option for women with
BRCA1 and BRCA2 mutations. There are reports in the literature that
insurance reimbursement for these procedures varies greatly. Because
health insurance coverage significantly affects medical decision-making,
current information regarding reimbursement practices of third-party
payers is needed. METHODS: Retrospective study of hospital billing
records of 38 women with documented BRCA1 or BRCA2 mutations who
underwent either a risk-reducing mastectomy or a risk-reducing
oophorectomy between March 1, 1997, and July 30, 2000. RESULTS: Complete
billing and reimbursement information was available for 35 women
undergoing a total of 39 risk-reducing surgeries. A total of 38 of 39
(97%) risk-reducing surgeries were covered in full, less applicable
coinsurance and deductibles. The rate of insurance reimbursement did not
vary with type of insurance, personal history of cancer, or type of
procedure. CONCLUSION: Insurance carriers reimbursed the vast majority
of BRCA mutation carriers undergoing risk-reducing surgery.
25
UI - 11811029
AU - Castex MP; Bertozzi AI; Rubie H; Domenech B; Duchayne E; Selves J;
TI -
Dastugue N; Danjoux M; Kulhein E; Galinier P; Robert A
[Testicular feminization, germinal tumor, NK lymphoma: what is the
relationship?]
SO - Arch Pediatr 2001 Dec;8(12):1337-40
AD - Unite d'hemato-oncologie, hopital des enfants, BP 3119, 31026 Toulouse,
France.
CASE REPORT: The authors report the case of a ten-year-old girl, who had
been treated for a malignant germinal tumour five years before,
presenting with a leukaemia-like syndrome associating bone pain, liver
and spleen nodules and bone marrow involvement. The cyto-pathological
analysis showed undifferentiated cells and CD56 and protein S100 were
found as the only positive markers. The child received several
subsequent lines of chemotherapy and ultimately died of the disease.
COMMENTS: Particular cytogenetic abnormalities were observed (iso1q10,
iso6p10) and were in favor of an unusual NK cell lymphoma. CONCLUSION:
This analysis revealed a XY genotype (testicular feminization syndrome).
26
UI - 11852357
AU - Gancberg D; Scourneau M; Verdebout JM; Larsimont D; Verhest A
TI -
[Detection of extra chromosomes 12 by fluorescent in situ hybridization
(FISH) in ovarian stromal tumors. Study of 12 cases and review of the
literature]
SO - Ann Pathol 2001 Oct;21(5):393-8
AD - Laboratoire d'Anatomie Pathologique, Institut Jules Bordet, 1, rue
Heger-Bordet, 1000 Bruxelles, Belgique, France.
Chromosomic aberrations play a major role in the initiation and the
progression of benign as well as malignant tumors. In particular,
trisomy 12 is frequently observed in female genitourinary tract tumors
and constitutes a recurrent and often unique anomaly in stromal ovarian
tumors such as fibrothecomas. Today, the genetic analysis of fresh or
fixed solid tumors is enabled by the fluorescent in situ hybridization
method (FISH). Using FISH and/or conventional cytogenetics, we analysed
12 ovarian stromal tumors (6 fibromas, 3 fibro thecomas and 3 thecomas).
All of these tumors were benign and trisomy 12 was observed in all
cases. Moreover, 3 cases presented trisomy and tetrasomy for chromosome
12 simultaneously. The high frequency of trisomy 12 in this tumor type
suggests that this abnormality might be implicated in ovarian
tumorigenesis.
27
UI - 11751530
AU - Gregoire L; Rabah R; Schmelz EM; Munkarah A; Roberts PC; Lancaster WD
TI -
Spontaneous malignant transformation of human ovarian surface epithelial
cells in vitro.
SO - Clin Cancer Res 2001 Dec;7(12):4280-7
AD - Department of Immunology and Microbiology, Karmanos Cancer Institute,
Wayne State University School of Medicine, 540 East Canfield Avenue,
Detroit, MI 48201, USA.
PURPOSE: Epithelial ovarian cancer has no reliable marker for early
detection and no known specific premalignant changes. Human ovarian
surface epithelial (HOSE) cells expressing human papillomavirus type 16
(HPV-16) E6/E7 genes undergo crisis, and surviving cells exhibit an
immortalized phenotype. Cells show an increasingly invasive phenotype on
collagen rafts over time. To ascertain the nature of this aberrant
growth, we characterized this spontaneous progression of HOSE cells from
a benign to an invasive phenotype using histopathology,
immunophenotyping, and tumorigenesis assays. EXPERIMENTAL DESIGN: At
various passages, cells were monitored for growth on collagen, response
to tumor necrosis factor alpha and daunorubicin, immunohistochemistry
and Western blot analysis of E-cadherin and beta-catenin, growth in soft
agar, and tumor formation in immunodeficient mice. RESULTS: As passage
number increased, cells became increasingly aggressive on collagen, with
more pronounced focal stratification and invasion. Furthermore,
late-passage cells were more resistant to the apoptotic effects of
TNF-alpha and daunorubicin than earlier-passage cells. E-cadherin
expression was limited to early-passage cells, whereas beta-catenin was
expressed regardless of passage. Cells invading collagen formed colonies
in soft agar at low efficiency but were not tumorigenic in
immunodeficient mice. Some cultures recovered from colonies grew in soft
agar at high efficiencies, and one was tumorigenic. CONCLUSIONS: HOSE
cells expressing E6/E7, over time, develop characteristics of malignant
cells and produce tumors consistent with an ovarian surface epithelium
lineage. Progression of HOSE cells from a benign to an invasive
phenotype in vitro may provide a model to dissect the progression of
ovarian cancer.
28
UI - 11879576
AU - Roberts D; Williams SJ; Cvetkovic D; Weinstein JK; Godwin AK; Johnson
TI -
SW; Hamilton TC
Decreased expression of retinol-binding proteins is associated with
malignant transformation of the ovarian surface epithelium.
SO - DNA Cell Biol 2002 Jan;21(1):11-9
AD - Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia,
Pennsylvania 19111, USA.
We have developed a modified form of suppression subtractive
hybridization (SSH) that allows multiple specimens of distinct
phenotypic groups to be compared for consistent differences in gene
expression. We applied this system to identify genes that were expressed
in normal rat ovarian surface epithelial (ROSE) cells but whose
expression was lost/downregulated in four independently transformed rat
ovarian cancer cell lines. Northern blot analysis using 14 of 28
nonredundant cDNA fragments from this difference library showed that the
mRNA transcripts were present in normal ROSE cells but lost or markedly
downregulated in four related transformed cell lines. Of particular
interest, cellular retinol-binding protein 1 (CRBP1) and retinol-binding
protein (RBP), two genes whose products are involved in retinol
transport and metabolism, were found to be downregulated in this ovarian
cancer model system. To determine if this change had relevance to human
ovarian cancer, we evaluated a series of human ovarian cancer cell lines
and a limited number of frozen human ovarian tumors and found lost or
decreased expression of CRBP1 and RBP relative to expression in human
ovarian surface epithelial (HOSE) cells. We hypothesize that the loss of
CRBP1 and RBP expression disrupts retinol metabolism and retinoic acid
production, which may facilitate the occurrence of genetic damage
leading to the malignant transformation of the ovarian surface
epithelium, the cells from which ovarian cancer arises.
29
UI - 11890988
AU - Sham JS; Tang TC; Fang Y; Sun L; Qin LX; Wu QL; Xie D; Guan XY
TI -
Recurrent chromosome alterations in primary ovarian carcinoma in Chinese
women.
SO - Cancer Genet Cytogenet 2002 Feb;133(1):39-44
AD - Department of Clinical Oncology, The University of Hong Kong, Hong Kong,
China.
Ovarian cancer is one of the most frequent gynecological malignancies
worldwide with a poor prognosis. Comparative genomic hybridiza
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