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Abramson Cancer CenterNCI CANCERLIT® Search: Hereditary Ovarian Cancer - June 2002
National Cancer Institute®
Last Modified: June 1, 2002
- Effect of prevention strategies on survival and quality-adjusted survival of women with BRCA1/2 mutations: an updated decision analysis.
- Adenovirus gene therapy for ovarian cancer.
- In vivo molecular chemotherapy and noninvasive imaging with an infectivity-enhanced adenovirus.
- Tumor classification by partial least squares using microarray gene expression data.
- Contribution of BRCA1 and BRCA2 to familial ovarian cancer: a gynecologic oncology group study.
- Enhancement of the adenoviral sensitivity of human ovarian cancer cells by transient expression of coxsackievirus and adenovirus receptor (CAR).
- Genetic testing for hereditary disease: attending to relational responsibility.
- Nuclear and mitochondrial distribution of organoamidoplatinum(II) lesions in cisplatin-sensitive and -resistant adenocarcinoma cells.
- Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer.
- Molecular events associated with dysplastic morphologic transformation and initiation of ovarian tumorigenicity.
- Tumour suppressor genes in sporadic epithelial ovarian cancer.
- Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer.
- [Hereditary ovarian cancer]
- Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at
- Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial.
- Prophylactic surgery in patients with inherited risk of ovarian cancer.
- BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.
- A molecular blueprint for targeting cancer?
- Loss of heterozygosity at chromosome 3p in epithelial ovarian cancer in China.
- Cancer studies explore targeted therapy, researchers seek new prevention strategies.
- Dominant-negative activity of a Brca1 truncation mutant: effects on proliferation, tumorigenicity in vivo, and chemosensitivity in a mouse
- Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO.
- Resistance to p53-mediated growth suppression in human ovarian cancer cells retain endogenous wild-type p53.
- Altered expression of the DNA repair protein, N-methylpurine-DNA glycosylase (MPG) in human gonads.
- Frequent LOH at hMLH1, a highly variable SNP in hMSH3, and negligible coding instability in ovarian cancer.
- Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred.
- Ovarian sarcoma and acute myelogenous leukaemia.
- Mutation analysis of the CHK2 gene in breast carcinoma and other cancers.
Table of Contents
1
UI - 12011131
AU - Grann VR; Jacobson JS; Thomason D; Hershman D; Heitjan DF; Neugut AI
TI -
Effect of prevention strategies on survival and quality-adjusted
survival of women with BRCA1/2 mutations: an updated decision analysis.
SO - J Clin Oncol 2002 May 15;20(10):2520-9
AD - Herbert Irving Comprehensive Cancer Center, Department of Medicine,
College of Physicians and Surgeons, Columbia University, 630 W 168th
Street, New York, NY 10032, USA.
PURPOSE: This study updates findings regarding the effects of
prophylactic surgery, chemoprevention, and surveillance on the survival
and quality-adjusted survival of women who test positive for BRCA1/2
mutations. MATERIALS AND METHODS: Markov modeling of outcomes was
performed in a simulated cohort of 30-year-old women who tested positive
for BRCA1/2 mutations. The model incorporated breast and ovarian cancer
incidence rates from the literature and mortality rates from the
Surveillance, Epidemiology, and End Results Program. Quality adjustment
of survival estimates were obtained from a survey of women aged 33 to 50
years. Sensitivity analyses were performed of varied assumptions
regarding timing and effects of preventive measures on cancer incidence
and adverse effects. RESULTS: A 30-year-old woman could prolong her
survival beyond that associated with surveillance alone by use of
preventive measures: 1.8 years with tamoxifen, 2.6 years with
prophylactic oophorectomy, 4.6 years with both tamoxifen and
prophylactic oophorectomy, 3.5 years with prophylactic mastectomy, and
4.9 years with both surgeries. She could prolong her quality-adjusted
survival by 2.8 years with tamoxifen, 4.4 years with prophylactic
oophorectomy, 6.3 years with tamoxifen and oophorectomy, and 2.6 years
with mastectomy, or with both surgeries. The benefits of all of these
strategies would decrease if they were initiated at later ages.
CONCLUSION: Women who test positive for BRCA1/2 mutations may derive
greater survival and quality adjusted survival benefits than previously
reported from chemoprevention, prophylactic surgery, or a combination.
Observational studies and clinical trials are needed to verify the
results of this analysis of the long-term benefits of preventive
strategies among BRCA1/2-positive women.
2
UI - 12011212
AU - Russell W
TI -
Adenovirus gene therapy for ovarian cancer.
SO - J Natl Cancer Inst 2002 May 15;94(10):706-7
3
UI - 12011224
AU - Hemminki A; Zinn KR; Liu B; Chaudhuri TR; Desmond RA; Rogers BE; Barnes
TI -
MN; Alvarez RD; Curiel DT
In vivo molecular chemotherapy and noninvasive imaging with an
infectivity-enhanced adenovirus.
SO - J Natl Cancer Inst 2002 May 15;94(10):741-9
AD - Division of Human Gene Therapy and Gene Therapy Center, Department of
Medicine, University of Alabama at Birmingham, 35294-3300, USA.
akseli@uab.edu
BACKGROUND: Adenovirus-based gene therapy is a promising approach to
treat advanced cancers that are resistant to other treatments. However,
many primary cells lack the requisite coxsackie-adenovirus receptor
(CAR), limiting the in vivo efficacy of gene therapy. Recently, a
modified adenovirus that is not dependent on CAR expression for
infectivity was developed. We used noninvasive imaging to investigate
the in vivo antitumor efficacy of gene therapy using this adenovirus in
an animal model of ovarian cancer. METHODS: The adenoviral vectors
RGDTKSSTR (CAR-independent) and AdTKSSTR (CAR-dependent) express herpes
simplex virus thymidine kinase (TK) for molecular chemotherapy and the
human somatostatin receptor subtype 2 (SSTR) for noninvasive nuclear
imaging. Subcutaneous or peritoneal human xenograft ovarian cancers were
established from highly aggressive SKOV3.ip1 cells in immune-deficient
mice. Adenoviral constructs were infected intratumorally or
intraperitoneally once a day for 3 days. Control mice received three
injections, one per day, of Ad5Luc1, a CAR-dependent adenoviral vector
that includes a luciferase marker gene. The somatostatin analogue
(99m)Tc-P2045 was used for noninvasive in vivo imaging of RGDTKSSTR that
was injected into subcutaneous tumors. For mice with peritoneal tumors,
survival was compared among the different treatment groups using
Kaplan-Meier analysis with the log-rank statistic. All statistical tests
were two-sided. RESULTS: Tumor-associated RGDTKSSTR could be detected 15
days after introduction of the vector. In the subcutaneous model, tumors
injected with RGDTKSSTR were statistically significantly smaller than
those injected with AdTKSSTR (P<.001). In the intraperitoneal model,
mice treated with RGDTKSSTR lived longer (survival at day 45 = 63.6%;
95% confidence interval [CI] = 35.2% to 92.0%) than those treated with
AdTKSSTR (survival at day 45 = 0%) or Ad5Luc1 (survival at day 45 =
18.1%; 95% CI = 0.0% to 41.0%). DISCUSSION: RGDTKSSTR shows antitumor
efficacy against ovarian cancer in vivo in animal models. The virus can
be imaged noninvasively and may have the potential to be a useful agent
for treating ovarian cancer.
4
UI - 11836210
AU - Nguyen DV; Rocke DM
TI -
Tumor classification by partial least squares using microarray gene
expression data.
SO - Bioinformatics 2002 Jan;18(1):39-50
AD - Center for Image Processing and Integrated Computing, University of
California, Davis, CA 95616, USA. nguyen@wald.ucdavis.edu
MOTIVATION: One important application of gene expression microarray data
is classification of samples into categories, such as the type of tumor.
The use of microarrays allows simultaneous monitoring of thousands of
genes expressions per sample. This ability to measure gene expression en
masse has resulted in data with the number of variables p(genes) far
exceeding the number of samples N. Standard statistical methodologies in
classification and prediction do not work well or even at all when N <
p. Modification of existing statistical methodologies or development of
new methodologies is needed for the analysis of microarray data.
RESULTS: We propose a novel analysis procedure for classifying
(predicting) human tumor samples based on microarray gene expressions.
This procedure involves dimension reduction using Partial Least Squares
(PLS) and classification using Logistic Discrimination (LD) and
Quadratic Discriminant Analysis (QDA). We compare PLS to the well known
dimension reduction method of Principal Components Analysis (PCA). Under
many circumstances PLS proves superior; we illustrate a condition when
PCA particularly fails to predict well relative to PLS. The proposed
methods were applied to five different microarray data sets involving
various human tumor samples: (1) normal versus ovarian tumor; (2) Acute
Myeloid Leukemia (AML) versus Acute Lymphoblastic Leukemia (ALL); (3)
Diffuse Large B-cell Lymphoma (DLBCLL) versus B-cell Chronic Lymphocytic
Leukemia (BCLL); (4) normal versus colon tumor; and (5)
Non-Small-Cell-Lung-Carcinoma (NSCLC) versus renal samples. Stability of
classification results and methods were further assessed by
re-randomization studies.
5
UI - 11972384
AU - Reedy M; Gallion H; Fowler JM; Kryscio R; Smith SA
TI -
Contribution of BRCA1 and BRCA2 to familial ovarian cancer: a
gynecologic oncology group study.
SO - Gynecol Oncol 2002 May;85(2):255-9
AD - Division of Gynecologic Oncology, University of Kentucky, Lexington, KY
40536, USA.
OBJECTIVES: The aim of the study was to determine the prevalence of
BRCA1 and BRCA2 germline mutations among ovarian cancer patients
ascertained to have a family history of ovarian cancer. METHODS: Ovarian
cancer patients were eligible if they had a family history of cancer
that met any one of the following criteria: (1) a first-degree relative
with ovarian cancer; (2) a second-degree relative with ovarian cancer
plus a first-degree relative with breast cancer (diagnosed younger than
50 years of age); or (3) a first- and a second-degree relative with
breast cancer (diagnosed younger than 50 years of age). The entire
coding sequence of BRCA1 and exon 11 of BRCA2 were screened for germline
alterations by single-strand conformation polymorphism analysis.
RESULTS: Of 26 eligible patients screened for mutations, 12 had
deleterious alterations, 8 in BRCA1 and 4 in BRCA2. A correlation was
noted between the presence of a BRCA1 mutation and the strength of
family history of breast ovarian cancer, with the likelihood of a
mutation increasing with the number of affected relatives (P = 0.0002).
No association was detected between the location of mutations in BRCA1
and the ratio of ovarian cancer cases relative to breast cancer (P =
0.28). CONCLUSIONS: Mutations in BRCA1 or BRCA2 are present in about 50%
of ovarian cancer patients with at least one first-degree relative with
disease, and in 70% of patients with two or more relatives with ovarian
cancer. (c) 2002 Elsevier Science (USA).
6
UI - 11972385
AU - Kim JS; Lee SH; Cho YS; Choi JJ; Kim YH; Lee JH
TI -
Enhancement of the adenoviral sensitivity of human ovarian cancer cells
by transient expression of coxsackievirus and adenovirus receptor (CAR).
SO - Gynecol Oncol 2002 May;85(2):260-5
AD - Clinical Research Center, Samsung Biomedical Research Institute, Seoul
135-710, Korea.
OBJECTIVE: The coxsackievirus and adenovirus receptor (CAR) is known to
be a primary receptor for attachment during adenovirus infection of
target cells and thus is closely related to adenoviral infection
efficiency. To extend this notion to human ovarian cancer, we
investigated the difference in expression levels of CAR in human ovarian
cancer cell lines and whether their adenoviral sensitivities are
enhanced by transient transfection of the CAR gene. METHODS: Adenoviral
infection efficiency was examined by flow cytometry analysis,
beta-galactosidase staining, and beta-galactosidase activity assay.
Expression of the CAR-specific mRNA and protein was analyzed by reverse
transcription polymerase chain reaction and flow cytometry,
respectively. RESULTS: Expression of CAR in human ovarian cancer cell
lines (SKOV3, 2774, PA-1, and OVCAR3) appeared to be correlated with
their susceptibilities to adenovirus-mediated gene delivery. The 2774
and PA-1 cells expressing an easily detectable level of CAR on the cell
surface showed a higher susceptibility to infection with both AdCMVGFP
and AdRSVbetagal than SKOV3 and OVCAR3 cells, both of which had hardly
detectable levels of CAR. Ectopic expression of the CAR gene by
transient transfection of these ovarian cancer cells resulted in a
dramatic increase in their adenoviral sensitivities. CONCLUSION: These
data show that the expression of CAR is closely related to
susceptibility to adenovirus infection in human ovarian cancer cells.
These results indicate that the CAR gene can be a useful tool in
boosting the efficiency of adenoviral vector-mediated gene therapy
against human ovarian cancer. (c) 2002 Elsevier Science (USA).
7
UI - 12026741
AU - Burgess MM; d'Agincourt-Canning L
TI -
Genetic testing for hereditary disease: attending to relational
responsibility.
SO - J Clin Ethics 2001 Winter;12(4):361-72
AD - Centre for Applied Ethics, University of British Columbia, Vancouver,
British Columbia. mburgess@ethics.ubc.ca
8
UI - 11962511
AU - Talarico T; Cullinane CM; Gray PJ; Webster LK; Deacon GB; Phillips DR
TI -
Nuclear and mitochondrial distribution of organoamidoplatinum(II)
lesions in cisplatin-sensitive and -resistant adenocarcinoma cells.
SO - Anticancer Drug Des 2001 Apr-Jun;16(2-3):135-41
AD - Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Fitzroy,
Australia.
The DNA binding pattern of the organoamidoplatinum(II) compound 1a is of
considerable interest because of its known activity against
cisplatin-resistant cells. The activity of 1a appears to be due at least
in part to a greater cellular uptake than cisplatin into
cisplatin-resistant cells, but little is known of the DNA reactions of
the organoamidoplatinum(II) compounds. In this study the level of DNA
cross-linking and total DNA lesions formed by 1 a were measured by
gene-specific Southern hybridization cross-linking assays and by
quantitative PCR in cisplatin-sensitive (2008) and in
cisplatin-resistant 2008/R human adenocarcinoma cell lines. The
surprising result was that the major difference between cisplatin and 1a
was that the number of interstrand cross-links induced by 1a were
approximately 5-fold greater than that induced by cisplatin in the
nuclear (but not mitochondrial) DNA of resistant cells, even though the
total number of lesions were essentially the same in both sensitive and
resistant cells. This result suggests that the extent of interstrand
cross-linking is a critical determinant of the cellular response to 1a
and that the enhanced uptake of 1a into resistant cells results in this
elevated level of cross-linking, leading to good activity of 1a against
cisplatin-resistant cells. It remains unclear as to why 1a exhibits such
selective damage to nuclear DNA, and insight into the molecular aspects
of this selectivity will provide new opportunities for the further
development of new platinum-based agents with activity against
cisplatin-resistant cells.
9
UI - 11979449
AU - Osorio A; de la Hoya M; Rodriguez-Lopez R; Martinez-Ramirez A; Cazorla
TI -
A; Granizo JJ; Esteller M; Rivas C; Caldes T; Benitez J
Loss of heterozygosity analysis at the BRCA loci in tumor samples from
patients with familial breast cancer.
SO - Int J Cancer 2002 May 10;99(2):305-9
AD - Department of Human Genetics, Centro Nacional de Investigaciones
Oncologicas, Madrid, Spain. aosorio@cnio.es
The BRCA1 and BRCA2 genes are responsible for a high proportion of
familial breast cancer; germline mutations in these genes confer a
lifetime risk of about 70% for developing breast cancer. Most of the
described deleterious mutations are small deletions or insertions that
originate a truncated protein; however, in many cases, they are amino
acid changes whose significance is unknown. In these cases, there are
some tests that can analyze the meaning of these variants, but most
remain unclassified. The BRCA genes are tumor suppressors and it is
believed that complete loss of the wild-type allele is a common
mechanism of inactivation in tumors from patients carrying a germline
deleterious mutation in these genes; if this is true, loss of
heterozygosity (LOH) analysis in the tumor sample could help to
distinguish if a rare variant is either a deleterious mutation or a
common polymorphism. In the present study, we performed LOH analysis at
the BRCA loci in 47 tumors from patients who belonged to high-risk
breast cancer families and were carriers of any type of alteration in
these genes. Our results suggest that (i) loss of the wild-type allele
is the most common mechanism of inactivation in tumors from patients who
carry a deleterious mutation in any of the genes, (ii) this loss is not
common when we analyze familial tumors not associated with mutations in
BRCA and (iii) LOH can be used to clarify variants of unknown
significance in the BRCA genes. Copyright 2002 Wiley-Liss, Inc.
10
UI - 12015763
AU - Yang DH; Smith ER; Cohen C; Wu H; Patriotis C; Godwin AK; Hamilton TC;
TI -
Xu XX
Molecular events associated with dysplastic morphologic transformation
and initiation of ovarian tumorigenicity.
SO - Cancer 2002 May 1;94(9):2380-92
AD - Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia,
Pennsylvania 19111, USA.
BACKGROUND: Disabled-2 (Dab2), a candidate tumor suppressor of ovarian
carcinoma, frequently (around 80%) loses its expression in ovarian
tumors. Expression of exogenous Dab2 in tumor cell lines negatively
regulates growth and suppresses the downstream signal of the Ras/mitogen
activated protein kinase mitogenic pathway. The inactivation of Dab2 is
believed to be an early event in ovarian tumorigenicity. METHODS: The
authors analyzed the correlation among expression of Dab2, presence of
basement membrane (collagen IV and laminin), morphologic alteration of
the surface epithelial cells, and expression of the mitotic index marker
Mib-1 in 50 archived ovarian tumors by an immunohistochemical approach.
The stainings of Dab2, Mib-1, collagen IV, and laminin in premalignant
lesions bordering both normal and neoplastic ovarian surface epithelium
from adjacent slides were analyzed in 50 ovarian tumors. RESULTS: In
these 50 ovarian tumors, the percentage of Mib-1 positive tumor cells
distributed in a wide range, from 1% to 75%, and there has no strong
correlation with the expression of Dab2. However, in the premalignant
regions bordering tumor and normal ovarian surface epithelium, the loss
of Dab2 expression closely correlated with the dysplastic morphologic
transition and Mib-1 expression of the ovarian surface epithelial cells.
In 20 foci in 12 out of the 50 tumors, a transition from normal to
neoplastic morphology within a contiguous epithelium was observed, and
in all cases the morphologic change correlated with the loss of Dab2
staining. In addition, the collagen and laminin staining of the basement
membrane were absent or weakened in pre-malignant epithelium prior to
loss of Dab2 expression in all these 20 cases. Nevertheless, collagen IV
and laminin were detectable in established adenomas on the same tumor
slides. CONCLUSIONS: The loss of Dab2 is closely associated with the
transition of ovarian surface epithelial cells to premalignant states
and is likely involved in the initiation of ovarian tumorigenicity.
Transient loss of collagen IV and laminin in the basement membrane of
the premalignant epithelium and subsequent inactivation of Dab2 are
common early events associated with tumorigenicity of the ovarian
surface epithelium. Copyright 2002 American Cancer Society.DOI
10.1002/cncr.10497
11
UI - 11882011
AU - Liu Y; Ganesan TS
TI -
Tumour suppressor genes in sporadic epithelial ovarian cancer.
SO - Reproduction 2002 Mar;123(3):341-53
AD - ICRF Molecular Oncology Laboratories, Institute of Molecular Medicine,
John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Ovarian cancer is the most frequent cause of death from gynaecological
malignancies in the western world, and sporadic epithelial ovarian
cancer is its most predominant form. The aetiology of sporadic ovarian
cancer remains unknown. Genetic studies have enabled a better
understanding of the evolution of tumour progression. A major focus of
research has been to identify tumour suppressor genes implicated in
sporadic ovarian cancer over the past decade. Several tumour suppressor
genes have been identified by strategies such as positional cloning and
differential expression display. Further research is warranted to
understand fully their contribution to the pathogenesis of sporadic
ovarian cancer.
12
UI - 11992549
AU - Kudoh K; Ichikawa Y; Yoshida S; Hirai M; Kikuchi Y; Nagata I; Miwa M;
TI -
Uchida K
Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and
response to chemotherapy in ovarian cancer.
SO - Int J Cancer 2002 Jun 1;99(4):579-82
AD - Department of Obstetrics and Gynecology, Self Defense Force Sendai
Hospital, Miyagi 983-8580, Japan. k2-kudoh@xa2.so-net.ne.jp
To define the involvement of p16/CDKN2 and p15/MTS2 tumor-suppressor
genes for response to chemotherapy in primary epithelial ovarian cancer,
we analyzed alterations of the gene in 45 patients who were treated with
primary cytoreductive surgery followed by 6 courses of
cis-diamminedichloroplatinum (II) (cisplatin)-based combination
chemotherapy. Homozygous deletion of p16/CDKN2 and p15/MTS2 genes was
found in 8 (18%) and 15 (33%) cases, respectively. Response to the
chemotherapy was confirmed by finding at second surgery after the
chemotherapy in 26 patients, resulting in 17 responders and 9
nonresponders. The abundance of gene deletion in nonresponders (56%) was
significantly higher (p = 0.0463) when compared to that in responders
(18%). Moreover, the deletion of genes was a significant poor prognostic
factor (p = 0.0441) in advanced ovarian cancer. These results suggest
that deletion of p16/CDKN2 and/or p15/MTS2 is a potential indicator for
poor chemotherapy response and adverse prognosis in ovarian cancer
patients. Copyright 2002 Wiley-Liss, Inc.
13
UI - 11519321
AU - Trifonov I; Todorova M; Uzunova Zh
TI -
[Hereditary ovarian cancer]
SO - Akush Ginekol (Sofiia) 2001;41 Suppl 4():3-7
14
UI - 11161856
AU - Paley PJ; Swisher EM; Garcia RL; Agoff SN; Greer BE; Peters KL; Goff BA
TI -
Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers
at prophylactic oophorectomy: a case for recommending hysterectomy at
surgical prophylaxis.
SO - Gynecol Oncol 2001 Feb;80(2):176-80
AD - Department of OB/GYN, Division of Gynecologic Oncology, University of
Washington School of Medicine, Seattle, Washington 98195, USA.
OBJECTIVE: BRCA-1 and BRCA-2 germline mutations increase the risk of
ovarian and breast cancer. Primary cancer of the fallopian tube is rare;
however, recent evidence suggests that patients harboring a germline
mutation conferring an increased risk of ovarian cancer may be at risk
for fallopian tube cancer as well. We discuss the finding of occult
fallopian tube cancer diagnosed at surgical prophylaxis in women
harboring BRCA-1 mutations. METHODS/RESULTS: Two patients undergoing
surgical prophylaxis to address an increase in ovarian cancer risk were
discovered to harbor occult primary fallopian tube carcinoma on final
pathology review. Mutational analysis confirmed the presence of a
deleterious mutation in BRCA-1 in both patients. CONCLUSION: Currently,
consensus opinions regarding ovarian cancer surgical prophylaxis in gene
mutation carriers do not include hysterectomy as part of the
preventative procedure. This report as well as a growing number of cases
of fallopian tube cancer reported in known BRCA-1 and BRCA-2 mutation
carriers has important implications for recommendations regarding
surgical prophylaxis in these women.
15
UI - 11454891
AU - Hortobagyi GN; Ueno NT; Xia W; Zhang S; Wolf JK; Putnam JB; Weiden PL;
TI -
Willey JS; Carey M; Branham DL; Payne JY; Tucker SD; Bartholomeusz C;
Kilbourn RG; De Jager RL; Sneige N; Katz RL; Anklesaria P; Ibrahim NK;
Murray JL; Theriault RL; Valero V; Gershenson DM; Bevers MW; Huang L;
Lopez-Berestein G; Hung MC
Cationic liposome-mediated E1A gene transfer to human breast and ovarian
cancer cells and its biologic effects: a phase I clinical trial.
SO - J Clin Oncol 2001 Jul 15;19(14):3422-33
AD - Department of Breast Medical Oncology, The University of Texas M.D.
Anderson Cancer Center, Houston, TX 77030, USA.
ghorto@notes.mdacc.tmc.edu
PURPOSE: Preclinical studies have demonstrated that the adenovirus type
5 E1A gene is associated with antitumor activities by transcriptional
repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene
therapy is known to induce regression of HER-2/neu-overexpressing breast
and ovarian cancers in nude mice. Therefore, we evaluated the
feasibility of intracavitary injection of E1A gene complexed with
DC-Chol cationic liposome (DCC-E1A) in patients with both
HER-2/neu-overexpressing and low HER-2/neu-expressing breast and ovarian
cancers in a phase I clinical trial. PATIENTS AND METHODS: An E1A gene
complexed with DCC-E1A cationic liposome was injected once a week into
the thoracic or peritoneal cavity of 18 patients with advanced cancer of
the breast (n = 6) or ovary (n = 12). RESULTS: E1A gene expression in
tumor cells was detected by immunohistochemical staining and reverse
transcriptase-polymerase chain reaction. This E1A gene expression was
accompanied by HER-2/neu downregulation, increased apoptosis, and
reduced proliferation. The most common treatment-related toxicities were
fever, nausea, vomiting, and/or discomfort at the injection sites.
CONCLUSION: These results argue for the feasibility of intracavitary
DCC-E1A administration, provide a clear proof of preclinical concept,
and warrant phase II trials to determine the antitumor activity of the
E1A gene.
16
UI - 11606116
AU - Morice P; Pautier P; Delaloge S
TI -
Prophylactic surgery in patients with inherited risk of ovarian cancer.
SO - Gynecol Oncol 2001 Nov;83(2):445-7
17
UI - 12039933
AU - Berry DA; Iversen ES Jr; Gudbjartsson DF; Hiller EH; Garber JE; Peshkin
TI -
BN; Lerman C; Watson P; Lynch HT; Hilsenbeck SG; Rubinstein WS; Hughes
KS; Parmigiani G
BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and
prevalence of other breast cancer susceptibility genes.
SO - J Clin Oncol 2002 Jun 1;20(11):2701-12
AD - Department of Biostatistics, University of Texas M.D. Anderson Cancer
Center, Houston, TX 77030-4009, USA. dberry@mdanderson.org
PURPOSE: To compare genetic test results for deleterious mutations of
BRCA1 and BRCA2 with estimated probabilities of carrying such mutations;
to assess sensitivity of genetic testing; and to assess the relevance of
other susceptibility genes in familial breast and ovarian cancer.
PATIENTS AND METHODS: Data analyzed were from six high-risk genetic
counseling clinics and concern individuals from families for which at
least one member was tested for mutations at BRCA1 and BRCA2.
Predictions of genetic predisposition to breast and ovarian cancer for
301 individuals were made using BRCAPRO, a statistical model and
software using Mendelian genetics and Bayesian updating. Model
predictions were compared with the results of genetic testing. RESULTS:
Among the test individuals, 126 were Ashkenazi Jewish, three were male
subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were
unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2
mutations. BRCAPRO performed well: for the 150 probands with the
smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion
testing positive was 32.7%; for the 151 probands with the largest
carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic
testing sensitivity was estimated to be at least 85%, with
false-negatives including mutations of susceptibility genes heretofore
unknown. CONCLUSION: BRCAPRO is an accurate counseling tool for
determining the probability of carrying mutations of BRCA1 and BRCA2.
Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an
estimated 15% of mutations. In the populations studied, breast cancer
susceptibility genes other than BRCA1 and BRCA2 either do not exist, are
rare, or are associated with low disease penetrance.
18
UI - 9916789
AU - Tlsty TD
TI -
A molecular blueprint for targeting cancer?
SO - Nat Genet 1999 Jan;21(1):64-5
19
UI - 11975680
AU - Zhang GL; Xu KL
TI -
Loss of heterozygosity at chromosome 3p in epithelial ovarian cancer in
China.
SO - Int J Gynecol Cancer 2002 Mar-Apr;12(2):198-201
AD - Department of Gynecological Oncology, Shanghai Cancer Hospital, Fu Da
University, Shanghai, China.
The aim of this investigation was to determine the relationship between
3p loss of heterozygosity (LOH) and the pathogenesis of ovarian cancer.
Fifty cases of epithelial ovarian tumor, including 40 cases with
malignant tumors and 10 cases with benign tumors, were examined by
polymerase chain reaction (PCR) with D3s1228 and D3s1038 microsatellite
polymorphism markers at 3p. Thirty-two of the 40 cases (80%) with
ovarian cancer showed LOH at 3p14 or 3p25, but only 1 of 10 cases
(10.0%) with benign ovarian tumor showed 3p LOH. Among them, 24 cases
(60.0%) had LOH at 3p14 and 16 cases (40.0%) at 3p25, as well as 8 cases
(20.0%) with codeletion on both 3p14 and 3p25. According to FIGO
staging, the frequency of LOH at 3p in ovarian cancer patients with
stage IIIa or IIIb was higher than that in patients with stage I or II
(P < 0.05), but there was no relationship between 3p LOH and the
pathologic types in epithelial ovarian cancer (P > 0.05). Since 3p LOH
commonly occurs in epithelial ovarian cancer and LOH at 3p14 and 3p25
correlates to the staging of ovarian cancer, it is suggested that there
are some candidate ovarian TSGs harbored in the 3p region and that the
detection of 3p LOHs may be used as a genetic marker for monitoring the
development of ovarian cancer.
20
UI - 12069652
AU - Stephenson J
TI -
Cancer studies explore targeted therapy, researchers seek new prevention
strategies.
SO - JAMA 2002 Jun 19;287(23):3063-7
21
UI - 11894135
AU - Sylvain V; Lafarge S; Bignon YJ
TI -
Dominant-negative activity of a Brca1 truncation mutant: effects on
proliferation, tumorigenicity in vivo, and chemosensitivity in a mouse
ovarian cancer cell line.
SO - Int J Oncol 2002 Apr;20(4):845-53
AD - Laboratoire d'Oncologie Moleculaire, Centre Jean Perrin, BP 392, 63 011
Clermont-Ferrand Cedex 1, France.
In order to generate an in vitro mouse model for the study of human
ovarian cancers, we compared the effects of a truncated Brca1 mutant
expression on cellular phenotype with those of a full-length sense and
antisense Brca1 expression in the ID-8 mouse epithelial ovarian cancer
cell line. The examined cellular processes include proliferation,
tumorigenicity in syngeneic mice in vivo and sensitivity/resistance to
several cytotoxic drugs. We found that the expression of a spontaneous
truncated Brca1 mutant in ID-8 cells which contain two endogenous
wild-type Brca1 alleles led to a dominant-negative effect of Brca1,
demonstrated by an increase in tumorigenicity in vivo and in
chemosensitivity. Expression of a truncated Brca1 mutant in a mouse
epithelial ovarian cancer cell line could thus provide a powerful in
vitro model for the study of human BRCA1-related ovarian tumorigenesis.
22
UI - 12048272
AU - Euhus DM; Smith KC; Robinson L; Stucky A; Olopade OI; Cummings S; Garber
TI -
JE; Chittenden A; Mills GB; Rieger P; Esserman L; Crawford B; Hughes KS;
Roche CA; Ganz PA; Seldon J; Fabian CJ; Klemp J; Tomlinson G
Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the
computer model BRCAPRO.
SO - J Natl Cancer Inst 2002 Jun 5;94(11):844-51
AD - The University of Texas Southwestern Medical Center at Dallas,
75390-9155, USA. david.euhus@UTSouthwestern.edu
BACKGROUND: Because BRCA gene mutation testing is costly, occasionally
uninformative, and frequently associated with ethical and legal issues,
careful patient selection is required prior to testing. Estimation of
BRCA gene mutation probability is an important component of pretest
counseling, but the accuracy of these estimates is currently unknown. We
measured the performance of eight cancer risk counselors and of a
computer model, BRCAPRO, at identifying families likely to carry a BRCA
gene mutation. METHODS: Eight cancer risk counselors and the computer
model BRCAPRO estimated BRCA gene mutation probabilities for 148
pedigrees selected from an initial sample of 272 pedigrees. The final
sample was limited to pedigrees with a proband affected by breast or
ovarian cancer and BRCA1 and BRCA2 gene sequencing results unequivocally
reported as negative or positive for a deleterious mutation.
Sensitivity, specificity, negative predictive value, positive predictive
value, and areas under receiver operator characteristics (ROC) curves
were calculated for each risk counselor and for BRCAPRO. All statistical
tests were two sided. RESULTS: Using a greater-than-10% BRCA gene
mutation probability threshold, the median sensitivity for identifying
mutation carriers was 94% (range = 81% to 98%) for the eight risk
counselors and 92% (range = 91% to 92%) for BRCAPRO. Median specificity
at this threshold was 16% (range = 6% to 34%) for the risk counselors
and 32% (range = 30% to 34%) for BRCAPRO (P =.04). Median area under the
ROC curves was 0.671 for the risk counselors (range = 0.620 to 0.717)
and 0.712 (range = 0.706 to 0.720) for BRCAPRO (P =.04). There was a
slight, but not statistically significant, improvement in all counselor
performance measures when BRCAPRO-assigned gene mutation probability
information was included with the pedigrees. CONCLUSIONS: Sensitivity
for identifying BRCA gene mutation carriers is similar for experienced
risk counselors and the computer model BRCAPRO. Because the computer
model consistently demonstrated superior specificity, overall
discrimination between BRCA gene mutation carriers and BRCA gene
mutation noncarriers was slightly better for BRCAPRO.
23
UI - 12014634
AU - Jin X; Burke W; Rothman K; Lin J
TI -
Resistance to p53-mediated growth suppression in human ovarian cancer
cells retain endogenous wild-type p53.
SO - Anticancer Res 2002 Mar-Apr;22(2A):659-64
AD - Department of Obstetrics and Gynecology, University of Michigan
Comprehensive Cancer Center, Ann Arbor 48109-0936, USA.
Cancer cells containing mutated p53 are sensitive to the re-introduction
of the wild-type (wt) p53. We sought to determine whether ovarian cancer
cells that retain wt p53 are sensitive to the re-introduction of wt p53.
Our results demonstrated that A2780 and PA-1 cells, which retain wt p53,
are more resistant to apoptosis and growth suppression induced by
exogenous expression of wt p53 than SKOV-3 and Caov-3 cells that contain
mutated p53. All cell lines, except PA-1, showed induction of the
p53-targeted genes. Further, inhibitors of p53-dependent apoptosis, mdm2
and Bcl-xL were not overexpressed in A2780 and PA-1 cells. These results
suggest that one major defect in PA-1 cells is due to abrogation of
induction of the p53-targets which is independent of mdm2 and Bcl-xL.
Although A2780 cells showed induction of the p53-targeted genes, the
cleavage of caspase-9 was undetectable. Therefore, p53-dependent
apoptosis may be blocked upstream or at the caspase-9 level in A2780
cells.
24
UI - 12014652
AU - Kim NK; An HJ; Kim HJ; Sohn TJ; Roy R; Oh D; Ahn JY; Hwang TS; Cha KY
TI -
Altered expression of the DNA repair protein, N-methylpurine-DNA
glycosylase (MPG) in human gonads.
SO - Anticancer Res 2002 Mar-Apr;22(2A):793-8
AD - Department of Biochemistry and Institute for Clinical Research, College
of Medicine, Pochon CHA University, Sungnam, Korea. nkkim@cha.ac.kr
BACKGROUND: The multifunctional mammalian MPG is responsible for a
damaged DNA base in the nucleus. The DNA repair enzyme is transported
from the cytoplasm to nucleus to repair the DNA base when it is damaged.
If the enzyme does not work properly, the damaged DNA may lead to
carcinogenesis, cell death, aging or infertility. MATERIALS AND METHODS:
This study was performed to determine mRNA expression and intracellular
localization of the DNA repair protein, N-methylpurine-DNA glycosylase
(MPG), in human ovary and testicular tissues, particularly in epithelial
ovarian tumor and spermatogenic (maturation) arrest infertile patients,
by RT-PCR and immunohistochemical staining using human MPG monoclonal
antibody. RESULTS: MPG mRNA expression in epithelial ovarian tumor and
spermatogenic arrest testis tissues was slightly higher than in normal
ovarian and testicular tissues, respectively. The present study
demonstrated new and unexpected patterns of cellular and subcellular
localization of this enzyme. In a normal ovary, immunostaining for MPG
was observed in the nucleus of oocyte, granulosa and stromal cells. MPG
was stained mostly in the nucleus and faintly-stained in the cytoplasm
of normal coelomic epithelium as well as in benign epithelial ovarian
tumors. However, the MPG expression of the nucleus in malignant
epithelial tumors, both serous and mucinous type, disappeared. The
spermatocyte and Leydig cells in normal testis were immunostained only
in the cytoplasm. The spermatocyte and Leydig cells in spermatogenic
arrest testis tissues showed up both in the nucleus and cytoplasm. The
subcellular localization of MPG in the tissues tested was heterogeneous,
while the altered MPG expression was found in ovarian tumor and
spermatogenic arrest testis. CONCLUSION: These results suggest MPG's
role in human gonadal tissues and raise the possibility that the altered
mRNA level and intracellular localization could be associated with
ovarian tumorigenesis and male infertility.
25
UI - 12014680
AU - Arzimanoglou II; Hansen LL; Chong D; Li Z; Psaroudi MC; Dimitrakakis C;
TI -
Jacovina AT; Shevchuk M; Reid L; Hajjar KA; Vassilaros S; Michalas S;
Gilbert F; Chervenak FA; Barber HR
Frequent LOH at hMLH1, a highly variable SNP in hMSH3, and negligible
coding instability in ovarian cancer.
SO - Anticancer Res 2002 Mar-Apr;22(2A):969-75
AD - Department of Obstetrics-Gynecology, Weill Medical College of Cornell
University, New York, NY 10021, USA. Arziman@lycosmail.com
BACKGROUND: Molecular alterations such as DNA microsatellite instability
(MSI/RER), single nucleotide polymorphism (SNP) and loss of
heterozygosity (LOH) can occur throughout the genome and be associated
with different types of cancer. In the present study, we aimed at
detecting molecular alterations within the mismatch DNA repair genes in
ovarian cancer (OC), using a sensitive, accurate and reliable protocol
we have developed. MATERIALS AND METHODS: A combination of
high-resolution GeneScan software analysis and automated DNA cycle
sequencing was used. RESULTS: Negligible coding MSI was observed in
selected sequences of mismatch DNA repair genes in our series of
sixty-two ovarian tumors and matched blood DNAs. Unlike MSI, loss of one
hMLH1 allele was scored in almost half (47%) of the informative cases.
In addition, an SNP in hMSH3/intron 5 was found to be highly variable in
OC patients. CONCLUSION: 1) Coding DNA instability is likely to be a
very rare event in OC and, therefore, may not significantly contribute
to the development of OC, and 2) the high frequency of LOH at hMLH1
observed in our ovarian tumors suggests that further investigation is
needed to determine if such a trend exists in other mismatch DNA repair
and/or critical genes.
26
UI - 11968083
AU - Oliveira C; Bordin MC; Grehan N; Huntsman D; Suriano G; Machado JC;
TI -
Kiviluoto T; Aaltonen L; Jackson CE; Seruca R; Caldas C
Screening E-cadherin in gastric cancer families reveals germline
mutations only in hereditary diffuse gastric cancer kindred.
SO - Hum Mutat 2002 May;19(5):510-7
AD - Cancer Genomics Program, Department of Oncology, University of
Cambridge, Hutchison/MRC Research Centre, Addenbrooke's Hospital,
Cambridge, UK.
The International Gastric Cancer Linkage Consortium (IGCLC) predicted
that up to 25% of families fulfilling the criteria for hereditary
diffuse gastric cancer (HDGC) would harbor CDH1 germline mutations. This
was based on observations from the low number of diffuse gastric cancer
families described at the time, and its validation would require
analysis of larger numbers. Here we report the results of germline CDH1
mutation screening in 39 kindred with familial aggregation of gastric
cancer, a subset of which fulfills the criteria defined by the IGCLC for
HDGC. CDH1 germline mutations were detected in four of 11 (36.4%) HDGC
families. No mutations were identified in 63.6% of HDGC families or in
kindred with familial aggregation of gastric cancer not fulfilling
criteria for HDGC. These results add support to the evidence that only
HDGC families harbor germline mutations in CDH1 and that genes other
than CDH1 remain to be identified. Copyright 2002 Wiley-Liss, Inc.
27
UI - 11920281
AU - Lacotte-Thierry L; Thierry A; Brizard F; Delwail V; Sadoun A; Guilhot F;
TI -
Brizard A
Ovarian sarcoma and acute myelogenous leukaemia.
SO - Hematol J 2001;2(6):404-5
28
UI - 12052256
AU - Ingvarsson S; Sigbjornsdottir BI; Huiping C; Hafsteinsdottir SH;
TI -
Ragnarsson G; Barkardottir RB; Arason A; Egilsson V; Bergthorsson JT
Mutation analysis of the CHK2 gene in breast carcinoma and other
cancers.
SO - Breast Cancer Res 2002;4(3):R4
AD - Institute for Experimental Pathology, University of Iceland, Reykjavik,
Iceland. siguring@hi.is
BACKGROUND: Mutations in the CHK2 gene at chromosome 22q12.1 have been
reported in families with Li-Fraumeni syndrome. Chk2 is an effector
kinase that is activated in response to DNA damage and is involved in
cell-cycle pathways and p53 pathways. METHODS: We screened 139 breast
tumors for loss of heterozygosity at chromosome 22q, using seven
microsatellite markers, and screened 119 breast tumors with
single-strand conformation polymorphism and DNA sequencing for mutations
in the CHK2 gene. RESULTS: Seventy-four of 139 sporadic breast tumors
(53%) show loss of heterozygosity with at least one marker. These
samples and 45 tumors from individuals carrying the BRCA2 999del5
mutation were screened for mutations in the CHK2 gene. In addition to
putative polymorphic regions in short mononucleotide repeats in a
non-coding exon and intron 2, a germ line variant (T59K) in the first
coding exon was detected. On screening 1172 cancer patients for the T59K
sequence variant, it was detected in a total of four breast-cancer
patients, two colon-cancer patients, one stomach-cancer patient and one
ovary-cancer patient, but not in 452 healthy individuals. A
tumor-specific 5' splice site mutation at site +3 in intron 8 (TTgt [a
--> c]atg) was also detected. CONCLUSION: We conclude that somatic CHK2
mutations are rare in breast cancer, but our results suggest a tumor
suppressor function for CHK2 in a small proportion of breast tumors.
Furthermore, our results suggest that the T59K CHK2 sequence variant is
a low-penetrance allele with respect to tumor growth.
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