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Abramson Cancer CenterNCI CANCERLIT® Search: Hereditary Ovarian Cancer - August 2002
National Cancer Institute®
Last Modified: August 1, 2002
- Genes and generalists: why we need professionals with added competencies.
- BRCA1 and BRCA2 mutations in Turkish familial and non-familial ovarian cancer patients: a high incidence of mutations in non-familial cases.
- Expression of MUC1 splice variants in benign and malignant ovarian tumours.
- BRCA2 mutation analysis of 87 Spanish breast/ovarian cancer families.
- Expression of the serine protease matriptase and its inhibitor HAI-1 in epithelial ovarian cancer: correlation with clinical outcome and tumor
- Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites.
- Of mice and women.
- Induction of ovarian cancer by defined multiple genetic changes in a mouse model system.
- Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer.
- The BRCA1 suppressor hypothesis: an explanation for the tissue-specific tumor development in BRCA1 patients.
- Transcriptional profiling reveals that several common fragile-site genes are downregulated in ovarian cancer.
- Epigenetic factors controlling the BRCA1 and BRCA2 genes in sporadic ovarian cancer.
- Common polymorphisms and somatic mutations in human base excision repair genes in ovarian and endometrial cancers.
- Clustering of cancer-related mutations in a subset of BRCA1 alleles: a study in the Spanish population.
- The role of the nurse in cancer genetics.
- XY female with a dysgerminoma and no mutation in the coding sequence of the SRY gene.
- BRCA mutations in Italian breast/ovarian cancer families.
- CYP1A1 gene polymorphism and risk of epithelial ovarian neoplasm.
- Polymorphisms of the endothelial nitric oxide synthase gene in ovarian cancer.
- Multidrug resistance gene-1 is a useful predictor of Paclitaxel-based chemotherapy for patients with ovarian cancer.
- Transitional cell ovarian carcinoma in a BRCA1 mutation carrier.
- Expression of angiopoietin-1, angiopoietin-2, and Tie2 genes in normal ovary with corpus luteum and in ovarian cancer.
- A rationale for the clinical development of the thymidylate synthase inhibitor ZD9331 in ovarian and other solid tumours.
- Genetic alterations in epithelial ovarian tumors analyzed by comparative genomic hybridization.
- Hereditary cancer: family history, diagnosis, molecular genetics, ecogenetics, and management strategies.
- Effects of genetic consultation on perception of a family risk of breast/ovarian cancer and determinants of inaccurate perception after
- Genetic insights into familial cancers-- update and recent discoveries.
- A BRCA1 mutation in Native North American families.
Table of Contents
1
UI - 10639883
AU - Reynolds PP; Benkendorf JL
TI -
Genes and generalists: why we need professionals with added
competencies.
SO - West J Med 1999 Nov-Dec;171(5-6):375-9
AD - Department of Medicine and History, Johns Hopkins University School of
Medicine, Baltimore, MD, USA. preynold@welchlink.welch.jhu.edu
2
UI - 12112655
AU - Yazici H; Glendon G; Yazici H; Burnie SJ; Saip P; Buyru F; Bengisu E;
TI -
Andrulis IL; Dalay N; Ozcelik H
BRCA1 and BRCA2 mutations in Turkish familial and non-familial ovarian
cancer patients: a high incidence of mutations in non-familial cases.
SO - Hum Mutat 2002 Jul;20(1):28-34
AD - Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, and
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital,
Toronto, Canada.
Ovarian cancer is a clinically important cancer in Turkey. The
contribution of BRCA1 and BRCA2 to ovarian cancer in Turkish patients
has not previously been described. In this study we investigated the
presence of BRCA1 and BRCA2 mutations in 102 consecutively ascertained,
hospital-based, ovarian cancer cases. Four out of 15 (26.7%, 95%
confidence interval (CI), 7.8%-55.1%) familial cases were found to carry
mutations in BRCA1. Thirteen of the 87 (14.9%, 95% CI, 7.5%-22.4%)
non-familial cases had BRCA1 and BRCA2 mutations, six in BRCA1, and
seven in BRCA2. We have further studied the non-familial ovarian cancer
cases to determine which subgroups have a likelihood of carrying
clinically important mutations. Our study shows that those Turkish
ovarian cancer patients with serous histopathology harbor a high
proportion of mutations (12/58, 20.7%, 95% CI, 10.3%-31.1%) compared to
all non-familial cases (14.9%) regardless of pathology. Within the
serous sub-group, those that were also diagnosed below age 50 have an
even greater percentage of mutations (8/28, 28.6%, 95% CI, 11.8%-45.3%).
Our findings demonstrate that a substantial proportion of Turkish
ovarian cancer patients, both with and without a family history, carry
BRCA1 and BRCA2 mutations, demonstrating the importance of BRCA1 and
BRCA2 in the development of ovarian cancer in this population. Copyright
2002 Wiley-Liss, Inc.
3
UI - 12115565
AU - Obermair A; Schmid BC; Packer LM; Leodolter S; Birner P; Ward BG;
TI -
Crandon AJ; McGuckin MA; Zeillinger R
Expression of MUC1 splice variants in benign and malignant ovarian
tumours.
SO - Int J Cancer 2002 Jul 10;100(2):166-71
AD - Queensland Centre for Gynaecological Cancer, Royal Brisbane Hospital,
Brisbane, Australia. a_obermair@hotmail.com
MUC1 is expressed on the surface of ovarian cancer cells. Nine different
splice variants of MUC1 have been described, but no study has reported
on the expression of MUC1 isoforms in human ovarian cancer. Our study
compares patterns of expression of MUC1 splice variants of malignant and
benign ovarian tumours. Ovarian tissue samples were taken from patients
with benign ovarian tumours (n = 34) and from patients who had surgery
for primary (n = 47) or recurrent (n = 8) ovarian cancer. RT-PCR for
MUC1 splice variants A, B, C, D, X, Y, Z, REP and SEC was performed and
their expression compared to clinical and histopathologic parameters.
Variants A, D, X, Y and Z were more frequently expressed in malignant
than in benign tumours. All primary ovarian cancer cases were positive
for variant REP but negative for variant SEC. No significant association
of the expression of MUC1 splice variants with the response to
chemotherapy or patient survival could be demonstrated. Expression of
MUC1 splice variants A, D, X, Y, Z and REP is associated with the
presence of malignancy, whereas expression of MUC1/SEC is associated
with the absence of malignancy. Copyright 2002 Wiley-Liss, Inc.
4
UI - 11843247
AU - Campos B; Diez O; Domenech M; Baena M; Pericay C; Balmana J; del Rio E;
TI -
Sanz J; Alonso C; Baiget M
BRCA2 mutation analysis of 87 Spanish breast/ovarian cancer families.
SO - Ann Oncol 2001 Dec;12(12):1699-703
AD - Servei de Genetica, Hospital de la Santa Creu i Sant Pau, Barcelona,
Spain.
BACKGROUND: It is estimated that about 5% -10% of breast cancer (BC)
cases is due to inherited predisposition. Early works reported that
45%-50% of site-specific BC families had BRCA1 mutations and 25%-35%
BRCA2 mutations. However, these percentages could have been
overestimated and likely vary among the populations studied. PATIENTS
AND METHODS: We analysed the BRCA2 gene in 87 Spanish breast/ovarian
cancer families in which the BRCA1 mutation screening was negative.
RESULTS: We detected 15 (17.2%) disease-causing mutations and 11
polymorphisms and unclassified variants. Four mutations were recurrent,
and five were novel. Seven (47%) mutations were found in site-specific
female BC families, five (33%) in families with OC cases, and three
(20%) mutations in families with male BC cases. There was incomplete
penetrance of the mutations in some families, and considerable
phenotypic variations with respect to the age of diagnosis and cancer
types. CONCLUSIONS: The percentage of mutations detected reinforces the
possibility that some of these families have mutations in genes other
than BRCA1 or BRCA2 that confer lower BC risks.
5
UI - 11948120
AU - Oberst MD; Johnson MD; Dickson RB; Lin CY; Singh B; Stewart M; Williams
TI -
A; al-Nafussi A; Smyth JF; Gabra H; Sellar GC
Expression of the serine protease matriptase and its inhibitor HAI-1 in
epithelial ovarian cancer: correlation with clinical outcome and tumor
clinicopathological parameters.
SO - Clin Cancer Res 2002 Apr;8(4):1101-7
AD - Department of Oncology, Lombardi Cancer Center, Georgetown University
Medical Center, Washington, DC 20007, USA.
PURPOSE: Matriptase is a type II transmembrane serine protease expressed
by cells of surface epithelial origin, including epithelial ovarian
tumor cells. Matriptase cleaves and activates proteins implicated in the
progression of ovarian cancer and represents a potential prognostic and
therapeutic target. The aim of this study was to examine the expression
of matriptase, and its inhibitor, hepatocyte growth factor activator
inhibitor-1 (HAI-1), in epithelial ovarian cancer and to assign
clinicopathological correlations. EXPERIMENTAL DESIGN: We have
determined by immunohistochemistry the expression of matriptase and
HAI-1 in 54 epithelial ovarian cancers. Statistical analyses of
immunohistochemistry expression data with clinical outcome and
clinicopathological parameters were then performed. RESULTS: Of 54
tumors tested, 39 (72%) and 11 (20%) were positive for matriptase and
for HAI-1, respectively. All HAI-1-positive tumors were also matriptase
positive. Analysis of clinicopathological parameters demonstrated a loss
of matriptase associated with stage III/IV tumors as compared with stage
I/II tumors (P = 0.030). There was also a loss of HAI-1 expression
associated with stage III/IV tumors (P = 0.039). Of 34 stage I/II
tumors, 28 (82%) stained positive for matriptase, and 10 (29%) stained
positive for HAI-1; 10 (29%) tumors showed coexpression. Of 20 stage
III/IV tumors, however, 11 stained positive for matriptase (55%), only 1
of which coexpressed HAI-1 (P = 0.039). CONCLUSIONS: Advanced-stage
ovarian tumors that express matriptase are more likely to do so in the
absence of its inhibitor, HAI-1, indicating that an imbalance in the
matriptase:HAI-1 ratio could be important in the development of advanced
disease. Such an imbalance could promote the proteolytic activity of
matriptase and, consequently, a more invasive phenotype.
6
UI - 11948121
AU - Milliken D; Scotton C; Raju S; Balkwill F; Wilson J
TI -
Analysis of chemokines and chemokine receptor expression in ovarian
cancer ascites.
SO - Clin Cancer Res 2002 Apr;8(4):1108-14
AD - Cancer Research UK Translational Oncology Laboratory, St. Bartholomew's
and the London, Queen Mary's School of Medicine and Dentistry, John Vane
Science Centre London, United Kingdom.
PURPOSE: Ascitic disease is a common occurrence in human ovarian cancer,
but it is unclear how the cellular composition of ascitic fluid is
determined. Because chemokines can determine host cell infiltration in
solid ovarian cancer, we assessed CC chemokine protein and CC chemokine
receptor expression in ovarian cancer ascites. EXPERIMENTAL DESIGN: We
used reverse transcription-PCR and RNase protection assay to determine
CC chemokine and chemokine receptor mRNA expression and ELISA to measure
CC chemokine protein levels. Flow cytometry was used to identify cell
populations and their chemokine receptor protein expression. RESULTS:
mRNA for the CC chemokines CCL2, -3, -4, -5, -8, and -22 was expressed
in cell isolates from ascites samples, and the corresponding proteins
were detected in ascitic fluid. mRNA for CC chemokine receptors CCR1,
-2a, -2b, -3, -4, -5, and -8 was detected in cells from ascites.
Fluorescence-activated cell-sorting analysis showed variable numbers of
macrophages and CD3(+) T lymphocytes (predominantly CD4(+)) within
ovarian cancer ascites. CD14(+) macrophages within ascites consistently
expressed protein for CCR1, -2, and -5. CCR1 was expressed by >60% of
all T cells, but more CD4(+) than CD8(+) T cells expressed CCR2 and -5.
A direct correlation was found between the CCL5 concentration and CD3(+)
T-cell infiltration. CONCLUSIONS: We conclude that there is a complex
chemokine/chemokine receptor network in ovarian cancer ascites. However,
associations between chemokine receptor expression, chemokine levels,
and cell counts were limited.
7
UI - 12086881
AU - Foulkes WD
TI -
Of mice and women.
SO - Cancer Cell 2002 Feb;1(1):11-2
AD - Program in Cancer Genetics, Department of Oncology, McGill University,
Montreal, QC, Canada H3G 1A4. william.foulkes@mcgill.ca
Transgenic mouse model faithfully reproduces human ovarian carcinoma and
offers new opportunities for understanding the natural history of this
frequently fatal disease.
8
UI - 12086888
AU - Orsulic S; Li Y; Soslow RA; Vitale-Cross LA; Gutkind JS; Varmus HE
TI -
Induction of ovarian cancer by defined multiple genetic changes in a
mouse model system.
SO - Cancer Cell 2002 Feb;1(1):53-62
AD - Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY
10021, USA. orsulics@mskcc.org
We have developed a mouse model for ovarian carcinoma by using an avian
retroviral gene delivery technique for the introduction of multiple
genes into somatic ovarian cells of adult mice. Ovarian cells from
transgenic mice engineered to express the gene encoding the avian
receptor TVA were efficiently infected in vitro with multiple vectors
carrying coding sequences for oncogenes and marker genes. When target
cells were derived from TVA transgenic mice deficient for p53, the
addition of any two of the oncogenes c-myc, K-ras, and Akt were
sufficient to induce ovarian tumor formation when infected cells were
injected at subcutaneous, intraperitoneal, or ovarian sites. We
demonstrated that the ovarian surface epithelium is the precursor tissue
for these ovarian carcinomas, and that introduction of oncogenes causes
phenotypic changes in the ovarian surface epithelial cells. The induced
ovarian tumors in mice resembled human ovarian carcinomas in their rapid
progression and intraperitoneal metastatic spread.
9
UI - 12053177
AU - Anand N; Murthy S; Amann G; Wernick M; Porter LA; Cukier IH; Collins C;
TI -
Gray JW; Diebold J; Demetrick DJ; Lee JM
Protein elongation factor EEF1A2 is a putative oncogene in ovarian
cancer.
SO - Nat Genet 2002 Jul;31(3):301-5
AD - Hamilton Regional Cancer Centre, Room 450, 699 Concession Street,
Hamilton, Ontario, L8V 5C2, Canada.
We have found that EEF1A2, the gene encoding protein elongation factor
EEF1A2 (also known as eEF-1 alpha 2), is amplified in 25% of primary
ovarian tumors and is highly expressed in approximately 30% of ovarian
tumors and established cell lines. We have also demonstrated that EEF1A2
has oncogenic properties: it enhances focus formation, allows
anchorage-independent growth and decreases the doubling time of rodent
fibroblasts. In addition, EEF1A2 expression made NIH3T3 fibroblasts
tumorigenic and increased the growth rate of ES-2 ovarian carcinoma
cells xenografted in nude mice. Thus, EEF1A2 and the process of protein
elongation are likely to be critical in the development of ovarian
cancer.
10
UI - 12086871
AU - Elledge SJ; Amon A
TI -
The BRCA1 suppressor hypothesis: an explanation for the tissue-specific
tumor development in BRCA1 patients.
SO - Cancer Cell 2002 Mar;1(2):129-32
11
UI - 12112530
AU - Denison SR; Becker NA; Ferber MJ; Phillips LA; Kalli KR; Lee J; Lillie
TI -
J; Smith DI; Shridhar V
Transcriptional profiling reveals that several common fragile-site genes
are downregulated in ovarian cancer.
SO - Genes Chromosomes Cancer 2002 Aug;34(4):406-15
AD - Division of Experimental Pathology, Department of Laboratory Medicine
and Pathology, Mayo Foundation, 200 First Street SW, Rochester, MN
55905, USA.
Previous transcriptional profiling analysis of 14 primary ovarian tumors
identified approximately 12,000 genes as decreased in expression by at
least twofold in one or more of the tumors sampled. Among those genes
were several known to be mapped to common fragile sites (CFSs), some of
which had previously been shown to exhibit a loss of expression in
ovarian carcinoma. Therefore, we selected a subset of genes to determine
whether they localized within CFSs. Of the 262 genes that were
downregulated at least twofold in 13 of 14 tumors, 10 genes were
selected based on the following criteria: localization to a CFS band;
documented aberrations in at least one malignancy; and feasibility of
scoring breakage at the specific CFS. Fluorescence in situ hybridization
analysis was performed using bacterial artificial chromosome clones
encompassing portions of the genes to determine the position of the
genes relative to their corresponding CFSs. Nine genes were determined
to localize within seven previously uncloned CFSs. Semiquantitative
reverse-transcription/polymerase chain reaction analysis of the cell
lines and primary ovarian tumors validated the downregulation of seven
of the 10 genes. We identified portions of seven uncloned CFSs and
provide data to suggest that several of the genes mapping within CFSs
may be inactivated in ovarian cancer. Copyright 2002 Wiley-Liss, Inc.
12
UI - 12124354
AU - Chan KY; Ozcelik H; Cheung AN; Ngan HY; Khoo US
TI -
Epigenetic factors controlling the BRCA1 and BRCA2 genes in sporadic
ovarian cancer.
SO - Cancer Res 2002 Jul 15;62(14):4151-6
AD - Department of Pathology, Queen Mary Hospital and the University of Hong
Kong, Hong Kong.
Hypermethylation of the BRCA1 promoter has previously been shown to
cause reduced mRNA expression in both breast and ovarian cancers.
Nothing is yet known of the expression pattern or methylation status of
the promoter region of BRCA2 in sporadic ovarian cancer. Whereas our
analysis of 30 sporadic ovarian carcinomas showed a statistically
significant reduction of BRCA1 mRNA expression (P = 0.001), it also
showed, in contrast, overexpression of BRCA2 mRNA (P = 0.002) in tumor
compared with nontumor. Hypermethylation of the BRCA1 promoter highly
correlated with decreased BRCA1 expression (P = 0.017). Methylated CpGs
at the BRCA2 promoter were either absent or at very low levels in tumor
DNA, whereas they were present at high levels in nontumor DNA. Such
hypomethylation also correlated with elevated levels of BRCA2 mRNA (P =
0.043) and showed a statistically significant correlation with tumor
stage (P = 0.037). This supports the role of methylation in BRCA2
contributing to the pathogenesis of sporadic ovarian cancer.
Furthermore, 14 (58.2%) and 9 (56.3%) of all of the cases with aberrant
BRCA mRNA expression and methylation patterns, respectively,
demonstrated opposing mRNA expression and methylation patterns of the
BRCA1 and BRCA2 genes within the same cases. Our findings suggest that
both genes may be involved in the development of sporadic ovarian
cancer.
13
UI - 11465542
AU - Pieretti M; Khattar NH; Smith SA
TI -
Common polymorphisms and somatic mutations in human base excision repair
genes in ovarian and endometrial cancers.
SO - Mutat Res 2001 Jan;432(3-4):53-9
AD - Department of Pathology, University of Kentucky, Lexington 40536, USA.
mpieretti@usamail.usouthal.edu
The purpose of this study was to determine whether the human APEX and
OGG1 genes, encoding proteins important in base excision repair (BER) of
DNA, contain nucleotide sequence polymorphisms or are mutated
somatically in tumors from women diagnosed with ovarian or endometrial
cancer. Based upon the analysis of germline DNA from 83 individuals, 63
with ovarian cancer and 20 with endometrial cancer, we found two
missense polymorphisms in APEX (Q51H and D 148E) and two missense (A3P
and S326C) and one intronic (Exon 5-15 bp) polymorphism in OGG1. The
frequencies of the various alleles (in the ovarian and endometrial
cancer patients combined) were 4.8% for 51-His and 56.2% for 148-Glu in
APEX, and 1.0% for 3-Pro and 20.0% for 326-Cys in OGG1. Somatic
mutations in APEX (P112L, W188X and R237C) were identified in three of
20 endometrial tumors, but no mutations were identified in APEX in 43
ovarian tumors, or in OGG1 at either tumor site. Given the crucial role
of the APEX and OGG1 proteins in BER of oxidative DNA damage, the
identified polymorphisms are good candidates for genetic epidemiologic
studies of cancer susceptibility, while the finding that three of 20
(15%) endometrial tumors have somatic mutations in APEX suggests that
inactivation of the BER pathway is important for the development of
endometrial cancer in at least a subset of cases.
14
UI - 12124814
AU - de la Hoya M; Sulleiro S; Osorio A; Diez O; Baiget M; Benitez J;
TI -
Diaz-Rubio E; Caldes T
Clustering of cancer-related mutations in a subset of BRCA1 alleles: a
study in the Spanish population.
SO - Int J Cancer 2002 Aug 10;100(5):618-9
AD - Laboratory of Molecular Oncology, Hospital Universitario San Carlos,
Madrid, Spain.
We have observed that the frequency of D17S855 short alleles (139 bp and
141 bp) in individuals carrying BRCA1 germline mutations is higher than
in controls (54% vs. 31%, p = 0.0004). By unambiguously establishing
mutation/D17S855 phase in 18 BRCA1-positive families, we find that most
(11 of 15 different mutations) BRCA1 defects are linked to chromosomes
with short alleles (OR = 8.21, 95% CI 1.97-39.32, p = 0.0007). We
suggest that BRCA1 mutations are not randomly distributed but clustered
in a subset of BRCA1 alleles that can be identified by D17S855
genotyping. Further analysis involving a larger set of mutations and
different populations are needed to clarify the relevance of this
unexpected finding. Copyright 2002 Wiley-Liss, Inc.
15
UI - 12040228
AU - Middelton L; Dimond E; Calzone K; Davis J; Jenkins J
TI -
The role of the nurse in cancer genetics.
SO - Cancer Nurs 2002 Jun;25(3):196-206
AD - Urology Oncology Branch, National Cancer Institute, National Institutes
of Health, Bethesda, Md. 20892-1873, USA.
Knowledge gained from the Human Genome Project and related genetic
research is already impacting clinical oncology nursing practice.
Because cancer is now understood to be a genetic disease, changes in the
traditional approaches to prevention, diagnosis, and therapeutic
management of cancer are becoming increasingly genetically based.
Therefore, to ensure competency in oncology nursing practice at all
levels, nurses must incorporate an understanding of the underlying
biology of carcinogenesis and the molecular rationale underlying
strategies to prevent, diagnose, and treat cancer.
16
UI - 12165453
AU - Morerio C; Calvari V; Rosanda C; Porta S; Gambini C; Panarello C
TI -
XY female with a dysgerminoma and no mutation in the coding sequence of
the SRY gene.
SO - Cancer Genet Cytogenet 2002 Jul 1;136(1):58-61
AD - Divisione di Ematologia ed Oncologia Pediatrica, Istituto Giannina
Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy.
We report a 46,XY 11-year-old girl with pure gonadal dysgenesis who
developed a dysgerminoma. The testis-determining gene SRY, a candidate
for sex reversal, whose alterations seem to correlate with dysgerminoma,
was analyzed and found to be normal; its coding sequence was negative
for deletions and mutations. DMRT-1 gene mapping on 9p and DAX-1 on Xp21
were also normal. These results suggest the involvement of other genes
in sex reversal and call into question the putative relationship between
SRY alterations and dysgerminoma.
17
UI - 11938448
AU - Nedelcu R; Liede A; Aube J; Finch A; Kwan E; Jack E; Narod SA; Randall
TI -
S; Hugel L; Clark K
BRCA mutations in Italian breast/ovarian cancer families.
SO - Eur J Hum Genet 2002 Feb;10(2):150-2
18
UI - 12144816
AU - Aktas D; Guney I; Alikasifoglu M; Yuce K; Tuncbilek E; Ayhan A
TI -
CYP1A1 gene polymorphism and risk of epithelial ovarian neoplasm.
SO - Gynecol Oncol 2002 Aug;86(2):124-8
AD - Department of Genetics, Hacettepe University Medical School, 06100,
Sihhiye, Ankara, Turkey. dilekaktas6@hotmail.com
OBJECTIVE: Gene-environment interactions have been the focus of a number
of recent studies of the occurrence of human cancers, and an association
between the risk and the CYP1A1*3 polymorphism has been noticed for
several cancers. Previous studies suggest that estrogens are involved in
the etiology of ovarian cancer. The cytochrome P450 1A1 (CYP1A1) gene
polymorphism may play role in the development of epithelial ovarian
neoplasm by detoxification of polycyclic hydrocarbons and other
compounds and the concentration of estrogens and their metabolites.
Therefore, we assessed the association of CYP1A1 gene polymorphism in
patients with epithelial ovarian neoplasm in the Turkish populations
through a case-control study. METHODS: Using an allele-specific
polymerase chain reaction (PCR)-based method, CYP1A1*3 polymorphism, in
exon 7 of the gene, was analyzed in 117 epithelial ovarian neoplasm
patients and 202 control subjects. RESULTS: The CYP1A1 Ile/Val genotype
significantly increased the risk for patients with epithelial ovarian
neoplasm (OR 5.7, 95% CI 3.34-9.76). Furthermore, there were statistical
differences in the distribution of CYP1A1 Val/Val genotype among all
patients (OR 5.85, 95% CI 2.40-14.25). In other words, the presence of
the Val allele significantly increased the risk of epithelial ovarian
neoplasm. Among benign tumors, the frequency of Ile/Val and Val/Val
genotypes was found to be statistically significant with an ORs of 6.01
and 4.38 (95% CI 2.61-13.84 and 1.04-18.38, respectively). In the benign
serous ovarian tumors, patients with Ile/Val and Val/Val revealed a 7.2-
and 10.5-fold higher risk of having ovarian carcinoma (95% CI 2.22-23.40
and 2.16-51.19), respectively. In the benign mucinous ovarian carcinoma
patients, the frequency of Ile/Val was found to be statistically
significant with an OR of 5.15 (95% CI 1.75-15.16). However, no patient
with Val/Val genotype was observed in this group and no statistical
distribution was performed. Among borderline tumors, CYP1A1 Ile/Val
genotype significantly increased the risk for patients (OR 5.15, 95% CI
1.75-15.16). However, only one patient was observed with the Val/Val
allele and the frequency of this genotype was not found to be
statistically different with an OR of 2.50 (95% CI 0.27-22.64). Among
ovarian cancer patients, there were statistically differences in the
distribution of CYP1A1 Ile/Val and Val/Val genotypes (OR 5.73, 95% CI
3.04-10.76; and OR 7.42, 95% CI 2.80-19.66), suggesting that patients
carrying these genotypes were at increased risk for ovarian carcinoma.
In serous carcinoma, patients with CYP1A1 Ile/Val and Val/Val revealed a
6.5- and 10-fold higher risk of having ovarian cancer (OR 7.09, 95% CI
3.30-15.22; and OR 8.77, 95% CI 2.83-27.14). In mucinous carcinoma,
patients with CYP1A1 Ile/Val and Val/Val also revealed a 5.4 and 10.5
times higher risk of having ovarian cancer. There were no statistical
significance in the distribution of Val allele among endometroid-type
cancer patients. CONCLUSIONS: Our data, although based on a small number
of subjects, suggest that variant alleles of CYP1A1 gene in ovarian
epithelial cells, directly or through other components, may contribute
to initiation of ovarian carcinogenesis.
19
UI - 12144818
AU - Hefler LA; Ludwig E; Lampe D; Zeillinger R; Leodolter S; Gitsch G;
TI -
Koelbl H; Tempfer CB
Polymorphisms of the endothelial nitric oxide synthase gene in ovarian
cancer.
SO - Gynecol Oncol 2002 Aug;86(2):134-7
AD - Department of Obstetrics and Gynecology, University of Vienna Medical
School, Vienna, Austria.
OBJECTIVE: The free radical nitric oxide is known to be critically
involved in ovarian carcinogenesis by inducing apoptosis and by
mediating various cytostatic and cytotoxic effects, but also by
promoting growth, invasion, and metastasis. METHODS: We investigated two
polymorphisms (exon 7 Glu298Asp and a 27-bp repeat in intron 4) of the
gene encoding endothelial nitric oxide synthase (Nos3) in 130 patients
with ovarian cancer, 26 patients with borderline ovarian cancer, and 133
healthy age-matched Caucasian women using PCR and pyrosequencing,
respectively. RESULTS: Genotypes and allelic frequencies did not differ
between patients with ovarian cancer and controls. Within the ovarian
cancer group, however, the presence of at least one mutant allele of
intron 4 was associated with advanced tumor stage and positive lymph
node involvement, but not with tumor grading. The presence of the mutant
allele of exon 7 was not associated with the investigated
clinicopathological parameters. No correlation with patients' overall
and disease-free survival was ascertained. CONCLUSIONS: We are the first
to report on Nos3 polymorphisms in ovarian cancer. Allelic variation
within intron 4 of Nos3 is associated with an advanced tumor stage and
positive lymph node involvement in ovarian cancer.
20
UI - 12144824
AU - Kamazawa S; Kigawa J; Kanamori Y; Itamochi H; Sato S; Iba T; Terakawa N
TI -
Multidrug resistance gene-1 is a useful predictor of Paclitaxel-based
chemotherapy for patients with ovarian cancer.
SO - Gynecol Oncol 2002 Aug;86(2):171-6
AD - Department of Obstetrics and Gynecology, Tottori University School of
Medicine, Yonago, 683-8504, Japan.
OBJECTIVE: The objective of this study was to determine the relationship
between multidrug resistance and sensitivity to paclitaxel (PTX) in
ovarian cancer. METHODS: We used human ovarian adenocarcinoma cell
lines, KF, a PTX-resistant cell line (KFTx), SK-OV-3, and KOC7c.
Additionally, 27 patients with ovarian cancer who had residual disease
were examined. All patients underwent postoperative chemotherapy
consisting of 175 mg/m(2) PTX and area under curve (AUC) 5 carboplatin.
The sensitivity of the cells to PTX or cisplatin (CDDP) was determined
by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assay. mRNA expression of multidrug resistance gene-1 (MDR-1) and
multidrug resistance-associated protein-1 (MRP-1) and MRP-2 was
determined by reverse transcription-polymerase chain reaction.
beta-Tubulin polymerization and Bcl-2 phosphorylation were examined by
Western blot analysis. RESULTS: Compared with KF, the IC(50) to PTX was
5.5-fold higher for KFTx, 0.3-fold for SK-OV-3, and 52.1-fold for KOC7c.
The IC(50) to CDDP was 0.7-, 4.2-, and 5.8-fold, respectively.
Expression of the MDR-1 gene was clearly observed in KFTx and KOC7c.
Expression of MRP-1 was observed in SK-OV-3 and KOC7c. Expression of
MRP-2 was detected only in KOC7c. CDDP enhanced beta-tubulin
polymerization induced by PTX in CDDP-sensitive cells. Bcl-2
phosphorylation appeared after exposure to IC(50) PTX in all cells.
Twenty-one patients responded to chemotherapy and six did not.
Expression of the MDR-1 gene for nonresponders was significantly higher
than that for responders (260.0 +/- 191.6 vs 9.3 +/- 21.8). With the
cutoff value of MDR-1 expression at 100, the predictive value for
chemoresponse was 96%. Expression of the MRP-1 and MRP-2 genes did not
differ between nonresponders and responders. CONCLUSION: MDR-1 gene
expression may be a useful predictor for PTX-based chemotherapy.
21
UI - 12151180
AU - Werness BA; DiCioccio RA
TI -
Transitional cell ovarian carcinoma in a BRCA1 mutation carrier.
SO - Obstet Gynecol 2002 Aug;100(2):385; discussion 385
22
UI - 12138242
AU - Hata K; Udagawa J; Fujiwaki R; Nakayama K; Otani H; Miyazaki K
TI -
Expression of angiopoietin-1, angiopoietin-2, and Tie2 genes in normal
ovary with corpus luteum and in ovarian cancer.
SO - Oncology 2002;62(4):340-8
AD - Department of Obstetrics and Gynecology, Shimane Medical University,
Izumo, Japan. hata31@shimane-med.ac.jp
OBJECTIVE: The recent discovery of angiopoietin-1 (Ang1) and
angiopoietin-2 (Ang2) has provided novel and important insights into the
molecular mechanisms of blood vessel formation. Ang1 and Ang2 bind with
similar affinity to the endothelial cell tyrosine kinase receptor Tie2.
Our purpose was to assess the potential role of the Ang/Tie2 system in
physiological and pathological angiogenesis in the ovary. METHODS: Ang1,
Ang2, and Tie2 gene expression in 14 normal ovaries with corpus luteum
(CL) and in 19 cases of ovarian cancer were analyzed by polymerase chain
reaction of RNA after reverse transcription. The level of each gene
expression was presented by the relative yield of each gene to the
beta(2)-microglobulin gene, respectively. Furthermore, cellular
distribution of Ang1 and Ang2 mRNA was examined by in situ
hybridization, and localization of Tie2 was studied by immunochemistry.
RESULTS: The Ang1, Ang2, and Tie2 gene expression in normal ovary with
CL ranged from 0.18 to 1.06 (median 0.54), 0.31-2.64 (median 1.01), and
0.10-0.47 (median 0.20), respectively. The expression of these same
genes in ovarian cancer ranged from 0.06 to 0.75 (median 0.14),
0.69-1.59 (median 1.12), and 0.04-0.35 (median 0.15), respectively. Ang1
gene expression in normal ovary with CL was significantly higher than
that in ovarian cancer (p = 0.0004). The gene expression levels of Ang2
and Tie2 were statistically the same in both groups. There was a
significant correlation between Ang1 gene expression and Tie2 gene
expression in normal ovary with CL (r = 0.619, p = 0.018). No such
significant correlation was found in ovarian cancer. Moreover, Ang2 gene
expression showed no significant correlation with the Tie2 gene
expression either in normal ovary with CL or in ovarian cancer.
Transcripts for Ang1 were observed in CL cells and endothelial cells
around CL, and in tumor cells and endothelial cells at the periphery of
tumor invasion. Ang2 transcripts were expressed in the same patterns.
Tie2 expression was positive primarily in the endothelial cells around
CL and in those at the periphery of tumor invasion. CONCLUSION: Our
results indicate that there is a difference in the Ang/Tie2 gene
expression between physiological and pathological angiogenesis in the
ovary. This finding may aid in the development of new therapeutic
interventions for ovarian cancer. Copyright 2002 S. Karger AG, Basel
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The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.
UI - 12084463
AU - Jackman AL; Melin CJ; Kimbell R; Brunton L; Aherne GW; Theti DS; Walton
TI -
M
A rationale for the clinical development of the thymidylate synthase
inhibitor ZD9331 in ovarian and other solid tumours.
SO - Biochim Biophys Acta 2002 Jul 18;1587(2-3):215-23
AD - The Section of Medicine, Institute of Cancer Research, 15 Cotswold Road,
Belmont, Surrey, Sutton, UK. annj@icr.ac.uk
ZD9331 is an antifolate drug that potently and specifically inhibits
thymidylate synthase (TS). In contrast with TS inhibitors such as
raltitrexed, it cannot be polyglutamated, leading to antitumour activity
independent of folylpolyglutamyl synthetase (FPGS) activity.The growth
inhibition IC50 values for ZD9331 and raltitrexed were determined for a
panel of 18 human tumour cell lines, that included six colon and six
ovarian. The colon lines largely displayed overlapping sensitivities to
both drugs with only one of the six lines being drug resistant. In
contrast, the ovarian cell lines displayed non-overlapping sensitivities
with four being highly resistant to raltitrexed and only one was
cross-resistant to ZD9331. Studies were undertaken to explain these
results. The colon and ovarian cell lines were characterised for TS
activity, and TS and FPGS mRNA expression. TS activity correlated with
sensitivity to ZD9331 (r=0.50; p=0.097) and raltitrexed (r=0.74;
p=0.0063). Provided the data from the highly drug-resistant cell lines
(BE and 41 M) were omitted, TS mRNA expression levels also correlated
with ZD9331 (r=0.77; p=0.013) and raltitrexed IC50 (r=0.84; p=0.0031).
FPGS mRNA expression correlated with higher sensitivity to raltitrexed
relative to ZD9331 (higher ZD9331/raltitrexed IC50 ratios) (r=0.62;
p=0.048). Similarly, cell lines with IC50 ratios>median expressed a
1.8-fold higher median level of FPGS mRNA (p=0.0087) compared with those
with ratios
UI - 12152163
AU - Hauptmann S; Denkert C; Koch I; Petersen S; Schluns K; Reles A; Dietel
TI -
M; Petersen I
Genetic alterations in epithelial ovarian tumors analyzed by comparative
genomic hybridization.
SO - Hum Pathol 2002 Jun;33(6):632-41
AD - Institute of Pathology and Department of Gynecology and Obstetrics,
Charite Hospital Berlin, Germany.
The genetic changes involved in the pathogenesis of ovarian carcinoma
are not completely understood. To investigate this matter, we studied
paraffin-embedded, microdissected tissue of 47 ovarian epithelial tumors
(9 adenomas, 11 tumors of low malignant potential [LMP], 14 serous
carcinomas, and 13 nonserous carcinomas) using comparative genomic
hybridization (CGH). (The primary data used in this study are available
at our CGH online tumor database at http://amba.charite.de/cgh.)
Chromosomal imbalances were found in 1 serous adenoma and in 7 LMP
tumors. In the latter the alterations appeared randomly and showed no
overlap with alterations found in invasive carcinomas. Although the mean
aberration number of low-grade serous carcinomas was comparable to LMP
tumors, the imbalances of the former occurred with high incidence (>50%)
and were found at different localizations. High-grade serous carcinomas
had more than twice as much chromosomal imbalances as low-grade serous
carcinomas and also had pronounced alterations. In serous carcinomas,
gains were found on 3q, 6p, 7, 8q, and 20, and losses were found on 4q,
6q, 12q, 13q, and 16q. Comparing serous and nonserous carcinomas, the
mean aberration number was comparable, but the number of high incidence
changes was lower, and the most frequent imbalances were losses on 13q
and gains on 20p. Overlapping alterations occurring in serous and
nonserous carcinomas were gains on 3q and 6p, as well as losses on 4q.
Chromosomal imbalances associated with poor prognosis of ovarian
carcinomas were gains on 6p, 7q, and 13q and losses on 15q, 17p, 18q,
and 21q. Our data indicate that serous LMP tumors and invasive
carcinomas have different genetic aberrations, indicating that invasive
carcinomas do not arise from preexisting serous LMP tumors. On the other
hand, there are common genetic abnormalities in serous and nonserous
carcinomas, suggesting that they have very early lesions in common but
take different paths of further development. Copyright 2002, Elsevier
Science (USA). All rights reserved.
UI - 11900873
AU - Lynch HT; Lynch JF
TI -
Hereditary cancer: family history, diagnosis, molecular genetics,
ecogenetics, and management strategies.
SO - Biochimie 2002 Jan;84(1):3-17
AD - Department of Preventive Medicine and Public Health, Creighton
University School of Medicine, 2500 California Plaza, Omaha, Nebraska
68131, USA. htlynch@creighton.edu
The translation of knowledge about hereditary breast cancer and its
improved control, as well as prevention through prophylactic surgery,
has been significantly accelerated through the veritable explosive
discoveries in molecular genetics inclusive of BRCA1 and BRCA2 germline
mutations. Needed however, among the physician community, medical
geneticists, and genetic counselors, is a raised level of knowledge
about hereditary breast cancer syndromes. Particular attention needs to
be given to their extant genotypic and phenotypic heterogeneity, their
natural history, and foremost, the requirement of a sufficiently
detailed family history, with knowledge as to how to interpret its
significance so that hereditary cancer syndrome can be diagnosed, should
it, in fact, exist in the particular family. Collectively, surveillance
and management programs can then be developed for the patient and his or
her high-risk relatives. We believe very firmly that this knowledge
needs to be extended to the individual patient(s), first- and
second-degree relatives so that they can benefit from this knowledge.
UI - 12160914
AU - Huiart L; Eisinger F; Stoppa-Lyonnet D; Lasset C; Nogues C; Vennin P;
TI -
Sobol H; Julian-Reynier C
Effects of genetic consultation on perception of a family risk of
breast/ovarian cancer and determinants of inaccurate perception after
the consultation.
SO - J Clin Epidemiol 2002 Jul;55(7):665-75
AD - Epidemiology and Social Sciences Unit (INSERM U379), Institut
Paoli-Calmettes, 232 Bd Ste Marguerite, 13273 Marseille cedex 09,
France.
The aim of this study was to assess the effects of cancer genetic
consultations on women's perception of their family risk of
breast/ovarian cancer, and to determine which factors were associated
with an inaccurate perception after the consultation. A multicenter
prospective survey was carried out on women (n = 397) attending cancer
genetic clinics in France for the first time, in which the perceived
family risk was measured both before and after the consultation, using
self-administered questionnaires. The effects of the consultation on
risk perception were significant among low (P <.001) and moderate risk
women (P <.05). However, after the consultation, 76.3% of the "low"-risk
women did not perceive their family as "low"-risk families, and 21.9% of
the moderate-risk women were still definitely sure there was a genetic
risk running in their family. The consultation did not affect the family
risk perception of the high risk women (n = 171): the risk was thought
to be very high both before (87.7%) and after (89.5%) the consultation
(NS); however 10.5% of this group still perceived their family as being
unlikely to be at risk after the consultation. In the low- and
moderate-risk groups after multivariate adjustment, the inaccurate
perceptions varied, depending on the clinics and on the psychosocial
context of the consultation: they increased when the consultee was
personally affected by cancer, and decreased when the consultee had a
health occupation. Cancer genetic consultations had only marginal
effects on the perception of family risk on the whole, although they
were significant in the case of low- and moderate-risk women. The
question arises as to whether a more comprehensive approach should be
implemented and how to go about providing efficient cancer risk
information in the context of health care systems.
UI - 12175530
AU - Marsh D; Zori R
TI -
Genetic insights into familial cancers-- update and recent discoveries.
SO - Cancer Lett 2002 Jul 26;181(2):125-64
AD - Cancer Genetics, Kolling Institute of Medical Research and Department of
Molecular Medicine, The University of Sydney, Royal North Shore
Hospital, St. Leonards, NSW 2065, Sydney, Australia.
debbie_marsh@med.usyd.edu.au
While the vast majority of cancers are believed to occur sporadically,
most forms of cancer, both adult and paediatric, have a hereditary
equivalent. In the case of adult malignancies, these include hereditary
breast and ovarian cancer and syndromes such as the multiple endocrine
neoplasias types 1 and 2 characterised by specific tumours of the
endocrine gland system. In the case of paediatric malignancies, these
include syndromes such as retinoblastoma and Wilms tumour. In a little
over a single decade, we have seen a tremendous increase in the
knowledge of the primary genetic basis of many of the familial cancer
syndromes. The majority of familial syndromes are inherited as autosomal
dominant traits including hereditary colon cancer and familial malignant
melanoma, however, the genetics behind autosomal recessive disorders
such as Bloom syndrome and Fanconi anaemia are also being elucidated. A
third mode of inheritance less well understood in the setting of
familial cancer is that of imprinting recently observed in a subset of
families with inherited paraganglioma. In this review, we discuss 31
genes inherited in an autosomal dominant manner associated with 20
familial cancer syndromes. Genes inherited in an autosomal recessive
manner linked to familial cancer syndromes are also discussed. The
identification of genes associated with familial cancer syndromes has in
some families enabled a 'molecular diagnosis' that complements clinical
assessment and allows directed cancer surveillance for those individuals
determined to be at-risk of disease.
UI - 11933205
AU - Liede A; Jack E; Hegele RA; Narod SA
TI -
A BRCA1 mutation in Native North American families.
SO - Hum Mutat 2002 Apr;19(4):460
AD - University of Toronto and Sunnybrook & Women's College, Health Sciences
Centre, Toronto, Canada. alex.liede@swchsc.on.ca
Germline mutations in the BRCA1 (MIM 113705) and BRCA2 (MIM 600185)
genes have been identified for breast and ovarian cancer families of
diverse ethnic backgrounds. To date, there have been no reports of
Native North American families with mutations in BRCA1 or BRCA2. Here we
report two families of aboriginal descent both with the same BRCA1
alterations (1510insG, 1506A>G). The families represent two aboriginal
Canadian tribes (Cree and Ojibwe), although a common ancestral origin is
likely. This is the first evidence of a BRCA1 mutation specific to
aboriginal peoples of North America. Copyright 2002 Wiley-Liss, Inc.
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