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Abramson Cancer CenterNCI CANCERLIT® Search: Hereditary Ovarian Cancer - February 2002
National Cancer Institute®
Last Modified: February 1, 2002
Table of Contents
1
UI - 11745676
AU - Evans MF; Herrington CS
TI -
Allelic imbalance is not restricted to numerically abnormal chromosomes
in epithelial ovarian tumours.
SO - J Pathol 2001 Nov;195(4):443-50
AD - Department of Pathology, Duncan Building, Royal Liverpool University
Hospital, Daulby Street, Liverpool L69 3GA, Merseyside, UK.
In this study, 23 low malignant potential (LMP) and 27 invasive
epithelial ovarian tumours have been examined by microdissection and
microsatellite polymerase chain reaction (PCR) for allelic imbalance
(AI) at loci on the p and q arms of chromosomes 1, 11, 17, and X, and
the data have been compared with interphase cytogenetics for numerical
abnormalities (aneusomy) of these chromosomes. AI was uncommon in LMP
tumours (5 of 23 at 9 of 146 informative loci) but was significantly
more common (p<0.001) in invasive carcinomas (21 of 27 at 47 of 168
informative loci). This difference remained when LMP tumours were
compared specifically with stage I carcinomas (p<0.001). A greater
number of loci were involved in AI amongst serous than amongst mucinous
carcinomas (p=0.015). AI was present at significantly more loci in
carcinomas showing aneusomy by interphase cytogenetics than in those
showing no numerical chromosome abnormalities (p<0.001). However,
amongst the carcinomas showing aneusomy, AI was as frequent at loci on
chromosomes with no numerical abnormality as at those with the numerical
changes. These data demonstrate that aneusomy and AI are interrelated
phenomena but that AI does not occur simply as a consequence of
numerical chromosome changes. Copyright 2001 John Wiley & Sons, Ltd.
2
UI - 11745677
AU - Piek JM; van Diest PJ; Zweemer RP; Jansen JW; Poort-Keesom RJ; Menko FH;
TI -
Gille JJ; Jongsma AP; Pals G; Kenemans P; Verheijen RH
Dysplastic changes in prophylactically removed Fallopian tubes of women
predisposed to developing ovarian cancer.
SO - J Pathol 2001 Nov;195(4):451-6
AD - Department of Obstetrics and Gynaecology, University Hospital Vrije
Universiteit, Amsterdam, The Netherlands.
The aim of this study was to investigate the occurrence of
(pre)neoplastic lesions in overtly normal Fallopian tubes from women
predisposed to developing ovarian carcinoma. The presence of
(pre)neoplastic lesions was scored in histological specimens from 12
women with a genetically determined predisposition for ovarian cancer,
of whom seven tested positive for a germline BRCA1 mutation. A control
group included 13 women. Immunohistochemistry was used to determine the
expression of p21, p27, p53, cyclin A, cyclin D1, bcl-2, Ki67,
HER-2/neu, and the oestrogen and progesterone receptors. Loss of
heterozygosity (LOH) analysis on the BRCA1 locus was also assessed on
dysplastic tissue by PCR studies. Of the 12 women with a predisposition
for ovarian cancer, six showed dysplasia, including one case of severe
dysplasia. Five harboured hyperplastic lesions and in one woman no
histological aberrations were found in the Fallopian tube. No
hyperplastic, dysplastic or neoplastic lesions were detected in the
Fallopian tubes of control subjects. In the cases studied,
morphologically normal tubal epithelium contained a higher proportion of
Ki67-expressing cells (p=0.005) and lower fractions of cells expressing
p21 (p<0.0001) and p27 (p=0.006) than in the control group. Even higher
fractions of proliferating cells were found in dysplastic areas (p=0.07)
and accumulation of p53 was observed in the severely dysplastic lesion.
Expression patterns of other proteins studied, including the hormone
receptors, were similar in cases and controls. One subject, a germline
BRCA1 mutation carrier, showed loss of the wild-type BRCA1 allele in the
severely dysplastic lesion. In conclusion, the Fallopian tubes of women
predisposed to developing ovarian cancer frequently harbour dysplastic
changes, accompanied by changes in cell-cycle and apoptosis-related
proteins, indicating an increased risk of developing tubal cancer.
Copyright 2001 John Wiley & Sons, Ltd.
3
UI - 11751427
AU - Riva F; Zuco V; Vink AA; Supino R; Prosperi E
TI -
UV-induced DNA incision and proliferating cell nuclear antigen
recruitment to repair sites occur independently of p53-replication
protein A interaction in p53 wild type and mutant ovarian carcinoma
cells.
SO - Carcinogenesis 2001 Dec;22(12):1971-8
AD - Centro di Studio per l'Istochimica del CNR, Piazza Botta 10, 27100
Pavia, Italy.
The tumour suppressor gene TP53 plays an important role in the
regulation of DNA repair, and particularly of nucleotide excision
repair. The influence of p53 status on the efficiency of the principal
steps of this repair pathway was investigated after UV-C irradiation in
the human ovarian carcinoma cell line IGROV-1 (expressing wild-type p53)
and in the derived clone IGROV-1/Pt1 (with p53 mutations at codons 270
and 282). Clonogenic survival after UV-C irradiation showed that
IGROV-1/Pt1 cells were approximately 2-fold more resistant to DNA damage
than parental cells. Modulation of p53 protein levels, cell cycle arrest
and apoptosis were induced in UV-irradiated IGROV-1 cells, but not in
the p53-mutant cell line. Exposure to UV or cisplatin induced
down-regulation of p53-replication protein A (RPA) interaction in
parental, but not in IGROV-1/Pt1 cells. However, persistent binding of
p53 to RPA did not affect the early steps of DNA repair. In fact, both
UV-induced DNA incision and the recruitment of proliferating cell
nuclear antigen (PCNA) to DNA repair sites occurred to a comparable
extent in p53-wild type and -mutant cell lines, although PCNA remained
associated with chromatin for a longer period of time in IGROV-1/Pt1
cells. Global genome repair, as detected by immunoblot analysis of
cyclobutane pyrimidine dimers, was not significantly different in the
two cell lines at 3 h after UV irradiation. In contrast, lesion removal
at 24 h was markedly reduced in IGROV-1/Pt1 cells, being approximately
25% of the initial amount of damage, as compared with approximately 50%
repair in parental cells. These results indicate that the presence of
mutant p53 protein and its persistent interaction with RPA do not affect
the early steps of nucleotide excision repair in IGROV-1/Pt1 cells.
Thus, repair defects in p53-mutant ovarian carcinoma cells may be
attributed to late events, possibly related to a reduced
removal/recycling of PCNA at repair sites.
4
UI - 11786728
AU - Hovig E; Rye PD; Warren DJ; Nustad K
TI -
CA 125: the end of the beginning.
SO - Tumour Biol 2001 Nov-Dec;22(6):345-7
AD - Central Laboratory, Norwegian Radium Hospital, Oslo, Norway.
CA 125, a high-molecular-weight mucin, was first defined in 1981 by the
monoclonal antibody OC125. Until recently, it has defied many attempts
to purify it from a variety of sources, although many research groups
have successfully raised antibodies that bind to CA 125. Nevertheless,
CA 125 has demonstrated its considerable value as a marker in monitoring
patients with ovarian cancer. This year, two research groups have
succeeded in cloning the high-molecular-weight mucin CA 125. Their
findings are summarized and the significance discussed in light of
existing data from the human genome. Copyright 2001 S. Karger AG, Basel
5
UI - 11786729
AU - O'Brien TJ; Beard JB; Underwood LJ; Dennis RA; Santin AD; York L
TI -
The CA 125 gene: an extracellular superstructure dominated by repeat
sequences.
SO - Tumour Biol 2001 Nov-Dec;22(6):348-66
AD - Department of Obstetrics and Gynecology, University of Arkansas for
Medical Sciences, Little Rock, AR 72205, USA. obrientimothyj@uams.edu
CA 125 has long presented problems to both clinicians and investigators
because there was no definitive information on its structure and
function. Here, we describe our work on cloning the CA 125 gene with the
anticipation that such information will provide the basis for
understanding its structure and its physiologic role in both normal and
malignant tissues. The CA 125 protein core is composed of a short
cytoplasmic tail, a transmembrane domain and an extraordinarily large
glycosylated extracellular structure. This structure is dominated by a
repeat domain composed of 156 amino acid repeat units which encompass
the epitope binding sites. The molecule also includes an amino terminal
domain of serine/threonine-rich sequences which would account for most
of the O-glycosylation known to be present in CA 125. CA 125 is an
unusually large transmembrane glycoprotein. Its release from the surface
of the cell is most probably dependent on cytoplasmic phosphorylation
followed by proteolytic cleavage. The extracellular domain is
characterized by a large number of repeat units (probably 60+) which
encompass an interactive disulfide bridged cysteine-loop and the site of
OC125 and M11 binding. Sequencing the gene provides us with the ability
to initiate the quest to understand the biological function of CA 125.
Copyright 2001 S. Karger AG, Basel
6
UI - 11780384
AU - Pan L; Tong Y; Jin Y; Zhou S; Zhang Y; Yang X; Mao N
TI -
Reversing drug resistance in the ovarian carcinoma cell line SKOV3/mdr1
in vitro by antisense oligodeoxynucleotides.
SO - Chin Med J (Engl) 2001 Sep;114(9):929-32
AD - Department of Obstetrics and Gynecology, Chinese Academy of Medical
Sciences, Peking Union Medical College Hospital, Beijing 100730, China.
OBJECTIVE: To investigate the effect of multidrug resistance gene 1
(mdr1) antisense oligodeoxynucleotides (ODNs) on reversing multidrug
resistance in the drug resistant ovarian carcinoma cell line SKOV3/mdr1.
METHODS: The ovarian carcinoma cell line SKOV3 transducted with a human
multidrug resistance gene (mdr1) served as the drug resistant model
(SKOV3/mdr1). The mdr1 antisense ODNs was transfected into SKOV3/mdr1
cells while mediated by lipofectamine. Reverse transcription-polymerase
chain reaction (RT-PCR) was used to measure the expression and the
amount of the mdr1 mRNA in the cells. The positive rate and function of
the mdr1 gene product P-glycoprotein (Pgp) in the mdr1 antisense ODNs
treated SKOV3/mdr1 cells were determined by flow cytometry and rhodamine
123 efflux. Drug resistance in the SKOV3/mdr1 cell line was observed by
MTT assay and cell colony culture. RESULTS: The mdr1 mRNA level was
decreased to about 60% of that of beta-actin after mdr1 antisense ODNs
treatment. The Pgp positive rate of mdr1 antisense ODNs treated
SKOV3/mdr1 cells decreased from 100% to 52.6% (P < 0.01). The
intracellular rhodamine 123 retention was increased from 9.1% to 33.8%
(P < 0.01). The chemoresistance to taxol decreased to 58% of SKOV3/mdr1
with mdr1 antisense ODN treatment. Compared with SKOV3/mdr1 cells in the
control group, under a certain range of drug concentrations, the number
of drug resistance colonies in mdr1 antisense ODNs treated SKOV3/mdr1
cells for taxol and doxorubicin decreased by 8.6 +/- 0.8 fold and 3.1
+/- 0.6 fold, respectively. Some non-specific functions during
oligodeoxyncleotide treatment was also detected. CONCLUSION: mdr1
expression in the SKOV1/mdr1 cell line was partially inhibited after
mdr1 antisense ODNs treatment at the mRNA and protein level, increasing
the chemotherapy sensitivity of this drug resistant ovarian carcinoma
cell line.
7
UI - 10885351
AU - Meijers-Heijboer EJ; Verhoog LC; Brekelmans CT; Seynaeve C;
TI -
Tilanus-Linthorst MM; Wagner A; Dukel L; Devilee P; van den Ouweland AM;
van Geel AN; Klijn JG
Presymptomatic DNA testing and prophylactic surgery in families with a
BRCA1 or BRCA2 mutation.
SO - Lancet 2000 Jun 10;355(9220):2015-20
AD - Department of Clinical Genetics, Erasmus University, Rotterdam, The
Netherlands.
BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes highly
predispose to breast and ovarian cancer. In families with BRCA1 or BRCA2
mutations, identification of mutation carriers is clinically relevant in
view of the options for surveillance and prevention. METHODS: We
assessed presymptomatic DNA testing and prophylactic surgery in 53
consecutive families presenting to the Rotterdam Family Cancer Clinic
with a known BRCA1 or BRCA2 mutation. We identified predictors for DNA
testing and prophylactic surgery with univariate and multivariate
analysis. FINDINGS: 682 unaffected individuals with a 50% risk (275
women and 271 men) or with a 25% risk (136 women) for carrying a
mutation were identified and offered a DNA test. Presymptomatic DNA
testing was requested by 48% (198 of 411) of women and 22% (59 of 271)
of men (odds ratio for difference between sexes 3.21 [95% CI 2.27-4.51];
p<0.001). In women, DNA testing was significantly more frequent at young
age, in the presence of children, and at high pre-test genetic risk for
a mutation. Of the unaffected women with an identified mutation who were
eligible for prophylactic surgery, 51% (35 of 68) opted for bilateral
mastectomy and 64% (29 of 45) for oophorectomy. Parenthood was a
predictor for prophylactic mastectomy but not for prophylactic
oophorectomy. Age was significantly associated with prophylactic
oophorectomy, but not with prophylactic mastectomy, although there was a
tendency towards mastectomy at younger ages. INTERPRETATION: In a
clinical setting, we show a high demand for BRCA1 and BRCA2 testing by
unaffected women at risk, and of prophylactic surgery by unaffected
women with the mutation. Young women with children especially opt for
DNA testing and prophylactic mastectomy.
8
UI - 11499060
AU - Frank TS; Critchfield GC
TI -
Identifying and managing hereditary risk of breast and ovarian cancer.
SO - Clin Perinatol 2001 Jun;28(2):395-406
AD - Myriad Genetic Laboratories, Salt Lake City, Utah, USA.
tfrank@myriad.com
In the past, all women with a family history of breast or ovarian cancer
were considered to be at increased risk of cancer themselves. The
discovery of BRCA1 and BRCA2 demonstrated that susceptibility to breast
and ovarian cancer can be inherited by women as a single-gene autosomal
dominant disorder. For such women, evaluation of family history is an
important screening tool to identify the possibility of hereditary
cancer risk but only genetic testing can provide definitive,
individualized risk assessment. Women who have inherited mutations in
BRCA1 or BRCA2 now have several medical management options to address
their increased risk of cancer. A well-educated community of health care
providers and patients can use hereditary risk assessment, including
genetic testing, to improve health care.
9
UI - 11791119
AU - Ueno NT; Yu D; Hung MC
TI -
E1A: tumor suppressor or oncogene? Preclinical and clinical
investigations of E1A gene therapy.
SO - Breast Cancer 2001;8(4):285-93
AD - Department of Molecualr and Cellular Oncology, The University of Texas,
M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 448, Houston,
TX 77030, USA. nueno@mdanderson.org
In the late 1980s, we have shown that the E1A gene can downregulate
HER-2/neu overexpression, thus reversing the tumorigenic and metastatic
phenotype. Further, E1A can function as a tumor suppressor gene by
inducing apoptosis and inhibiting metastasis. At The University of Texas
M. D. Anderson Cancer Center, we have been investigating the adenovirus
type 5 E1A gene as a potential therapeutic gene in breast and ovarian
cancer since 1995 by using cationic liposome as gene delivery system. In
this chapter, we recount our development of E1A as a therapeutic gene.
10
UI - 11791820
AU - McCann S; MacAuley D
TI -
Management of familial breast and ovarian cancer cases.
SO - Br J Gen Pract 2002 Jan;52(474):57
11
UI - 11781689
AU - Barkardottir RB; Sarantaus L; Arason A; Vehmanen P; Bendahl PO; Kainu T;
TI -
Syrjakoski K; Krahe R; Huusko P; Pyrhonen S; Holli K; Kallioniemi OP;
Egilsson V; Kere J; Nevanlinna H
Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer
families.
SO - Eur J Hum Genet 2001 Oct;9(10):773-9
AD - Department of Pathology, University Hospital of Iceland, Iceland.
rosa@landspitali.is
The 999del5 mutation is the single, strong BRCA2 founder mutation in
Iceland and the most common BRCA1/2 founder mutation in Finland. To
evaluate the origin and time since spreading of the 999del5 mutation in
Iceland and in Finland, we constructed haplotypes with polymorphic
markers within and flanking the BRCA2 gene in a set of 18 Icelandic and
10 Finnish 999del5 breast cancer families. All Icelandic families
analysed shared a common core haplotype of about 1.7 cM. The common
ancestors for the Icelandic families studied were estimated to trace
back to 340-1000 years, not excluding the possibility that the mutation
was brought to Iceland during the settlement of the country. Analysis of
the Finnish families revealed two distinct haplotypes. A rare one, found
in three families in the old settlement region in southwestern Finland,
shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5
haplotype. A distinct approximately 6 cM haplotype was shared by seven
999del5 Finnish families estimated to have a common ancestry 140-300
years ago. These families cluster in two geographical regions in
Finland, in the very same area as those with the rare haplotype and also
in the most eastern, late settlement region of Finland. The results may
indicate a common ancient origin for the 999del5 mutation in Iceland and
in Finland, but distinct mutational events cannot be ruled out. The
surprising finding of the same mutation in two completely different
haplotypes in a sparsely populated area in Finland may suggest gene
conversion.
12
UI - 11774736
AU - Kigawa J; Sato S; Shimada M; Takahashi M; Itamochi H; Kanamori Y;
TI -
Terakawa N
p53 gene status and chemosensitivity in ovarian cancer.
SO - Hum Cell 2001 Sep;14(3):165-71
AD - Department of Obstetrics and Gynecology, Tottori University, School of
Medicine.
Recent studies suggest that drug induced apoptosis relates to the
sensitivity. p53 gene, which has a pivotal role in inducing apoptosis,
frequently mutates in ovarian cancer. Therefore, p53 gene status and
chemosensitivity in epithelial ovarian cancer is discussed.
Nonresponders to chemotherapy had mutations of the p53 gene more
frequently (83% for nonresponders vs. 16% for responders) in patients
with epithelial ovarian cancer undergoing platinum-base chemotherapy.
Apoptotic index was significantly greater in tumors with wild-type p53
gene than those without the gene. p53 gene transduction markedly
enhanced the sensitivity to cisplatin (CDDP) and CDDP-induced apoptosis,
but did not affect the sensitivity to paclitaxel (PTX) nor PTX-induced
apoptosis in ovarian cancer cells without p53 gene. The combination
treatment with a recombinant adenovirus carrying a wild-type p53 gene
(AxCAp53) and CDDP significantly suppressed tumor growth of ovarian
cancer cells with and without p53 gene, compared with a single treatment
of either AxCAp53 or CDDP in ovarian cancer xenograft. Apoptotic index
was significantly higher and proliferating cell nuclear antigen labeling
index was relatively lower in an ovarian cancer xenograft without p53
gene receiving combination treatment, compared with a single treatment
of either CDDP or AxCAp53, suggesting that the transduction of p53 gene
induces apoptosis, but does not enhance the DNA repair system. A
significant survival advantage was observed in the combination treatment
compared with other treatments in carcinoma peritonitis models. In
conclusion, p53 gene status contributes the sensitivity to CDDP in
ovarian cancer. Additionally, combination treatment of p53 gene
transduction and CDDP may be an effective therapeutic modality for
ovarian cancer without wild-type p53 gene.
13
UI - 11807777
AU - Buchholz TA; Wu X; Hussain A; Tucker SL; Mills GB; Haffty B; Bergh S;
TI -
Story M; Geara FB; Brock WA
Evidence of haplotype insufficiency in human cells containing a germline
mutation in BRCA1 or BRCA2.
SO - Int J Cancer 2002 Feb 10;97(5):557-61
AD - Department of Radiation Oncology, The University of Texas M. D. Anderson
Cancer Center, Houston, TX 77030, USA. tbuchhol@notes.mdacc.tmc.edu
The BRCA1 and BRCA2 gene products are thought to play important roles in
the processing of DNA damage. To assess whether heterozygous mutations
in these genes are associated with cellular radiosensitivity, we
performed an in vitro radiation clonogenic survival assay on dermal
fibroblasts obtained from 8 sequence-proven BRCA heterozygotes (6 BRCA1,
2 BRCA2). These data were compared to results obtained from a previous
set of 17 prospectively studied cancer patients who had a negligible
risk for a BRCA mutation. In addition, results from radiation-induced
chromatid break assay performed on lymphocytes obtained from 9 BRCA
heterozygotes (8 BRCA1, 1 BRCA2) were compared to results from a control
group of 18 women with no cancer history. Results from both assays
suggested that cells containing a heterozygous mutation in BRCA1 or
BRCA2 were more radiosensitive than controls. For the fibroblast
studies, the mean surviving fraction at 2 Gy (SF2) for carriers was
0.279 vs. 0.348 for the control set (p = 0.007). For the lymphocyte
studies, the mean number of chromatid breaks after 125 cGy of radiation
was 0.79 breaks per cell for the carriers vs. 0.45 for the controls (p =
0.0005). There was no apparent difference in the radiosensitivity
between cells with BRCA1 vs. BRCA2 mutations (p = 0.769), although the
small sample size minimizes the certainty of this observation. These
preliminary results are consistent with a relationship between a
germline mutation in BRCA1 or BRCA2 and a hypersensitivity to radiation.
This phenotype could possibly predispose to an increased risk of
radiation-induced mutagenesis and carcinogenesis. Copyright 2001
Wiley-Liss, Inc.
14
UI - 11782386
AU - Shridhar V; Sen A; Chien J; Staub J; Avula R; Kovats S; Lee J; Lillie J;
TI -
Smith DI
Identification of underexpressed genes in early- and late-stage primary
ovarian tumors by suppression subtraction hybridization.
SO - Cancer Res 2002 Jan 1;62(1):262-70
AD - Department of Experimental Pathology, Division of Laboratory Medicine,
Mayo Clinic, Rochester, Minnesota 55905, USA. shridv@exrch.mayo.edu
To identify novel tumor suppressor genes involved in ovarian
carcinogenesis, we generated four down-regulated suppression subtraction
cDNA libraries from two early-stage (stage I/II) and two late-stage
(stage III) primary ovarian tumors, each subtracted against cDNAs
derived from normal ovarian epithelial cell brushings. Approximately
600-700 distinct clones were sequenced from each library. Comparison of
down-regulated clones obtained from early- and late-stage tumors
revealed genes that were unique to each library which suggested
tumor-specific differences. We found 45 down-regulated genes that were
common in all four libraries. We also identified several genes, the role
of which in tumor development has yet to be elucidated, in addition to
several under expressed genes, the potential role of which in
carcinogenesis has been described previously (Bagnoli et al., Oncogene,
19: 4754-4763, 2000; Yu et al., Proc. Natl. Acad. Sci. USA, 96: 214-219,
1999; Mok et al., Oncogene, 12: 1895-1901, 1996). The differential
expression of a subset of these genes was confirmed by semiquantitative
reverse transcription-PCR using glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) as control in a panel of 15 stage I and 15 stage III tumors of
mixed histological subtypes. Chromosomal sorting of library sequences
revealed that several of the genes mapped to known regions of deletion
in ovarian cancer. Loss of heterozygosity (LOH) analysis revealed
multiple genomic regions with a high frequency of loss in both early-
and late-stage tumors. To determine whether loss of expression of some
of the genes corresponds to loss of an allele by LOH, we used a
microsatellite marker for one of the novel genes on 8q and have shown
that loss of expression of this novel gene correlates with loss of an
allele by LOH. In conclusion, our analysis has identified down-regulated
genes, which map to known as well as novel regions of deletions and may
represent potential candidate tumor suppressor genes involved in ovarian
cancer.
15
UI - 11802208
AU - de la Hoya M; Osorio A; Godino J; Sulleiro S; Tosar A; Perez-Segura P;
TI -
Fernandez C; Rodriguez R; Diaz-Rubio E; Benitez J; Devilee P; Caldes T
Association between BRCA1 and BRCA2 mutations and cancer phenotype in
Spanish breast/ovarian cancer families: implications for genetic
testing.
SO - Int J Cancer 2002 Feb 1;97(4):466-71
AD - Laboratory of Molecular Oncology, Hospital Universitario San Carlos,
Madrid, Spain.
Index cases from a clinically relevant cohort of 102 Spanish families
with at least 3 cases of breast and/or ovarian cancer (at least 1 case
diagnosed before age 50) in the same lineage were screened for germline
mutations in the entire coding sequence and intron boundaries of the
breast cancer susceptibility genes BRCA1 and BRCA2. Overall, the
prevalence of mutations was 43% in female breast/ovarian cancer
families, 15% in female breast cancer families and 100% in male breast
cancer families. Three recurrent mutations (185delAG, 589delCT and
A1708E) explained 63% of BRCA1-related families. Early age at diagnosis
of breast cancer, ovarian cancer, bilateral breast cancer, concomitant
breast/ovarian cancer in a single patient and prostate cancer but not
unilateral breast cancer were associated with BRCA1 and BRCA2 mutations.
Male breast cancer was associated with BRCA2 mutations. The presence of
male breast cancer was the only cancer phenotype that distinguished
BRCA2- from BRCA1-related families. We have developed a logistic
regression model for predicting the probability of harbouring a mutation
in either BRCA1 or BRCA2 as a function of the cancer phenotype present
in the family. The predictive positive and negative values of this model
were 77.4% and 79%, respectively (probability cutoff of 30%). The
findings of our work may be a useful tool for increasing the
cost-effectiveness of genetic testing in familial cancer clinics.
Copyright 2001 Wiley-Liss, Inc.
16
UI - 11802209
AU - Meindl A; German Consortium for Hereditary Breast and Ovarian Cancer
TI -
Comprehensive analysis of 989 patients with breast or ovarian cancer
provides BRCA1 and BRCA2 mutation profiles and frequencies for the
German population.
SO - Int J Cancer 2002 Feb 1;97(4):472-80
AD - Department of Medical Genetics, Ludwig-Maximilians University, Munich,
Germany. alfons@pedgen.med.uni-muenchen.de
The main focus of this German-wide multi-center study was to establish a
BRCA1/2 mutation profile and to determine family types with high
frequencies of mutations in these genes. In a comprehensive study, the
entire coding sequences of the breast cancer genes BRCA1 and BRCA2 were
analyzed in 989 unrelated patients from German breast/ovarian cancer
families. A total of 77 BRCA1 and 63 BRCA2 distinct deleterious
mutations were found in 302 patients. More than (1/3) of these mutations
are novel and might be specific for the German population. Eighteen
common mutations were found in 68% of cases in BRCA1 and 13 recurrent
mutations in 44% of cases in BRCA2, facilitating prescreening
approaches. Haplotype analysis indicate that 14 out of 20 recurrent
mutations are likely originating from a common founder. An additional 50
different rare sequence variants with unknown relevance for
tumorigenesis were found in 72 families. Correlation of BRCA1/BRCA2
detection rates with family history identified families with both breast
and ovarian cancer to be at highest risk for BRCA1/BRCA2 mutations (43%
and 10%, respectively), followed by families with at least 2
premenopausal cases of breast cancer (24% BRCA1 and 13% BRCA2
mutations). These data provide strong evidence for further predisposing
genes in the German population. In breast cancer families with 2 or 3
affected females but only a single or no premenopausal case, mutations
were detected with low frequencies (about 10% or less for both genes).
The decision for or against molecular diagnosis is now aided by
considering the expected mutation detection rates that greatly depend on
family history and structure. Copyright 2001 Wiley-Liss, Inc.
17
UI - 11826460
AU - Levin T; Reichelt J; Heimdal K; Moller P
TI -
[Information to families with hereditary breast and ovarian cancer]
SO - Tidsskr Nor Laegeforen 2001 Nov 20;121(28):3292-4
AD - Seksjon for genetisk veiledning Avdeling for kreftgenetikk Det Norske
Radiumhospital 0310 Oslo. pal.moller@klinmed.uio.no
BACKGROUND: Under Norwegian legislation, persons at risk should make the
initial contact with the proper health personnel, and not vice versa. It
may be argued that the physician should be allowed to make contact with
persons at risk of preventable or curable disorders. MATERIAL AND
METHODS: We identified all first-degree relatives of all 75 BRCA1
mutation carriers diagnosed within a given period of time and asked them
whether or not they had been informed by their relatives. RESULTS: After
two years, 60/63 (95%) adult sisters and daughters had made contact with
us; the remaining three (5%) had been informed. In comparison, 18/45
(40%) adult brothers and sons had contacted us. INTERPRETATION: The
legislation constituted no barrier to offering health services to the
target group. Information on our services had reached all close
relatives who could benefit from them. This may be representative for
curable inherited disorders. We examined inherited cancer limited to
females; similar studies on inherited cancers in males and on other
curable inherited disorders should be performed. Outside the framework
of the present study, we are aware of rare examples of distant cousins
who have not been properly informed through their families. One legally
acceptable way of identifying mutation carrier families is to test all
patients with breast or ovarian cancer for causative mutations. Health
services should be monitored to make future decisions based on empirical
evidence.
18
UI - 11810077
AU - Walker GR; Schlesselman JJ; Ness RB
TI -
Family history of cancer, oral contraceptive use, and ovarian cancer
risk.
SO - Am J Obstet Gynecol 2002 Jan;186(1):8-14
AD - Sylvester Comprehensive Cancer Center, University of Miami School of
Medicine, Florida, USA.
OBJECTIVE: The purpose of this study was to determine whether women with
a family history of ovarian cancer are at reduced risk of ovarian cancer
from the use of oral contraceptives and to compare their risk with that
of women with no family history of ovarian cancer. STUDY DESIGN: A
diagnosis of epithelial ovarian cancer were ascertained from 39
hospitals in 3 northeastern states. Personal interviews with the women
and 1367 control subjects provided data that allowed us to estimate the
relative risk of ovarian cancer in relation to a family history of
cancer and total duration of oral contraception. RESULTS: Among the 33
case patients and 24 control subjects with a first-degree family history
of ovarian cancer, risk of ovarian cancer declined with increasing
duration of oral contraception (P =.01). Risk reduction from short-term
use of oral contraceptives (< or = 48 months) did not differ
significantly by family history (combined estimate of odds ratio, 0.72;
90% CI, 0.59%-0.87%). Risk reduction from long-term use of oral
contraceptives (>48 months) was greater in women with a positive family
history of ovarian cancer (odds ratio, 0.12) than in women with a
negative family history of ovarian cancer (odds ratio, 0.51; test of
interaction, P =.04; 692 case patients, 1279 control subjects).
CONCLUSION: Four to 8 years of oral contraception may substantially
reduce the risk of ovarian cancer by age 70 years in women with a family
history of the disease, from approximately 4 women per 100 women who did
not use oral contraceptives to only 2 women per 100 women who did use
oral contraceptives.
19
UI - 10746681
AU - Huang LW; Garrett AP; Muto MG; Colitti CV; Bell DA; Welch WR; Berkowitz
TI -
RS; Mok SC
Identification of a novel 9 cM deletion unit on chromosome 6q23-24 in
papillary serous carcinoma of the peritoneum.
SO - Hum Pathol 2000 Mar;31(3):367-73
AD - Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham
and Women's Hospital, Harvard Medical School, Boston, MA, USA.
To define regions of deletion on chromosome 6q in papillary serous
carcinoma of the peritoneum (PSCP), we analyzed 103 tumor tissues from
53 patients by using 11 polymorphic microsatellite markers spanning loci
from 6q23 to 6q27. Allelic losses on 6q were observed in 42 of 53
(79.2%) cases. We identified 3 distinct regions with a high percentage
(>40%) of loss of heterozygosity. The first region is located at 6q23-24
and defined by D6S311 (15 of 35 informative cases, 42.9%). Detailed
deletion mapping of chromosome 6q23-24 in these tumor samples identified
a novel 9 cM minimal deletion region flanked by D6S250 and ESR. The
second one is located at 6q25.1-25.2 and defined by D6S448 (17 of 36
informative cases, 47.2%). A second minimal deletion region of 4 cM was
flanked by D6S420 and D6S442. The third region is located at 6q27 and
defined by D6S297 (9 of 19 informative cases, 47.4%). Comparing these
results with our cases of advanced staged invasive serous epithelial
ovarian carcinoma (SEOC), we observed that allelic losses at D6S311
(6q23) and D6S149 (6q27) were significantly higher for PSCP than for
SEOC. The pattern of allelic loss at each tumor site within an
individual patient was also studied. A total of 36 cases displayed
allelic loss for at least 1 of multiple tumor sites, and 35 of these
patients exhibited nonidentical patterns of allelic loss at various
tumor sites of the same patient. Furthermore, an alternating pattern of
allelic loss in the same patient was identified in 3 of 53 patients
studied. These results show that allelic losses on 6q are very frequent
in PSCP, and we show 2 discrete minimal deletion regions on 6q,
suggesting the existence of at least 2 tumor suppressor genes within 6q
that may be involved in the pathogenesis of PSCP. In addition, the
finding of different patterns of allelic loss at different tumor sites
within the same patient indicate a mutifocal origin in some PSCP cases.
These results provide strong evidence to support our previous reports
that PSCP is a multifocal disease entity.
20
UI - 11150382
AU - Werness BA
TI -
Identification of a novel 9 cM deletion unit on chromosome 6q23-24 in
papillary serous carcinoma of the peritoneum.
SO - Hum Pathol 2000 Dec;31(12):1535
21
UI - 11526715
AU - Greggi S; Legge F; Mancuso S
TI -
[Familial ovarian carcinoma]
SO - Minerva Ginecol 2001 Feb;53(1 Suppl 1):3-5
AD - Istituto di Clinica Ostetrica e Ginecologica, Universita Cattolica del
Sacro Cuore, Roma.
22
UI - 11526718
AU - Ferrandina G; Legge F; Fagotti A; Fanfani F; Mancuso S; Scambia G
TI -
[Biological factors with prognostic significance in ovarian cancer]
SO - Minerva Ginecol 2001 Feb;53(1 Suppl 1):40-5
AD - Istituto di Clinica Ostetrica e Ginecologica, Universita Cattolica del
Sacro Cuore, Roma.
23
UI - 11526726
AU - Saponara R; Menditto A; Russo G; Musone R; Balbi GC; Balbi C
TI -
[Review of the literature on BRCA 1 and BRCA 2]
SO - Minerva Ginecol 2001 Feb;53(1 Suppl 1):72-4
AD - Istituto di Clinica Ostetrica e Ginecologica, Seconda Universita degli
Studi, Napoli.
24
UI - 11743636
AU - Herrera CA; Xu L; Bucana CD; Silva el VG; Hess KR; Gershenson DM; Fidler
TI -
IJ
Expression of metastasis-related genes in human epithelial ovarian
tumors.
SO - Int J Oncol 2002 Jan;20(1):5-13
AD - Department of Gynecologic Oncology, The University of Texas M.D.
Anderson Cancer Center, Houston, TX 77030, USA.
We examined the expression level of several genes that regulate distinct
steps of metastasis in 55 formalin-fixed, paraffin-embedded, archival
specimens of primary human ovarian carcinoma from patients undergoing
curative surgery. The expression of vascular endothelial growth
factor/vascular permeability factor (VEGF/VPF), basic fibroblast growth
factor (bFGF), E-cadherin, type IV collagenase, matrix metalloproteinase
(MMP-2 and MMP-9), and interleukin 8 (IL-8) was examined by a
colorimetric in situ mRNA hybridization technique. The expression level
of E-cadherin, MMP-2, MMP-9, VEGF, and IL-8 mRNA correlated with disease
stages. The ratio of type IV collagenase expression (mean of the
expression of MMP-2 and MMP-9) to E-cadherin expression (MMP:E-cadherin
ratio) increased with increasing stage of disease (p<0.0001). Death
rates significantly increased with high MMP:E-cadherin ratio (p=0.0005).
Multivariate analysis of overall survival showed that the MMP:E-cadherin
ratio was a significant independent prognostic factor, even after
adjustment for known prognostic factors, such as histology, stage, and
age.
25
UI - 11780319
AU - Ye D; Xie X; Lu W; Chen H; Cheng B
TI -
Growth inhibition of interleukin-2 receptor gene-transduced peripheral
blood lymphocytes on human ovarian cancer cells.
SO - Chin Med J (Engl) 2001 Mar;114(3):303-7
AD - Department of Oncology, Women's Hospital, School of Medicine, Zhejiang
University, Hangzhou 310006, China.
OBJECTIVE: To investigate the growth inhibition of interleukin-2
receptor (IL-2R) gene-transduced peripheral blood lymphocytes (PBLs) on
human ovarian cancer cells. METHODS: Interleukin-2 (IL-2) and IL-2R
genes were transfected into human ovarian cancer cell line 3AO and PBLs,
respectively, using the same Fugene vector. Twenty-four hours later
transfected and nontransfected PBLs were cocultured with transfected and
nontransfected 3AO for 48 hours. cytotoxicity of PBLs on 3AO was
detected by the MTT assay. RESULTS: The morphology of IL-2-transduced
3AO and IL-2R-transduced PBLs remained unchanged. 3AO cells could be
transfected with the IL-2 gene and expressed IL-2 mRNA, and PBLs could
be transfected with the IL-2R gene and expressed IL-2R mRNA. IL-2
transduced 3AO cells enhanced their response to the cytotoxicity of
PBLs. Furthermore, growth inhibition of PBLs to 3AO cells increased
significantly when the IL-2R was transfected into PBLs and when the IL-2
gene was transfected into 3AO cells and the two were combined.
CONCLUSIONS: IL-2R gene transduced PBLs are able to enhance their
cytotoxicity on IL-2 gene transduced ovarian cancer cells. This method
may be a new way to investigate IL-2 gene therapy for ovarian cancer.
26
UI - 11780195
AU - Guan J; Ma L; Wei L
TI -
Characteristics of ovarian cancer cells transduced by the bicistronic
retroviral vector containing GM-CSF and HSV-TK genes.
SO - Chin Med J (Engl) 2001 Feb;114(2):147-51
AD - Department of Gynecology and Obstetrics, People's Hospital, Peking
University, Beijing 100044, China.
OBJECTIVES: To explore whether HSV-TK (herpes simplex virus thymidine
kinase) and GM-CSF (granulocyte-macrophage colony-stimulating factor)
genes could be linked by internal ribosome entry site (IRES) in one
retroviral vector and expressed by ovarian cancer cells following
transfection, and to observe the characteristics of the transduced
cells. METHODS: Retroviral vector pLGM-I-TK was constructed by linking
the HSV-TK gene and GM-CSF gene with the IRES sequence. By using the
"ping-pong" technique, pLGM-I-TK was transfected into the packaging cell
line, PA317, to produce a PA317/TK-GM cell line. Using the resulting
viral supernatant to infect the ovarian cancer cell line SKOV3, PCR and
RT-PCR were used to explore the integration and transcription of HSV-TK
and GM-CSF genes. The cytotoxicity of GCV (gancyclovir) on SKOV3/TK-GM
was determined by MTT assay and the bystander effect of the HSV-TK/GCV
system was also assessed. ELISA was used to measure the expression of
GM-CSF by the transgene cells. RESULTS: The bicistronic retroviral
vector constructed could be successfully transduced into PA317 and the
titer of the retroviral vector was about 8.6 x 10(5) cfu/ml. PCR and
RT-PCR demonstrated the successful integration and transcription of
HSV-TK and GM-CSF genes transduced into the SKOV3 cell. SKOV3/TK-GM
cells could be killed by GCV, and the IC50 was 0.7 microgram/ml. The
bystander effect was demonstrated. The expression level of GM-CSF in
SKOV3/TK-GM was 60.4 ng.ml-1 x 10(6) cells-1 x 2 days-1. CONCLUSION: The
IRES sequence can be used to construct retroviral vectors to facilitate
co-transfection of two genes. SKOV3/TK-GM cells can simultaneously
express the HSV-TK and GM-CSF genes with biological activities which
could be useful for enhancing the function of immune cells on the basis
of suicide gene therapy.
27
UI - 11779836
AU - Manderson EN; Mes-Masson AM; Novak J; Lee PD; Provencher D; Hudson TJ;
TI -
Tonin PN
Expression profiles of 290 ESTs mapped to chromosome 3 in human
epithelial ovarian cancer cell lines using DNA expression
oligonucleotide microarrays.
SO - Genome Res 2002 Jan;12(1):112-21
AD - Department of Human Genetics, McGill University, Montreal, Quebec H3A
1B1, Canada.
We have investigated previously the utility of oligonucleotide
expression microarray technology in an analysis of four spontaneously
transformed epithelial ovarian cancer (EOC) cell lines, TOV-21G,
TOV-81D, OV-90, and TOV-112D. Here, we examine the expression of 290
expressed sequence tags (ESTs) that map to human chromosome 3 in a
primary culture derived from normal ovarian surface epithelium (NOSE),
NOV-31, and the four spontaneously transformed EOC cell lines. One of
these cell lines, OV-90, harbors a deletion of an entire chromosome 3p
arm. Whereas the most aggressive cell lines (OV-90, TOV-112D, and
TOV-21G) exhibited the highest levels of expression, assessed by the
mean of expression values of all ESTs, OV-90 showed the lowest mean of
expression of ESTs that map to the 3p arm in comparison with TOV-112D
and TOV-21G. This difference in expression profile of 3p ESTs in OV-90
is also reflected in the ratio of expression of ESTs on 3p versus the 3q
arm and in that the expression values of ESTs that map to 3p were more
often lower than higher in OV-90 in two-way comparisons with NOV-31,
TOV-21G, and TOV-112D. The loss of a 3p arm does not affect the pattern
of differential expression in analyses based on the range of numeric
expression values of each EST or fold differences in expression for each
EST in comparison with NOV-31. However, 25 differentially expressed ESTs
were identified on the basis of threefold differences in expression
values between NOV-31 and any EOC cell line; and six of these ESTs were
differentially expressed uniquely in OV-90. The investigation of these
ESTs could facilitate the identification of novel chromosome 3 genes
implicated in ovarian tumorigenesis.
28
UI - 11807889
AU - Hughes C; Lerman C; Schwartz M; Peshkin BN; Wenzel L; Narod S; Corio C;
TI -
Tercyak KP; Hanna D; Isaacs C; Main D
All in the family: evaluation of the process and content of sisters'
communication about BRCA1 and BRCA2 genetic test results.
SO - Am J Med Genet 2002 Jan 15;107(2):143-50
AD - Department of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, USA. chanita@mail.med.upenn.edu
Despite the potential importance of family communication, little is
known about the process and content of communicating BRCA1/2 test
results to relatives. The objectives of this observational study were to
describe the process and content of communicating BRCA1/2 test results
to sisters, and to evaluate whether the proband's carrier status
influenced communication outcomes. Participants were 43 women who were
the first family member to have genetic testing (probands). Probands
reported on communication outcomes for 81 sisters. Process and content
variables were evaluated 1-month after receipt of BRCA1/2 test results
using the Family Communication Questionnaire (FCQ). Overall, BRCA1/2
test results were communicated to 85% of sisters, and carriers
communicated their results to significantly more sisters compared to
uninformative (96% vs. 76%, FET = 0.02). The most important reason for
communicating results was to provide genetic risk information; however,
compared to uninformatives, carriers communicated their results to
significantly more sisters to obtain emotional support (74%) and to get
advice about medical decisions (42%) (FET = 0.001). Carriers also
discussed the possibility of discrimination and recommendations for
cancer management with significantly more sisters. Among sisters to whom
BRCA1/2 test results were not communicated, the most important reason
for not sharing test results was because of emotionally distant
relationships. The results of this study suggest that probands are
likely to quickly communicate their BRCA1/2 test results to relatives
and that although needs for social support may motivate family
communication, emotionally distant relationships may be a barrier to
communication with relatives. Copyright 2001 Wiley-Liss, Inc.
29
UI - 11821951
AU - Liu Y; Emilion G; Mungall AJ; Dunham I; Beck S; Le Meuth-Metzinger VG;
TI -
Shelling AN; Charnock FM; Ganesan TS
Physical and transcript map of the region between D6S264 and D6S149 on
chromosome 6q27, the minimal region of allele loss in sporadic
epithelial ovarian cancer.
SO - Oncogene 2002 Jan 17;21(3):387-99
AD - ICRF Molecular Oncology Laboratories, John Radcliffe Hospital,
Headington, Oxford, OX3 9DS, UK.
We have previously shown a high frequency of allele loss at D6S193 (62%)
on chromosomal arm 6q27 in ovarian tumours and mapped the minimal region
of allele loss between D6S297 and D6S264 (3 cM). We isolated and mapped
a single non-chimaeric YAC (17IA12, 260-280 kb) containing D6S193 and
D6S297. A further extended bacterial contig (between D6S264 and D6S149)
has been established using PACs and BACs and a transcript map has been
established. We have mapped six new markers to the YAC; three of them
are ESTs (WI-15078, WI-8751, and TCP10). We have isolated three cDNA
clones of EST WI-15078 and one clone contains a complete open reading
frame. The sequence shows homo
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