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NCI CANCERLIT® Search: Hereditary Ovarian Cancer - October 2001
National Cancer Institute®
Ultima Vez Modificado: 21 de noviembre del 2001
Table of Contents
1
UI - 21338552
AU - Manahan KJ; Taylor DD; Gercel-Taylor C
TI -
Clonal heterogeneity of p53 mutations in ovarian cancer.
SO - Int J Oncol 2001 Aug;19(2):387-94
AD - University of Michigan School of Medicine, Ann Arbor, MI, USA.
We analyzed clonal populations of ovarian cancer cells for heterogeneity
in p53 mutations (exons 4-9) and chemosensitivity. UL-3A cells were
developed from a patient with stage IIIC ovarian adenocarcinoma.
Heterogeneity in p53 mutations was demonstrated, ranging from point
mutations to deletions in exons 4, 6 and 7. UL-3A cells contained two
point mutations, in codon 248 of exon 7 and in codon 76 of exon 4. Five
groups of clones were identified according to the p53 mutations. UL-3A
clones with low p53 levels were more sensitive to CDDP (LD50 <8.0
microg/ml). Heterogeneity of p53 mutations may provide growth advantage
during disease progression or chemotherapy.
2
UI - 21381862
AU - Markman M
TI -
Is it good clinical judgment or selection bias?
SO - Curr Oncol Rep 2001 Sep;3(5):377-8
3
UI - 21385151
AU - Sylvain V; Lafarge S; Bignon YJ
TI -
Molecular pathways involved in response to ionizing radiation of ID-8
mouse ovarian cancer cells expressing exogenous full-length Brca1 or
truncated Brca1 mutant.
SO - Int J Oncol 2001 Sep;19(3):599-607
AD - Laboratoire d'Oncologie Moleculaire, Centre Jean Perrin, 58 Rue
Montalembert, BP 392, 63 011 Clermont-Ferrand Cedex 1, France.
BRCA1 germline mutations have been linked to the development of
hereditary breast and ovarian cancers. Recent studies suggest that BRCA1
may function in the regulation of basic cellular processes, including
gene transcription, and sensing and/or repair of DNA damage. To further
delineate the BRCA1 upstream and downstream steps involved in its role
in the cellular response to ionizing radiation, we compared the effects
of expression of an exogenous full-length Brca1 with those of a
truncated Brca1 mutant in the ID-8 mouse ovarian cancer cell line after
irradiation. We found that expression of both full-length and truncated
Brca1 increased resistance to ionizing radiation. Expression of
truncated, but not full-length, Brca1 then allowed us to identify new
potential downstream targets of mutated BRCA1 like MAPK/ERK pathway
members and also key genes involved in mutated BRCA1 signaling pathway
response to ionizing radiation such as p53 and p21WAF1/CIP1. We
therefore established an in vitro mouse model for studying the molecular
effects of human BRCA1 germline mutations.
4
UI - 21445654
AU - Sivridis E; Giatromanolaki A
TI -
Prognostic aspects on endometrial hyperplasia and neoplasia.
SO - Virchows Arch 2001 Aug;439(2):118-26
AD - Department of Pathology, Democritus University of Thrace,
Alexandroupolis, Greece. esivrid@med.duth.gr
There are various forms of endometrial hyperplasia which, in terms of
prognosis and therapy, can be subdivided into those having cytological
atypia and those lacking this feature. The former may progress into
invasive endometrial malignancy through a transitional non-invasive
stage. This is a continuous process and, as a result, the distinction
between an atypical hyperplasia and an intraepithelial adenocarcinoma
(IEA) or an adenocarcinoma with stromal invasion is not histologically
reproducible. The concept of endometrioid neoplasia, which includes the
entire spectrum of the aforementioned proliferating endometrial lesions,
was introduced. Adenocarcinomas arising from an atypical hyperplasia are
invariably of the endometrioid cell type, whereas those developing from
an atrophic endometrium may be either of the endometrioid or of the
non-endometrioid cell type. Endometrioid adenocarcinomas arising through
the hyperplasia-neoplasia sequence are oestrogen induced and tend to be
well differentiated and less invasive of the myometrium, lack lymphatic
and metastatic involvement and have an excellent prognosis.
Oestrogen-induced adenocarcinomas are also endometrioid, arising from an
atrophic or a rather weakly proliferating endometrium, but these
neoplasms are frequently of higher histological grade and have a
somewhat less favourable prognosis. Finally, endometrial carcinomas of
the non-endometrioid cell type, mainly serous papillary and clear cell
carcinomas, are non-oestrogen induced, non-hyperplasia associated and
show adverse aggressive histological features and an extremely poor
prognosis. The antigenic characteristics and the molecular events
associated with the development of these forms of endometrial malignancy
are distinct and allow the description of, at least, two pathogenetic
types of endometrial carcinoma.
5
UI - 21439147
AU - Nicoletti MI; Valoti G; Giannakakou P; Zhan Z; Kim JH; Lucchini V;
TI -
Landoni F; Mayo JG; Giavazzi R; Fojo T
Expression of beta-tubulin isotypes in human ovarian carcinoma
xenografts and in a sub-panel of human cancer cell lines from the
NCI-Anticancer Drug Screen: correlation with sensitivity to microtubule
active agents.
SO - Clin Cancer Res 2001 Sep;7(9):2912-22
AD - Department of Oncology, Mario Negri Institute for Pharmacological
Research, 24125 Bergamo, Italy. nicoletti@marionegri.it
Paclitaxel resistance has been associated with overexpression of
P-glycoprotein and alterations involving tubulin. To investigate the
clinical relevance of these in vitro resistance mechanisms, we
established 12 human ovarian carcinoma xenografts, using samples from
patients before the start of therapy or after paclitaxel treatment.
These xenografts showed a wide range of sensitivity to paclitaxel, and
in 4 of them, very low levels of multidrug resistance-1 expression were
detected. Using quantitative PCR and human specific primers, the
expression of five beta-tubulin isotypes was determined. HM40 was the
predominant, accounting for 84.7-98.7% of all tubulin; expression of the
other four isotypes (Hbeta9, Hbeta4, H5beta, and Hbeta2) was also
detected but at lower levels. No correlation could be demonstrated
between isotype expression and paclitaxel sensitivity in these 12
xenografts. A similar pattern of beta-tubulin isotype expression was
observed in a subset of cell lines from the National Cancer
Institute-Anticancer Drug Screen. In these cell lines, however, a
significant correlation between increased expression of Hbeta4 isotype
and resistance to paclitaxel was found. Taken together, these results
suggest that altered expression of specific beta-tubulin isotypes may
not play a significant role in paclitaxel sensitivity in vivo and argue
against a possible significance in a clinical setting.
6
UI - 21454126
AU - Piek JM; van Diest PJ; Zweemer RP; Kenemans P; Verheijen RH
TI -
Tubal ligation and risk of ovarian cancer.
SO - Lancet 2001 Sep 8;358(9284):844
7
UI - 21450459
AU - Lahti-Domenici J; Rapakko K; Paakkonen K; Allinen M; Nevanlinna H;
TI -
Kujala M; Huusko P; Winqvist R
Exclusion of large deletions and other rearrangements in BRCA1 and BRCA2
in Finnish breast and ovarian cancer families.
SO - Cancer Genet Cytogenet 2001 Sep;129(2):120-3
AD - Department of Clinical Genetics, University of Oulu/Oulu University
Hospital, P.O. Box 22, FIN-90220, Oulu, Finland.
In the Finnish population, identified mutations in BRCA1 and BRCA2
account for a less than expected proportion of hereditary breast and
ovarian cancer. All previous studies performed in our country have
concentrated on finding germ-line mutations in the coding and
splice-site regions of these two genes. Therefore, we wanted to use a
different methodological approach and search for large genomic
rearrangements, to exclude the possibility of biased BRCA1 and BRCA2
mutation spectra due to known limitations of the previously used
PCR-based detection methods. Our results support earlier notions that
other genes than BRCA1 and BRCA2 will explain a majority of the still
unexplained cases of hereditary susceptibility to breast and ovarian
cancer.
8
UI - 21450461
AU - Cao Q; Abeysinghe H; Chow O; Xu J; Kaung H; Fong C; Keng P; Insel RA;
TI -
Lee WM; Barrett JC; Wang N
Suppression of tumorigenicity in human ovarian carcinoma cell line
SKOV-3 by microcell-mediated transfer of chromosome 11.
SO - Cancer Genet Cytogenet 2001 Sep;129(2):131-7
AD - Department of Pathology and Laboratory Medicine, University of Rochester
School of Medicine and Dentistry, NY, USA.
To determine the pathogenic role of chromosomes 11 and 17 in the
carcinogenesis of human ovarian cancers, neo(R)-tagged chromosome 11 or
17 was transferred from cell lines A9H11 or A9H17, respectively, into
the ovarian carcinoma cell line SKOV-3 using microcell-mediated
chromosome transfer. The chromosome transfer was verified by polymerase
chain reaction detection of the neo(R) gene, fluorescence in situ
hybridization detection of an extra chromosome 11, and microsatellite
polymorphism detection of an exogeneous chromosome 11. Five SKOV-3/A9H11
hybrids and five SKOV-3/A9H17 hybrid clones were generated. For the
chromosome 11 transfer, complete suppression of tumorigenicity was
observed in four clones, (11)9-8 and 11(H)7-2, 11(H)8-3, and 11(H)7-2,
100 days post implantation. For the chromosome 17 transfer, no complete
suppression of tumorigenicity was observed. However, an increased
latency period ranging from 25 to 49 days in contrast to 7 days for the
SKOV-3 parental line, and a significant reduction in tumor size was
observed. There was no correlation between the in vitro growth rate and
the tumorigenicity or length of latency period. Our results demonstrate
functionally that chromosome 11 may carry a tumor suppressor gene(s)
while chromosome 17 may carry a tumor growth-inhibitor gene(s) for the
ovarian carcinoma cell line, SKOV-3.
9
UI - 21423015
AU - Francis-Thickpenny KM; Richardson DM; van Ee CC; Love DR; Winship IM;
TI -
Baguley BC; Chenevix-Trench G; Shelling AN
Analysis of the TGF beta functional pathway in epithelial ovarian
carcinoma.
SO - Br J Cancer 2001 Sep 1;85(5):687-91
AD - Department of Obstetrics and Gynaecology, Research Centre in
Reproductive Medicine, National Women's Hospital, Auckland, Australia.
Epithelial ovarian carcinoma is often diagnosed at an advanced stage of
disease and is the leading cause of death from gynaecological neoplasia.
The genetic changes that occur during the development of this carcinoma
are poorly understood. It has been proposed that IGFIIR, TGFbeta1 and
TGFbetaRII act as a functional unit in the TGFbeta growth inhibitory
pathway, and that somatic loss-of-function mutations in any one of these
genes could lead to disruption of the pathway and subsequent loss of
cell cycle control. We have examined these 3 genes in 25 epithelial
ovarian carcinomas using single-stranded conformational polymorphism
analysis and DNA sequence analysis. A total of 3 somatic missense
mutations were found in the TGFbetaRII gene, but none in IGFRII or
TGFbeta1. An association was found between TGFbetaRII mutations and
histology, with 2 out of 3 clear cell carcinomas having TGFbetaRII
mutations. This data supports other evidence from mutational analysis of
the PTEN and beta-catenin genes that there are distinct developmental
pathways responsible for the progression of different epithelial ovarian
cancer histologic subtypes. Copyright 2001 Cancer Research Campaign.
10
UI - 21468601
AU - Gershoni-Baruch R; Dagan E; Israeli D; Kasinetz L; Kadouri E; Friedman E
TI -
Association of the C677T polymorphism in the MTHFR gene with breast
and/or ovarian cancer risk in Jewish women.
SO - Eur J Cancer 2000 Dec;36(18):2313-6
AD - Institute of Human Genetics, Rambam Medical Center, Haifa, Israel.
rgershoni@rambam.health.gov.il
The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR)
gene is associated with reduced enzyme activity, hyperhomocysteinaemia
and increased risk for atherosclerosis in homozygotes. We examined the
frequency of this mutation and its association with disease pattern in
491 Jewish women with either sporadic (n = 355; 72%) or hereditary (n =
136; 28%) breast and/or ovarian cancer and in 69 asymptomatic BRCA1/2
mutation carriers, genotyped for the three predominant Jewish founder
BRCA1/2 mutations (185delAG, 5382insC and 6174delT). 677T homozygotes
were equally distributed among women with sporadic breast and/or ovarian
cancer (71/355; 20.0%) and among BRCA1/2 mutation carriers (43/205;
21.0%) (P=non-significant). 677T homozygotes were equally distributed
among women diagnosed with breast cancer prior to (22/122; 18.0%) and
after 42 years of age (42/243; 17.3%). Among BRCA1/2 carriers, the rate
of 677T homozygotes in manifesting cancer (32/136; 23.5%) and
asymptomatic individuals (11/69; 15.9%) was not significantly different.
The rate of 677T homozygotes (24/72; 33.3%) was higher (P=0.0026) among
women with bilateral breast cancer and those with both breast and
ovarian carcinoma than among those with unilateral breast cancer
(64/365; 17.5%). Differences in morbidity (one versus multiple
breast/ovarian tumours) are mainly attributed to 677T homozygosity and
partly to BRCA1/2 mutations. Confirmation of these data, namely, that
the 677T allele is significantly more common in cases of bilateral
breast cancer or combined breast and ovarian cancer would have important
clinical implications.
11
UI - 21283055
AU - Bergthorsson JT; Ejlertsen B; Olsen JH; Borg A; Nielsen KV; Barkardottir
TI -
RB; Klausen S; Mouridsen HT; Winther K; Fenger K; Niebuhr A; Harboe TL;
Niebuhr E
BRCA1 and BRCA2 mutation status and cancer family history of Danish
women affected with multifocal or bilateral breast cancer at a young
age.
SO - J Med Genet 2001 Jun;38(6):361-8
AD - Department of Medical Genetics, Institute for Medical Biochemistry and
Genetics, Panum Institute, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
nonni@rsp.is
INTRODUCTION: A small fraction of breast cancer is the result of
germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes.
Mutation carriers frequently have a positive family history of breast
and ovarian cancer, are often diagnosed at a young age, and may have a
higher incidence of double or multiple primary breast tumours than
breast cancer patients in general. OBJECTIVES: To estimate the
prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish
patients affected with bilateral or multifocal breast cancer and to
determine the relationship of mutation status to family history of
cancer. SUBJECTS: From the files of the Danish Breast Cancer Cooperative
Group (DBCG), we selected 119 breast cancer patients diagnosed before
the age of 46 years with either bilateral (n=59) or multifocal (n=61)
disease. METHODS: DNA from the subjects was screened for BRCA1 and BRCA2
mutations using single strand conformation analysis (SSCA) and the
protein truncation test (PTT). Observed and expected cancer incidence in
first degree relatives of the patients was estimated using data from the
Danish Cancer Registry. RESULTS: Twenty four mutation carriers were
identified (20%), of whom 13 had a BRCA1 mutation and 11 carried a BRCA2
mutation. Two mutations in BRCA1 were found repeatedly in the material
and accounted for seven of the 24 (29%) mutation carriers. The mutation
frequency was about equal in patients with bilateral (22%) and
multifocal breast cancer (18%). The incidence of breast and ovarian
cancer was greatly increased in first degree relatives of BRCA1 and
BRCA2 mutation carriers, but to a much lesser degree in relatives of
non-carriers. An increased risk of cancer was also noted in brothers of
non-carriers. CONCLUSIONS: A relatively broad spectrum of germline
mutations was observed in BRCA1 and BRCA2 and most of the mutations are
present in other populations. Our results indicate that a diagnosis of
bilateral and multifocal breast cancer is predictive of BRCA1 and BRCA2
mutation status, particularly when combined with information on the
patients' age at diagnosis and family history of breast/ovarian cancer.
12
UI - 21317608
AU - Gad S; Scheuner MT; Pages-Berhouet S; Caux-Moncoutier V; Bensimon A;
TI -
Aurias A; Pinto M; Stoppa-Lyonnet D
Identification of a large rearrangement of the BRCA1 gene using
colour bar code on combed DNA in an American breast/ovarian cancer
family previously studied by direct sequencing.
SO - J Med Genet 2001 Jun;38(6):388-92
13
UI - 21328978
AU - Sarantaus L; Vahteristo P; Bloom E; Tamminen A; Unkila-Kallio L; Butzow
TI -
R; Nevanlinna H
BRCA1 and BRCA2 mutations among 233 unselected Finnish ovarian carcinoma
patients.
SO - Eur J Hum Genet 2001 Jun;9(6):424-30
AD - Department of Obstetrics and Gynecology, Helsinki University Central
Hospital, Biomedicum Helsinki, P.O. Box 700 (Haartmaninkatu 8),
FIN-00029 HUS, Finland.
Germline mutations of BRCA1 and BRCA2 predispose to hereditary
breast-ovarian cancer syndrome. In Finland, 20 different BRCA1/2
mutations have been identified, and 13 of them are founder mutations
that account for the vast majority of Finnish BRCA1/2 families. The
purpose of our study was to determine the prevalence of BRCA1/2
mutations in unselected Finnish ovarian carcinoma patients and to
evaluate the relationship between mutation carrier status and
personal/family history of cancer. Two hundred and thirty-three patients
were screened for all the 20 BRCA1/2 mutations known in the Finnish
population. Additionally, a subgroup of patients with personal history
of breast cancer and/or family history of breast and/or ovarian cancer
was screened for novel BRCA1/2 mutations. Thirteen patients (5.6%) had
mutations: eleven in BRCA1 and two in BRCA2. All the mutation-positive
patients were carriers of the previously known Finnish BRCA1/2
mutations, and seven recurrent founder mutations accounted for 12 of the
13 mutations detected. A logistic regression analysis was used to
determine the odds of mutation for ovarian carcinoma patients. The most
significant predictor of a mutation was the presence of both breast and
ovarian cancer in the same woman, but family history of breast cancer
was also strongly related to mutation carrier status. Although BRCA1/2
mutation testing is not warranted in the general Finnish ovarian cancer
patient population, patients who have also been diagnosed with breast
cancer or have family history of breast or breast and ovarian cancer
could benefit from referral to genetic counselling and mutation testing.
14
UI - 21443289
AU - Syed V; Ulinski G; Mok SC; Yiu GK; Ho SM
TI -
Expression of gonadotropin receptor and growth responses to key
reproductive hormones in normal and malignant human ovarian surface
epithelial cells.
SO - Cancer Res 2001 Sep 15;61(18):6768-76
AD - Department of Surgery, Division of Urology, University of Massachusetts
Medical School, Worcester, Massachusetts 01655, USA.
Epidemiological data have implicated reproductive hormones as probable
risk factors for ovarian cancer (OCa) development. Although pituitary
and sex hormones have been reported to regulate OCa cell growth, no
information is available regarding whether and how they influence normal
ovarian surface epithelial (OSE) cell proliferation. To fill this data
gap, this study has compared cell growth responses to gonadotropins and
sex steroids in primary cultures of human OSE (HOSE) cells with those
observed in immortalized, nontumorigenic HOSE cells and in OCa cell
lines. Both malignant and normal cell lines/cultures responded equally
well to the stimulatory actions of luteinizing hormone and
follicle-stimulating hormone and to 17beta-estradiol and estrone,
although the latter estrogen has a much lower affinity for estrogen
receptor than does the former estrogen. In normal HOSE cell
cultures/lines, 5alpha-dihydrotestosterone was found to be more
effective than testosterone in stimulating cell growth, but in OCa cell
lines, 5alpha-dihydrotestosterone and testosterone are equally potent.
One OCa cell line, OVCA 433, was found to be nonresponsive to androgen
stimulation. In general, primary cultures of normal HOSE cells exhibited
the greatest hormone-stimulated growth responses (>10-fold enhancement),
followed by immortalized HOSE cell lines (4-5-fold enhancement) and by
OCa cell lines (2-4-fold enhancement). Interestingly, progesterone (P4),
at low concentrations (10(-11) to 10(-10) M), was stimulatory to HOSE
and OCa cell growth, but at high doses (10(-8) to 10(-6) M), P4 exerted
marked inhibitory effects. In all cases, cotreatment of a cell
culture/line with a hormone and its specific antagonist blocked the
effect of the hormone, confirming specificity of the hormonal action.
Taken together, these data support the hypothesis that reproductive
states associated with rising levels of gonadotropins, estrogen, and/or
androgen promote cell proliferation in the normal OSE, which favors
neoplastic transformation. Conversely, those states attended by high
levels of circulating P4, such as that seen during pregnancy, induce OSE
cell loss and offer protection against ovarian carcinogenesis.
15
UI - 21463149
AU - McDonnell SK; Schaid DJ; Myers JL; Grant CS; Donohue JH; Woods JE; Frost
TI -
MH; Johnson JL; Sitta DL; Slezak JM; Crotty TB; Jenkins RB; Sellers TA;
Hartmann LC
Efficacy of contralateral prophylactic mastectomy in women with a
personal and family history of breast cancer.
SO - J Clin Oncol 2001 Oct 1;19(19):3938-43
AD - Division of Medical Oncology, Mayo Clinic Cancer Center, Mayo Clinic and
Mayo Foundation, Rochester, MN 55905, USA.
PURPOSE: To estimate the efficacy of contralateral prophylactic
mastectomy in women with a personal and family history of breast cancer.
PATIENTS AND METHODS: We followed the course of 745 women with a first
breast cancer and a family history of breast and/or ovarian cancer who
underwent contralateral prophylactic mastectomy at the Mayo Clinic
between 1960 and 1993. Family history information and cancer follow-up
information were obtained from the medical record, a study-specific
questionnaire, and telephone follow-up. Life-tables for contralateral
breast cancers, which consider age at first breast cancer, current age,
and type of family history, were used to calculate the number of breast
cancers expected in our cohort had they not had a prophylactic
mastectomy. RESULTS: Of the 745 women in our cohort, 388 were
premenopausal (age < 50 years) and 357 were post- menopausal. Eight
women developed a contralateral breast cancer. Six events were observed
among the premenopausal women, compared with 106.2 predicted, resulting
in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to
97.9%). For the 357 postmenopausal women, 50.3 contralateral breast
cancers were predicted, whereas only two were observed, representing a
96.0% risk reduction (95% CI, 85.6% to 99.5%). CONCLUSION: The incidence
of contralateral breast cancer seems to be reduced significantly after
contralateral prophylactic mastectomy in women with a personal and
family history of breast cancer.
16
UI - 20487065
AU - Piver MS
TI -
Insurance policies for prophylactic mastectomy: to cover or not to
cover?
SO - Ann Surg Oncol 2000 Oct;7(9):714
17
UI - 21381734
AU - Dong Y; Kaushal A; Bui L; Chu S; Fuller PJ; Nicklin J; Samaratunga H;
TI -
Clements JA
Human kallikrein 4 (KLK4) is highly expressed in serous ovarian
carcinomas.
SO - Clin Cancer Res 2001 Aug;7(8):2363-71
AD - Centre of Molecular Biotechnology, School of Life Sciences, Queensland
University of Technology, Brisbane, Queensland 4001, Australia.
Previous studies indicated that a new member of the human kallikrein
(KLK) gene family, KLK4, was expressed in prostate, breast, and
endometrial carcinoma cell lines and may have potential as a tumor
marker. The aim of this study was to examine the expression of KLK4 in
the normal ovary and ovarian tumors of different histology, stage, and
differentiation and to determine its association with ovarian tumor
progression. Using reverse transcription-PCR, Southern blot, and
densitometry analyses, we found the level of KLK4 expression was higher
in late stage serous (SER) epithelial-derived ovarian carcinomas than in
normal ovaries, mucinous epithelial tumors, and granulosa cell tumors.
KLK4 was highly expressed in all of the SER ovarian carcinoma cell lines
(eight of eight), SER epithelial carcinomas (11 of 11), and two
adenomas, whereas it was expressed at a lower level (or not at all) in
normal ovaries (four of six), mucinous epithelial tumors (three of
four), endometrioid carcinomas (four of five), clear cell carcinomas
(two of three), or granulosa cell tumors (three of six). Of particular
interest, KLK4 mRNA variants were detected in SER ovarian carcinoma cell
lines and primary cultured ovarian tumor cells, but they were not
present in normal ovaries. In situ hybridization analysis showed that
KLK4 mRNA transcripts are localized to adenocarcinoma cells of ovarian
tumor tissues. Similarly, immunohistochemical staining of ovarian
carcinoma sections showed immunoreactivity to KLK4 protein product (hK4)
antipeptide antibodies. In addition, intracellular hK4 levels, as
detected on Western blot analysis, were induced by 100 nM estrogen
treatment of the estrogen receptor positive ovarian carcinoma cell line
OVCAR-3, >8-24 h. Our results show that the level of KLK4 expression and
expression of KLK4 mRNA variants are associated with progression of
ovarian cancer, particularly late stage SER adenocarcinomas. Moreover,
hK4 may be a candidate marker for the diagnosis and/or monitoring of
ovarian epithelial carcinomas.
18
UI - 21381736
AU - Obiezu CV; Scorilas A; Katsaros D; Massobrio M; Yousef GM; Fracchioli S;
TI -
Rigault de la Longrais IA; Arisio R; Diamandis EP
Higher human kallikrein gene 4 (KLK4) expression indicates poor
prognosis of ovarian cancer patients.
SO - Clin Cancer Res 2001 Aug;7(8):2380-6
AD - Department of Pathology and Laboratory Medicine, Mount Sinai Hospital,
Toronto, Ontario, M5G 1X5 Canada.
PURPOSE: Kallikrein gene 4 (KLK4, also known as prostase/KLK-L1),
located on chromosome 19q13.4, is one of the newly discovered members of
the human KLK-like gene family. This gene is up-regulated by androgens
in the LNCaP prostatic carcinoma cell line and by androgens and
progestins in the BT-474 breast cancer cell line. On the basis of its
apparent association with hormonally regulated tissues, we have
undertaken to examine the prognostic value of KLK4 expression in 147
malignant ovarian tissues. EXPERIMENTAL DESIGN: Tumors were pulverized,
total RNA was extracted, and cDNA was prepared by reverse transcription.
KLK4 was amplified by PCR using gene-specific primers, and its identity
was verified by sequencing. Ovarian tissues were then classified as
KLK4-positive or -negative, based on ethidium bromide visualization of
the PCR product on agarose gels. RESULTS: KLK4 was found to be expressed
in 69 (55%) of 147 of ovarian cancer samples. We found a strong positive
association between KLK4 expression and tumor grade (P = 0.02) and
clinical stage (P < 0.001). Univariate survival analysis revealed that
patients with ovarian tumors positive for KLK4 expression had an
increased risk for relapse and death (P = 0.003 and 0.001,
respectively). Whereas knowledge of KLK4 status did not significantly
increase the prognostic power of the multivariate models, additional
analyses did determine that KLK4 was an independent unfavorable
prognostic factor in patients with grade 1 and 2 tumors. CONCLUSIONS:
Our findings indicate that KLK4 expression is associated with more
aggressive forms of ovarian cancer.
19
UI - 21381739
AU - Hata K; Fujiwaki R; Nakayama K; Miyazaki K
TI -
Expression of the Endostatin gene in epithelial ovarian cancer.
SO - Clin Cancer Res 2001 Aug;7(8):2405-9
AD - Department of Obstetrics and Gynecology, Shimane Medical University,
Izumo 693-8501, Japan. hata31@shimane-med.ac.jp
Endostatin, a M(r) 20,000 COOH-terminal fragment of collagen XVIII, is
currently in preclinical development as a novel antiangiogenic agent.
The gene expression of this molecule in 23 normal ovaries with follicle
or corpus luteum and in 64 cases of epithelial ovarian cancer (27
serous, 18 mucinous, 13 endometrioid, 4 clear cell, and 2
undifferentiated carcinomas) was analyzed by PCR of RNA after reverse
transcription. Seven of the cases were of low malignant potential. With
regard to staging, 23 cases had stage I disease, 5 had stage II disease,
29 had stage III disease, and 7 had stage IV disease. The level of
endostatin gene expression was described in terms of the ratio of the
relative yield of the endostatin gene to that of the beta2-microglobulin
gene. Endostatin gene expression in ovarian cancers (median, 0.14;
range, 0.02-1.11) was significantly higher than that in normal ovaries
with follicle or corpus luteum (median, 0.08; range, 0.03-0.26; P =
0.009). International Federation of Gynecology and Obstetrics stage (P =
0.009) and residual tumor (P = 0.005) were significantly associated with
endostatin gene expression; however, other clinicopathological features
(e.g., patient age at diagnosis, histological subtype, and histological
grade) were not significantly associated with endostatin gene
expression. Survival data were available for all patients. Univariate
Cox regression analysis showed the prognosis of the patients with high
endostatin gene expression [equal to or greater than the median (> or
=0.14)] to be significantly worse than that of patients with low
endostatin gene expression [less than the median (<0.14); P = 0.044].
Our results with regard to the gene expression of this endogenous
inhibitor of angiogenesis present a new insight to understand the
biology of epithelial ovarian cancer and may lead to the development of
a new therapeutic strategy for epithelial ovarian cancer.
20
UI - 21381745
AU - Konecny G; Untch M; Arboleda J; Wilson C; Kahlert S; Boettcher B; Felber
TI -
M; Beryt M; Lude S; Hepp H; Slamon D; Pegram M
Her-2/neu and urokinase-type plasminogen activator and its inhibitor in
breast cancer.
SO - Clin Cancer Res 2001 Aug;7(8):2448-57
AD - Division of Hematology-Oncology, Department of Medicine, University of
California Los Angeles School of Medicine, Los Angeles, CA 90095-1678,
USA. gkonecny@ucla.edu
PURPOSE: Recent studies suggest that HER-2/neu specifically promotes the
invasive capacity of tumor cells by up-regulating secretion of the
proteolytic enzyme, urokinase-type plasminogen activator (uPA), or its
inhibitor, plasminogen activator inhibitor-1 (PAI-1), in colon and
gastric cancer. It was the purpose of this study to: (a) evaluate the
association between HER-2/neu and uPA and PAI-1 expression in a large
primary breast cancer cohort; (b) perform the first multivariate
analysis, including HER-2/neu, uPA, and PAI-1 in breast cancer; and (c)
define the effect of HER-2/neu overexpression on uPA and PAI-1
expression in breast cancer cells. EXPERIMENTAL DESIGN: HER-2/neu, uPA,
and PAI-1 were measured as continuous variables by ELISA in primary
breast cancer tissue extracts from 587 patients with clinical follow-up
and analyzed for correlations with clinical outcome. Furthermore, a
full-length human HER-2/neu cDNA was introduced into five human breast
cancer cell lines to define the effects of HER-2/neu overexpression on
uPA and PAI-1 expression. In addition, we tested whether HER-2/neu
antibodies could reverse any given alteration of uPA and PAI-1 levels.
RESULTS: Our findings indicate a weak positive association between
HER-2/neu and uPA (r = 0.147; P < 0.001) and no association between
HER-2/neu and PAI-1 (r = 0.07; P = 0.085). HER-2/neu overexpression (>
or =400 fmol/mg) and high levels of uPA/PAI-1 (> or =5.5 ng/mg and/or >
or =14 ng/mg, respectively) were significantly associated with shorter
disease-free survival (DFS; P < 0.001 and P = 0.003) and metastasis-free
survival (MFS; P = 0.015 and P < 0.001). Multivariate analysis revealed
prognostic independence between HER-2/neu and the uPA/PAI-1 axis for DFS
and MFS. Both uPA and PAI-1 had no significant discriminatory effect
among HER-2/neu-positive patients for DFS. The prognostic value of
HER-2/neu overexpression for MFS, however, was significantly enhanced by
elevated uPA expression (P = 0.053). Stable transfection of the
HER-2/neu gene into multiple human breast cancer cell lines resulted in
consistent down-regulation of uPA or PAI-1 expression. In addition,
anti-HER-2/neu antibodies did not significantly affect uPA or PAI-1
expression in human cancer cell lines naturally overexpressing
HER-2/neu. CONCLUSIONS: The present findings suggest that the invasive
phenotype elicited by HER-2/neu overexpression in breast cancer is not a
direct effect of uPA or PAI-1 expression. HER-2/neu and the uPA/PAI-1
axis have been shown to affect the invasive capacity of breast cancer
independently. Determination of uPA can provide significant additional
prognostic information for MFS in HER-2/neu-positive and -negative
patients.
21
UI - 21381752
AU - Casado E; Gomez-Navarro J; Yamamoto M; Adachi Y; Coolidge CJ; Arafat WO;
TI -
Barker SD; Wang MH; Mahasreshti PJ; Hemminki A; Gonzalez-Baron M; Barnes
MN; Pustilnik TB; Siegal GP; Alvarez RD; Curiel DT
Strategies to accomplish targeted expression of transgenes in ovarian
cancer for molecular therapeutic applications.
SO - Clin Cancer Res 2001 Aug;7(8):2496-504
AD - Division of Human Gene Therapy, Department of Medicine, 1824 Sixth
Avenue South, University of Alabama at Birmingham, Birmingham, AL 35294,
USA.
PURPOSE: The purpose of the study was to determine the capability of the
midkine (MK) and cycooxygenase-2 (cox-2) gene promoter regions to
function as tumor-specific promoters for use in targeted gene therapy of
ovarian cancer. EXPERIMENTAL DESIGN: Established and primary ovarian
cancer and mesothelial cells were transduced by adenoviral vectors
containing a reporter or thymidine kinase gene expressed under the
control of the MK, cox-2, or cytomegalovirus (CMV) promoters. SCID or
C57BL/6 mice were injected i.p. with these same vectors. In vitro
reporter gene expression and cellular cytotoxicity was determined using
luciferase and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) assays, respectively. Acute toxicity in vivo was assessed
by histological evaluation of harvested tissues. RESULTS: Consistent
activation of the MK and cox-2 promoters was noted in all of the ovarian
cancer cell lines in addition to primary ovarian cancer cells. In
contrast, reduced reporter activity was reported in mesothelial cells
transduced with adenoviruses containing the test promoters, which was
especially apparent for the cox-2 promoter. Additionally, the cox-2
promoter exhibited significantly lower reporter gene levels in liver and
peritoneum than the control promoter in in vivo experiments. Tumor-cell
killing induced by Adcox-2 MTK was comparable to that observed with
AdCMVTK. However, a clear differential toxicity pattern was observed in
favor of animals treated with Adcox-2 MTK when compared with controls.
CONCLUSIONS: These data clearly demonstrate that the transcriptional
control afforded by the cox-2 promoter is tumor-specific and is able to
mitigate associated toxicity in normal tissue while maintaining
therapeutic efficacy in the context of an ovarian cancer molecular
chemotherapeutic approach.
22
UI - 21419909
AU - Pinsky LE; Culver JB; Hull J; Levy-Lahad E; Daly M; Burke W
TI -
Why should primary care physicians know about breast cancer genetics?
SO - West J Med 2001 Sep;175(3):168-73
AD - Department of Medicine, Division of General Internal Medicine,
University of Washington Medical Center, 1959 NE Pacific, Box 354760,
Seattle, WA 98195, USA. lpinsky@u.washington.edu
23
UI - 21438125
AU - Manavi M; Bauer M; Baghestanian M; Berger A; Kucera E; Pischinger K;
TI -
Battistutti W; Czerwenka K
Oncogenic potential of c-erbB-2 and its association with c-K-ras in
premalignant and malignant lesions of the human uterine endometrium.
SO - Tumour Biol 2001 Sep-Oct;22(5):299-309
AD - Department of Gynecology and Obstetrics, Division of Special Gynecology,
University Hospital of Vienna, Austria.
The aim of this study was to detect activated c-K-ras by gene point
mutation and to find c-erbB-2 gene amplification with p185 expression in
association with the c-K-ras gene product p21 in the human endometrium.
Specimens obtained from 25 normal, 31 hyperplastic and 72 malignant
samples of the human endometrium were examined for point mutation in
codons 12, 13 and 61 of the c-K-ras by direct sequencing and c-erbB-2
gene amplification with p185 and p21 expression by differential
polymerase chain reaction (DPCR) and immunohistochemistry. Neither the
normal endometrium nor endometrial hyperplasias were found to have
mutations in the c-K-ras gene, although a double mutation of codons 12
and 13 as a single-point mutation was observed in one case of
endometrioid carcinoma (2.8%). In each of two other cases of
endometrioid carcinoma (2/72), two single-point mutations of codon 13
(5.6%) were shown. Using DPCR, we found c-erbB-2 to be amplified in 15
premalignant (48%) and 45 malignant (63%) samples. We noticed that
nonamplification of the c-erbB-2 gene was associated with the absence of
immunoreactivity. Our data indicate that, while c-erbB-2 plays a role in
the early development of endometrioid carcinomas, c-K-ras gene
activation by point mutation does not. Copyright 2001 S. Karger AG,
Basel
24
UI - 21423451
AU - Tutt A; Bertwistle D; Valentine J; Gabriel A; Swift S; Ross G; Griffin
TI -
C; Thacker J; Ashworth A
Mutation in Brca2 stimulates error-prone homology-directed repair of DNA
double-strand breaks occurring between repeated sequences.
SO - EMBO J 2001 Sep 3;20(17):4704-16
AD - The Breakthrough Toby Robins, Breast Cancer Research Centre, Institute
of Cancer Research, Fulham Road, London SW3 6JB, UK.
Mutation of BRCA2 causes familial early onset breast and ovarian cancer.
BRCA2 has been suggested to be important for the maintenance of genome
integrity and to have a role in DNA repair by homology- directed
double-strand break (DSB) repair. By studying the repair of a specific
induced chromosomal DSB we show that loss of Brca2 leads to a
substantial increase in error-prone repair by homology-directed
single-strand annealing and a reduction in DSB repair by conservative
gene conversion. These data demonstrate that loss of Brca2 causes
misrepair of chromosomal DSBs occurring between repeated sequences by
stimulating use of an error-prone homologous recombination pathway.
Furthermore, loss of Brca2 causes a large increase in genome-wide
error-prone repair of both spontaneous DNA damage and mitomycin
C-induced DNA cross-links at the expense of error-free repair by sister
chromatid recombination. This provides insight into the mechanisms that
induce genome instability in tumour cells lacking BRCA2.
25
UI - 21450701
AU - Hashiguchi Y; Tsuda H; Yamamoto K; Inoue T; Ishiko O; Ogita S
TI -
Combined analysis of p53 and RB pathways in epithelial ovarian cancer.
SO - Hum Pathol 2001 Sep;32(9):988-96
AD - Department of Obstetrics and Gynecology, Osaka City General Hospital,
Osaka, Japan.
Disruptions of the p16-CDK4/cyclin D1-pRb pathway (RB pathway) and the
p14ARF-MDM2-p53 pathway (p53 pathway) are important mechanisms in the
development of human malignancies. In this study, we investigated RB and
p53 pathways in 46 epithelial ovarian cancers (EOCs). In the RB pathway,
16 (34.8%) of 46 cases had p16 gene alterations or loss of expression.
The deletion of the p16 gene was a rare event. In 7 cases, we observed
methylation in the 5'CpG island in the promoter region of the p16 gene.
Abnormal expressions of pRb and CDK4/cyclin D1 were 10.9% and 30.4%,
respectively. In the p53 pathway, 10 (21.7%) of 46 cases had p14ARF gene
alterations or abnormal expression. In 4 cases, methylation in the 5'CpG
island in the promoter region of the p14ARF gene was present. MDM2
overexpression was a rare event. Thirty-six (78.3%) of 46 patients had
p53 gene alterations or expression. In our studied cases, p14ARF
abnormalities were independent of p16 abnormalities. Abnormal RB and p53
pathways were present in 60.9% and 80.4% of cases, respectively. In
conclusion, disruptions of p53 and RB pathways are frequent events and
the inverse correlations were present between the abnormality of p16 and
p14ARF in EOCs. Copyright 2001 by W.B. Saunders Company
26
UI - 21457144
AU - Brzovic PS; Rajagopal P; Hoyt DW; King MC; Klevit RE
TI -
Structure of a BRCA1-BARD1 heterodimeric RING-RING complex.
SO - Nat Struct Biol 2001 Oct;8(10):833-7
AD - Department of Biochemistry and Biomolecular Structure Center, University
of Washington, Seattle, Washington 98195-7742, USA.
The RING domain of the breast and ovarian cancer tumor suppressor BRCA1
interacts with multiple cognate proteins, including the RING protein
BARD1. Proper function of the BRCA1 RING domain is critical, as
evidenced by the many cancer-predisposing mutations found within this
domain. We present the solution structure of the heterodimer formed
between the RING domains of BRCA1 and BARD1. Comparison with the RING
homodimer of the V(D)J recombination-activating protein RAG1 reveals the
structural diversity of complexes formed by interactions between
different RING domains. The BRCA1-BARD1 structure provides a model for
its ubiquitin ligase activity, illustrates how the BRCA1 RING domain can
be involved in associations with multiple protein partners and provides
a framework for understanding cancer-causing mutations at the molecular
level.
27
UI - 21462525
AU - Vaurs-Barriere C; Penault-Llorca F
TI -
[Molecular abnormalities in epithelial ovarian tumors: present and
future]
SO - Bull Cancer 2001 Aug;88(8):741-51
AD - Service d'anatomie et cytologie pathologiques, Centre Jean-Perrin, 52,
rue Montalembert, BP 392, 63011 Clermont-Ferrand Cedex 01.
Ovarian cancer is the fourth most common cancer in women. Its pronostic
is dreadful and, in spite of numerous studies, the steps of ovarian
carcinogenesis are unclear. Histologically, three sub-types of ovarian
tumors (benign, borderline and invasive) are distinguished, suggesting
the existence of a continuum. However, as each sub-type presents its own
biologic characteristics, the hypothesis of the progression of a
pre-neoplastic precursor (benign or borderline tumor) into an invasive
tumor is still open to discussion. Numerous molecular biological studies
have been conducted on ovarian tumors, with the aims of identifying
their molecular abnormalities and better understanding the process of
ovarian carcinogenesis. Synthesis of the published data (concerning
oncogene amplification and/or surexpression, loss of heterozygosity,
tumor suppressor gene inactivation, microsatellite instability) shows
that there are numerous abnormalities, confirming the heterogeneity and
the complexity of these tumors. Hence, it remains very difficult to draw
a scheme of ovarian carcinogenesis. Nevertheless, in a near future the
new technology of laser microdissection may improve the quality of the
results and the study of early ovarian lesions. Indeed, with this
technique, it becomes possible to isolate well-defined and homogeneous
cell populations and to study small or architecturally complex (su
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