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Abramson Cancer CenterNCI CANCERLIT® Search: BRCA1 Gene - January 2002
National Cancer Institute®
Last Modified: January 1, 2002
Table of Contents
1
UI - 11447881
AU - Van den Ouweland AM
TI -
[From gene to disease; from BRCA1 OR BRCA2 to breast cancer]
SO - Ned Tijdschr Geneeskd 2001 Jun 23;145(25):1228
2
UI - 11499181
AU - Memarzadeh S; Berek JS
TI -
Advances in the management of epithelial ovarian cancer.
SO - J Reprod Med 2001 Jul;46(7):621-9; discussion 629-30
AD - Division of Gynecologic Oncology, University of California-Los Angeles
School of Medicine, 27-136 CNS, 10833 Le Conte Avenue, Los Angeles, CA
90095-1740, USA.
More than 23,400 new cases of ovarian cancer and 13,900 deaths are
expected in the United States this year. Epithelial ovarian cancer is
the most common histologic type of ovarian malignancy. Although there
have been advances in the chemotherapeutic treatment of ovarian cancer,
the five year survival of women with advanced-stage disease is 25-30%.
Because the disease is typically asymptomatic until the disease has
metastasized and because effective screening strategies are not
unavailable, 70-75% of women present with advanced-stage disease. Of
ovarian cancer cases, 90-95% are sporadic and 5-10% associated with
germ-line mutations, including BRCA1 and BRCA2. Known risk factors for
ovarian cancer include nulliparity and a strong family history of
ovarian cancer. The use of oral contraceptives is known to decrease the
risk of ovarian cancer: five years of use will decrease the risk by 50%.
The staging of ovarian cancer (according to the International Federation
of Obstetrics and Gynecology) requires surgical exploration. Determining
the extent of disease is essential to appropriate management. Survival
in patients with metastatic disease is improved in those who undergo
optimal primary cytoreductive surgery. Adjuvant chemotherapy is
recommended in patients with high-risk, early-stage disease and all
patients with advanced-stage disease. Standard chemotherapy is a
combination of paclitaxel and carboplatin. Selected patients with
recurrent disease can undergo secondary cytoreductive surgery.
Second-line chemotherapy for patients who initially respond to
paclitaxel and carboplatin and who have a prolonged disease
progression-free intervals (longer than 12 months) can be re-treated
with either drug or both. Those whose responses to initial therapy were
less successful can be treated with other chemotherapeutic agents--e.g.,
liposomal doxorubicin, topotecan, etoposide, gemcitabine or taxotere.
3
UI - 11554927
AU - Ibe S; Fujita K; Toyomoto T; Shimazaki N; Kaneko R; Tanabe A; Takebe I;
TI -
Kuroda S; Kobayashi T; Toji S; Tamai K; Yamamoto H; Koiwai O
Terminal deoxynucleotidyltransferase is negatively regulated by direct
interaction with proliferating cell nuclear antigen.
SO - Genes Cells 2001 Sep;6(9):815-24
AD - Faculty of Science and Technology, Department of Applied Biological
Science, Science University of Tokyo, Noda, Chiba 278-8510, Japan.
BACKGROUND: The repertoires of Ig and TcR are generated by a
combinatorial rearrangement of variable (V), diversity (D), and joining
(J) segments (V(D)J recombination) in B- and T-cells. Terminal
deoxynucleotidyltransferase (TdT) adds extra nucleotides (N nucleotides)
at the junctions of the gene segments to enhance the Ig and TcR genes
diversity. Using an anti-TdT antibody column, TdT has been purified as a
member of a megadalton protein complex from rat thymus. The N region
would be synthesized with the large protein complex. RESULTS: The cDNAs
for proliferating cell nuclear antigen (PCNA) were isolated by yeast
two-hybrid screening as the gene products which directly interacted with
TdT. The interaction between PCNA and TdT was confirmed by
co-immunoprecipitation, both in vitro and in vivo. TdT binds directly to
a PCNA trimer, as shown by gel filtration. TdT interacts with PCNA in
its DNA polymerization domain (DPD), but not in its BRCA-1 C-terminal
(BRCT) domain. TdT activity was reduced to 17% of the maximum value by
TdT/PCNA complex formation. CONCLUSION: TdT interacts directly with PCNA
through its DPD. A functional consequence of this interaction is the
negative regulation of TdT activity. These findings suggest that TdT
catalyses the addition of N nucleotides under the negative control of
PCNA during V(D)J recombination.
4
UI - 11583951
AU - Kataoka A; Tada M; Yano M; Furuuchi K; Cornain S; Hamada J; Suzuki G;
TI -
Yamada H; Todo S; Moriuchi T
Development of a yeast stop codon assay readily and generally applicable
to human genes.
SO - Am J Pathol 2001 Oct;159(4):1239-45
AD - First Department of Surgery, Hokkaido University School of Medicine,
Sapporo, Japan.
We established a yeast-based method to screen chain-terminating
mutations that is readily applicable to any gene of interest. Based on
the finding that 18- to 24-base-long homologous sequences are sufficient
for gap repair in vivo in yeast, we used a strategy to amplify a
test-gene fragment with addition of 24-bp sequences homologous to both
cut-ends of a yeast expression vector, pMT18. After co-transformation
with the amplified fragment and the linearized pMT18, each yeast
(Saccharomyces cerevisiae) cell automatically forms a single-copy
circular plasmid (because of CEN/ARS), which expresses a test-gene::ADE2
chimera protein. When the reading frame of the test-gene contains a
nonsense or frameshift mutation, truncation of the chimera protein
results in lack of ADE2 activity, leading to formation of a red colony.
By using a nested polymerase chain reaction using proofreading Pfu
polymerase to ensure specificity of the product, the assay achieved a
low background (false positivity). We applied the assay to BRCA1, APC,
hMSH6, and E-cadherin genes, and successfully detected mutations in mRNA
and genomic DNA. Because this method--universal stop codon
assay--requires only 4 to 5 days to screen a number of samples for any
target gene, it may serve as a high-throughput screening system of
general utility for chain-terminating mutations that are most prevalent
in human genetic diseases.
5
UI - 11598149
AU - Zweemer RP; Ryan A; Snijders AM; Hermsen MA; Meijer GA; Beller U; Menko
TI -
FH; Jacobs IJ; Baak JP; Verheijen RH; Kenemans P; van Diest PJ
Comparative genomic hybridization of microdissected familial ovarian
carcinoma: two deleted regions on chromosome 15q not previously
identified in sporadic ovarian carcinoma.
SO - Lab Invest 2001 Oct;81(10):1363-70
AD - Department of Obstetrics and Gynaecology, VU Medical Center, Amsterdam,
The Netherlands. rp.zweemer.humgen@med.vu.nl
The vast majority of familial ovarian cancers harbor a germline mutation
in either the breast cancer gene BRCA1 or BRCA2 tumor suppressor genes.
However, mutations of these genes in sporadic ovarian cancer are rare.
This suggests that in contrast to hereditary disease, BRCA1 and BRCA2
are not commonly involved in sporadic ovarian cancer and may indicate
that there are two distinct pathways for the development of ovarian
cancer. To characterize further differences between hereditary and
sporadic cancers, the comparative genomic hybridization technique was
employed to analyze changes in copy number of genetic material in a
panel of 36 microdissected hereditary ovarian cancers. Gains at
8q23-qter (18 of 36, 5 cases with high-level amplifications),
3q26.3-qter (18 of 36, 2 cases with high-level amplifications), 11q22
(11 of 36) and 2q31-32 (8 of 36) were most frequent. Losses most
frequently occurred (in decreasing order of frequency) on 8p21-pter (23
of 36), 16q22-pter (19 of 36), 22q13 (19 of 36), 9q31-33 (16 of 36),
12q24 (16 of 36), 15q11-15 (16 of 36), 17p12-13 (14 of 36), Xp21-22 (14
of 36), 20q13 (13 of 36), 15q24-25 (12 of 36), and 18q21 (12 of 36).
Comparison with the literature revealed that the majority of these
genetic alterations are also common in sporadic ovarian cancer.
Deletions of 15q11-15, 15q24-25, 8p21-ter, 22q13, 12q24 and gains at
11q22, 13q22, and 17q23-25, however, appear to be specific to hereditary
ovarian cancer. Aberrations at 15q11-15 and 15q24-25 have not yet been
described in familial ovarian cancer. In these regions, important tumor
suppressor genes, including the hRAD51 gene, are located. These and
other yet unknown suppressor genes may be involved in a specific
carcinogenic pathway for familial ovarian cancer and may explain the
distinct clinical presentation and behavior of familial ovarian cancer.
6
UI - 11606115
AU - Ansink AC; Burger CW; Seynaeve C
TI -
Occult cancer in the fallopian tube in patients with a BRCA-1 germline
mutation.
SO - Gynecol Oncol 2001 Nov;83(2):445
7
UI - 11606116
AU - Morice P; Pautier P; Delaloge S
TI -
Prophylactic surgery in patients with inherited risk of ovarian cancer.
SO - Gynecol Oncol 2001 Nov;83(2):445-7
8
UI - 11668223
AU - Runnebaum IB; Wang-Gohrke S; Vesprini D; Kreienberg R; Lynch H; Moslehi
TI -
R; Ghadirian P; Weber B; Godwin AK; Risch H; Garber J; Lerman C; Olopade
OI; Foulkes WD; Karlan B; Warner E; Rosen B; Rebbeck T; Tonin P; Dube
MP; Kieback DG; Narod SA
Progesterone receptor variant increases ovarian cancer risk in BRCA1 and
BRCA2 mutation carriers who were never exposed to oral contraceptives.
SO - Pharmacogenetics 2001 Oct;11(7):635-8
AD - Department of Obstetrics and Gynecology, University of Ulm, Ulm,
Germany.
Oral contraceptives have been shown to be protective against hereditary
ovarian cancer. The variant progesterone receptor allele named PROGINS
is characterized by an Alu insertion into intron G and two additional
mutations in exons 4 and 5. The PROGINS allele codes for a progesterone
receptor with increased stability and increased hormone-induced
transcriptional activity. We studied the role of the PROGINS allele as a
modifying gene in hereditary breast and ovarian cancer. The study
included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian
cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers
with neither cancer. Fifty-eight women had both forms of cancer. Five
hundred and ninety-five women had a BRCA1 mutation and 183 women had a
BRCA2 mutation. Overall, there was no association between disease status
and the presence of the PROGINS allele. Information on oral
contraception use was available for 663 of the 778 carriers of BRCA1 or
BRCA2 mutations. Among the 449 subjects with a history of oral
contraceptive use (74 cases and 365 controls), no modifying effect of
PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI)
0.5-1.3]. Among the 214 carriers with no past exposure to oral
contraceptives, the presence of one or more PROGINS alleles was
associated with an OR of 2.4 for ovarian cancer, compared to women
without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI
1.4-4.3). The association was present after adjustment for ethnic group
and for year of birth.
9
UI - 11673680
AU - Brewster A; Helzlsouer K
TI -
Breast cancer epidemiology, prevention, and early detection.
SO - Curr Opin Oncol 2001 Nov;13(6):420-5
AD - Department of Medical Oncology, Johns Hopkins School of Medicine,
Baltimore, Maryland, USA.
Breast cancer remains a worldwide public health concern despite the fact
that mortality rates have been declining in some countries as a result
of improvements in adjuvant therapy and screening for breast cancer. In
the prevention arena, advances in our understanding of the effects of
tamoxifen have led to the investigations of newer agents that may
provide extended options for breast cancer prevention in high-risk
women. For women who are carriers of a mutation in the breast cancer
susceptibility genes BRCA1 or BRCA2, prophylactic oophorectomy and
bilateral mastectomy have emerged as preventative surgical options that
can significantly impact breast cancer risk. In addition, the
identification of potentially modifiable risk factors for breast cancer
such as dietary folate intake, alcohol consumption, physical activity,
and certain anthropometric factors provides opportunities for
intervening in breast cancer prevention both among women at average and
high risk. The challenge remains in overcoming the limitations of
mammography and clinical breast examination by developing and evaluating
new technologies for breast cancer screening such as digital mammogram
and breast magnetic resonance imaging.
10
UI - 11673682
AU - Zellars R; Frassica D
TI -
Radiation therapy in the management of breast cancer: an annual review
of selected publications.
SO - Curr Opin Oncol 2001 Nov;13(6):431-5
AD - Johns Hopkins Oncology Center, Lutherville, Maryland 21093, USA.
Radiation oncology is essential in the management of breast cancer. Each
year the scientific literature is replete with evidence of radiation's
role in the treatment of this disease. The goal of this article is to
motivate the reader to discuss and critically review some of these
publications. The authors have made a subjective selection of clinical
publications addressing radiation and breast cancer from the past 13
months. Articles were chosen on the basis of their ability to influence
both current and future therapy. Some readers will no doubt disagree
with our choices; however, if this disappointment generates discussion
and review of these and other articles, we have achieved our goal.
11
UI - 11688463
AU - Colgan TJ; Murphy J; Cole DE; Narod S; Rosen B
TI -
Occult carcinoma in prophylactic oophorectomy specimens: prevalence and
association with BRCA germline mutation status.
SO - Am J Surg Pathol 2001 Oct;25(10):1283-9
AD - Mount Sinai Hospital and the Department of Laboratory Medicine and
Pathobiology, University of Toronto, Ontario, Canada.
tcolgan@mtsinai.on.ca
Prophylactic oophorectomy (PO) is an option for women at increased risk
for ovarian carcinoma. In this study the value of intensive pathologic
examination of PO specimens and accompanying resected tissues in the
identification of occult carcinoma and any association of occult
carcinoma with BRCA germline mutation status were ascertained. Specimens
from 60 consecutive PO patients, who were not suspected of having any
ovarian tumor at the time of surgery, were subjected to standardized,
complete pathologic examination in a prospective study over an 8-year
period. Extra-ovarian tissues were examined as well, but they were not
subject to the same standardized protocol. Any occult carcinoma of the
ovaries or fallopian tubes was noted. The BRCA status and follow-up of
patients were obtained, if available. Fifty-five of the 60 PO specimens
did not show any evidence of malignancy. Of the 32 patients in this
group followed for >1 year, all are alive and well. The remaining five
patients, all BRCA1 mutation positive, showed occult carcinoma of the
ovaries and/or in situ or invasive carcinoma of a fallopian tube. One of
these five patients has died of abdominal carcinomatosis; four continue
to be well, but follow-up is <4 years in all cases. Occult carcinoma is
present in a small proportion of BRCA-positive or unknown PO patients
and may be of prognostic significance. The entire ovaries and tubes from
PO patients should be submitted for histologic examination to identify
malignancy.
12
UI - 11693810
AU - von Smitten K
TI -
Prophylactic breast surgery for women with BRCA1 and BRCA2 germline
mutations.
SO - Tumori 2001 Jul-Aug;87(4):S13-5
AD - Breast Surgery Unit, Helsinki University Central Hospital, Hus, Finland.
karl.von.smitten@hus.fi
13
UI - 11704836
AU - Atlas E; Stramwasser M; Mueller CR
TI -
A CREB site in the BRCA1 proximal promoter acts as a constitutive
transcriptional element.
SO - Oncogene 2001 Oct 25;20(48):7110-4
AD - Cancer Research Laboratories, Department of Biochemistry, Queen's
University, Kingston, Ontario, Canada.
Transcriptional regulation of the BRCA1 proximal promoter has been
suggested to play a role in the decreased expression of BRCA1 observed
in sporadic breast cancer. Computer analysis of the sequence of the
proximal promoter reveals the presence of a potential CREB site. We have
identified CREB/ATF-1 as the factor interacting with this site in
nuclear extracts from MCF-7 and T-47D cells. This site is shown to be
important for the constitutive expression of the promoter in these
cells, as well as in Hep G2 cells. Despite the presence of this site,
the BRCA1 promoter is not responsive to cAMP induction. It appears that
CREB acts as a constitutive positive element for BRCA1 expression and
that any mechanism inactivating CREB function would have a dramatic
effect on BRCA1 expression.
14
UI - 11712780
AU - Charafe-Jauffre E; Eisinger F; Mathoulin-Portier MP; Sobol H; Jacquemier
TI -
J
PS2 expression in BRCA1-associated breast cancers.
SO - Anticancer Res 2001 Jul-Aug;21(4B):2877-81
AD - Department de Pathologie Institut Paoli-Calmettes, Marseille, France.
BACKGROUND: PS2-expression is controlled by estrogens and is a
prognostic factor for long-term and post-relapse survival. Breast
carcinomas associated with a BRCA1 mutation (BRCA1-BC'S) exhibit many
specific features, particularly for ER expression. Our purpose was to
determine if pS2-expression was different in BRCA1-BC's compared with
sporadic breast cancers. MATERIALS AND METHODS: We studied, by
immunohistochemistry pS2-cxpression in a series of 33 BRCA1-BC's and a
series of 193 sporadic cases according to many parameter including
hormone receptors (ER and PR). RESULTS: In BRCA1-BC's, pS2 was expressed
in only 10/33 (30.3%) carcinomas, and 4/4 (100%) ER positive: among
sporadic carcinomas, 133/193 (68.9%) cases were pS2-positive,
102/127(80.37%) ER positive; the difference was significant (p<0.0001).
In univariate analysis, pS2-expression was correlated with many
parameters including hormonal receptor status and absence of BRCA1
mutation. In multivariate analysis, pS2-expression was still correlated
with ER but no more with BRCA1 mutation. CONCLUSION: pS2-expression in
BRCA1-BC's was significantly different from sporadic breast cancer
(p<0.0001) and correlated in a multivariate analysis with the same
factors in sporadic and BRCA1-BC's but not with BRCA1 mutation.
15
UI - 11759652
AU - Narod SA; Sun P; Risch HA; Hereditary Ovarian Cancer Clinical Study
TI -
Group
Ovarian cancer, oral contraceptives, and BRCA mutations.
SO - N Engl J Med 2001 Dec 6;345(23):1706-7
16
UI - 11759653
AU - Friedenson B
TI -
Ovarian cancer, oral contraceptives, and BRCA mutations.
SO - N Engl J Med 2001 Dec 6;345(23):1707
17
UI - 11733976
AU - Smith SA; Richards WE; Caito K; Hanjani P; Markman M; DeGeest K; Gallion
TI -
HH
BRCA1 germline mutations and polymorphisms in a clinic-based series of
ovarian cancer cases: a Gynecologic Oncology Group study.
SO - Gynecol Oncol 2001 Dec;83(3):586-92
AD - Division of Gynecologic Oncology, University of Kentucky, Combs Research
Building, Room 124C, 800 Rose Street, Lexington, Kentucky 40536, USA.
OBJECTIVE: The aims of this study were to determine the frequency of
BRCA1 gene alterations in an unselected, clinic-based series of ovarian
cancer cases; to evaluate the usefulness of family history in predicting
the likelihood of a disease-causing mutation; and to document the
occurrence of polymorphic variants in BRCA1 and to determine their
distribution among families accordingly to history of breast and/or
ovarian cancer. METHOD: Two hundred fifty-eight women with primary
epithelial ovarian cancer, entered onto a nonclinical protocol of the
Gynecologic Oncology Group, were analyzed for BRCA1 germline alterations
by single-strand conformation polymorphism analysis. RESULTS:
Protein-truncating mutations in BRCA1 were identified in 12 patients
(4.6%). The median age of cancer diagnosis in BRCA1 mutation carriers
was 47 years compared to 57 years in patients without mutations (P =
0.02). All but 1 of the patients with BRCA1 mutations reported a family
history of breast and/or ovarian cancer and 8 had a first-degree
relative with cancer. Twelve mutations of unknown significance were also
identified. An association was also noted between the presence of common
polymorphisms in BRCA1 and family history of cancer. Polymorphisms were
present at higher frequency among women without a family history of
cancer compared to women with positive family histories, suggesting they
are associated with reduced risk. CONCLUSION: In a clinic-based series
of ovarian cancer patients, germline BRCA1 mutations were detected in 12
of 258 (4.6%) patients. A strong correlation was noted between the
presence of mutations and family history of breast and/or ovarian
cancer, indicating that these women are most likely to benefit from
genetic susceptibility testing. (c)2001 Elsevier Science.
18
UI - 11701949
AU - Stec I; van Vliet M; van Eijk R; Meijers H; Kroeze KH; Dauwerse JG; van
TI -
Ommen GJ; Cornelisse CJ; den Dunnen JT; Devilee P
A partial BRCA1 sequence homology mapping to 4q28.
SO - Cytogenet Cell Genet 2001;94(1-2):26-9
AD - Department of Human and Clinical Genetics, Leiden University Medical
Center, Leiden, The Netherlands. I.Stec@LUMC.nl
Using a BRCA1 cDNA probe in Southern analysis, we detected a sequence of
348 bp on 4q28 that is homologous to the 3' end of BRCA1. A 28-kb
sequence contig has been assembled spanning the homologous region, which
we designated BRCA1-h. An open reading frame was identified encoding a
sequence of 82 amino acids; 22 of the last 23 amino acids are identical
to the last 23 residues of BRCA1. BLAST-searches, RT-PCR and
RACE-experiments have been unable to provide evidence that BRCA1-h is
part of an expressed gene. Copyright 2001 S. Karger AG, Basel
19
UI - 11685871
AU - Swisher E
TI -
Hereditary cancers in obstetrics and gynecology.
SO - Clin Obstet Gynecol 2001 Sep;44(3):450-63
AD - University of Washington, Seattle, Washington, USA.
swishere@u.washington.edu
The lack of information regarding the effectiveness of screening
strategies, chemoprevention, or surgical prophylaxis, and the
uncertainty regarding penetrance and risk modification has led many
experts to recommend that genetic testing for BRCA1, BRCA2, and other
cancer susceptibility genes be performed only in a research setting.
Patients, however, are likely to increasingly request access to genetic
testing and deserve up-to-date counseling about recent advancements in
our knowledge. The primary care physician should concentrate on
identifying women likely to be at high-risk for cancer for further
referral, allowing the cancer genetics specialist to track down medical
records, clarify the pedigree, discuss genetic testing, and provide
access to the appropriate cancer specialist to discuss risk reduction.
20
UI - 11589066
AU - Coukos G; Rubin SC
TI -
Gene therapy for ovarian cancer.
SO - Oncology (Huntingt) 2001 Sep;15(9):1197-204, 1207; discussion 1207-8
AD - Department of Obstetrics and Gynecology, Division of Gynecologic
Oncology, University of Pennsylvania Medical Center, Philadelphia,
Pennsylvania, USA. GCoukos@mail.obgyn.upenn.edu
Advances in molecular virology and biotechnology have led to the
engineering of vectors that can efficiently transfer genes to target
cells. Gene therapy strategies were developed along two lines: Cytotoxic
approaches involve the transfer of genes that encode enzymes, which
convert inactive prodrugs into cytotoxic drugs. Corrective gene therapy
approaches aim to repair specific molecular alterations in signal
transduction mechanisms that control the cell cycle or induce apoptosis.
Clinical evidence suggests that gene therapies are best suited for
patients with minimal residual disease. Multimodality approaches with
conventional strategies and novel therapeutic tools in various
combinations will most likely prove advantageous, compared to
single-modality treatments. However, clinical trials will need to test
these hypotheses.
21
UI - 11594337
AU - Hallowell N; Jacobs I; Richards M; Mackay J; Gore M
TI -
Surveillance or surgery? A description of the factors that influence
high risk premenopausal women's decisions about prophylactic
oophorectomy.
SO - J Med Genet 2001 Oct;38(10):683-91
22
UI - 11719181
AU - Mendell JT; Dietz HC
TI -
When the message goes awry: disease-producing mutations that influence
mRNA content and performance.
SO - Cell 2001 Nov 16;107(4):411-4
AD - Howard Hughes Medical Institute, Institute of Genetic Medicine, Johns
Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD
21205, USA.
Mutations that cause disease commonly occur in the coding sequence and
directly influence protein structure and function. However, many
diseases result from mutations that influence various aspects of mRNA
metabolism, including processing, export, stability, and translational
control.
23
UI - 11720902
AU - Laud K; Hornez L; Gourdou I; Belair L; Arnold A; Peyrat JP; Djiane J
TI -
Expression of BRCA1 gene in ewe mammary epithelial cells during
pregnancy: regulation by growth hormone and steroid hormones.
SO - Eur J Endocrinol 2001 Dec;145(6):763-70
AD - Laboratoire de Biologie Cellulaire et Moleculaire, Institut National de
la Recherche Agronomique, 78352 Jouy-en-Josas Cedex, France.
OBJECTIVE: Steroid hormones (estradiol and progesterone) in association
with prolactin and growth hormone are involved in lobulo alveolar
development of the mammary gland during pregnancy. We hypothesized that
the BRCA1 gene may be induced by these different hormones. METHODS AND
RESULTS: In this study, we have demonstrated by Northern blot and in
situ hybridization, that the expression of ovine (o) BRCA1 mRNA in
mammary epithelial cells increased dramatically during a short period in
the second half of pregnancy (days 70 to 112) and decreased at the end
of pregnancy. The increase in oBRCA1 mRNA expression is concomitant with
rapid lobulo alveolar growth. Using an in vivo protocol to artificially
induce mammary gland development, we demonstrated by the real-time
RT-PCR method that growth hormone in association with estrogen,
progesterone and hydrocortisone induces an increase of BRCA1 mRNA
expression in the ewe mammary gland. Moreover, we showed that estradiol
and progesterone induce oBRCA1 expression in primary cultures of ewe
mammary gland. CONCLUSIONS: These results suggest that BRCA1 is a
potential regulator of the effects of steroid hormones and growth
hormone in the induction of mammary epithelial cell proliferation.
24
UI - 11508855
AU - Dimitrov SD; Matouskova E; Forejt J
TI -
Expression of BRCA1, NBR1 and NBR2 genes in human breast cancer cells.
SO - Folia Biol (Praha) 2001;47(4):120-7
AD - Institute of Molecular Genetics, Academy of Sciences of the Czech
Republic, Prague.
BRCA1 is a tumour suppressor gene with a caretaker function in the
DNA-damage repair and the maintenance of genome integrity. The human
BRCA1 and NBR2 genes and the homologous Brcal and Nbr1 mouse genes are
situated head-to-head on human chromosome 17q21 and on mouse chromosome
11, respectively. Their transcription start sites, located on opposite
DNA strands, are separated by 218 bp in humans, and by 289 bp in mice.
Because of this intimate contact and because of our previous observation
of a quasi-reciprocal expression pattern of Brca1 and Nbr1 in mouse
spermatogenesis, we estimated here the relative mRNA expression of
BRCA1, NBR1 (next-to-BRCA1) and NBR2 genes in a panel of permanent cell
lines and primary cell cultures derived from human breast cancer or
normal mammary tissue. The analysis revealed highly significant
downregulation of BRCA1 in 11 out of 12 examined tumour cell lines and
primary cell cultures as compared to non-malignant mammary cells. Two
isoforms of NBR1(1A) and the classical NBR1(1B) transcripts were found
in cells from malignant mammary tissues, all of them downregulated in
respect to normal cells. The expression of NBR2 differed, being
increased in three permanent tumour cell lines and slightly decreased in
all primary breast cancer cell cultures. The in silico analysis revealed
two new putative domains of the predicted NBR1 protein, suggesting its
role in the ubiquitin pathway. The recent identification of the
ubiquitin protein ligase activity of BRCA1 implies a possible functional
connection between both genes.
25
UI - 11743182
AU - Normile D
TI -
Evolutionary genomics. The ups and downs of evolution.
SO - Science 2001 Dec 14;294(5550):2281-2
26
UI - 11794203
AU - Offit K; Robson M; Schrag D
TI -
Prophylactic mastectomy in carriers of BRCA mutations.
SO - N Engl J Med 2001 Nov 15;345(20):1498-9; discussion 1499-500
27
UI - 11794204
AU - Narod S
TI -
Prophylactic mastectomy in carriers of BRCA mutations.
SO - N Engl J Med 2001 Nov 15;345(20):1498; discussion 1499-500
28
UI - 11794205
AU - Riggs T
TI -
Prophylactic mastectomy in carriers of BRCA mutations.
SO - N Engl J Med 2001 Nov 15;345(20):1499; discussion 1499-500
29
UI - 11794206
AU - Stoutjesdijk MJ; Barentsz JO
TI -
Prophylactic mastectomy in carriers of BRCA mutations.
SO - N Engl J Med 2001 Nov 15;345(20):1499; discussion 1499-500
30
UI - 11407860
AU - Kachhap SK; Vetale SP; Dange P; Ghosh SN
TI -
Reduced expression of the BRCA1 gene and increased chromosomal
instability in MCF-7 cell line.
SO - Cell Biol Int 2001;25(6):547-51
AD - Cell Biology Division, Cancer Research Institute, Tata Memorial Centre,
Parel, Mumbai 400012, India.
Using clonal cell cultures, a significant increase in chromosomal
aberrations (aneuplolidy, dicentrics and chromatid breaks) were observed
in MCF-7 cells compared with HeLa. BRCA1 expression was lower in MCF-7
cells than in HeLa cells. Since BRCA1 is known to play a role in the
maintenance of chromosomal integrity, the increase in chromosomal
aberrations in MCF-7 clones suggests that downregulation of BRCA1
expression could be one of the possible mechanisms for increased
chromosomal instability in this cell line. Copyright 2001 Academic
Press.
31
UI - 11668617
AU - Geisler JP; Hatterman-Zogg MA; Rathe JA; Lallas TA; Kirby P; Buller RE
TI -
Ovarian cancer BRCA1 mutation detection: Protein truncation test (PTT)
outperforms single strand conformation polymorphism analysis (SSCP).
SO - Hum Mutat 2001 Oct;18(4):337-44
AD - Division of Gynecologic Oncology, University of Iowa Hospitals and
Clinics, Iowa City, Iowa, USA.
Recent studies have shown that the BRCA1 tumor suppressor gene plays a
role in the development of both hereditary and sporadic ovarian cancer.
Since several different mechanisms may give rise to tumor gene defects,
a better understanding of these mechanisms may identify BRCA1 as an
attractive therapeutic target in ovarian cancer. Sequencing this large
gene is not practical on a population-wide basis. The optimal screening
strategy is yet to be determined. The purpose of our study is to compare
two common screening techniques: the protein truncation test (PTT) and
single strand conformational polymorphism analysis (SSCP). Ninety-four
patients with epithelial ovarian cancer and available snap-frozen tissue
were screened for BRCA1 mutations by both PTT (five individual PCR
reactions with complete translation of the product in the TNT System
(Promega, Madison, WI)) and SSCP (41 individual PCR reactions covering
the entire coding sequence). All abnormal results were confirmed by
sequencing. A paired peripheral blood DNA sample was utilized to
determine if the sequence abnormality was a germline mutation.
Twenty-three mutations in BRCA1 were found in 22 patients (14 germline,
eight somatic, one unknown) including four novel mutations: E489X,
3558delT, 3871delGTCT, del exon 7-10. Although the predictive value of a
negative test was close for the two methods (PTT 99.1%, SSCP 99.8%), the
comparison of positive predictive value overwhelmingly favored PTT
(100.0%, vs. 26.4%, respectively). The specificity for PTT was 100.0%
while the sensitivity was 82.6%. While for SSCP, the specificity was
99.0% and the sensitivity was only 60.9%. The concordance rate for the
two screening tests was 88.9%. Only SSCP can detect missense mutations.
PTT is a superior screening test for truncating BRCA1 mutations that are
expected to be of clinical significance. Copyright 2001 Wiley-Liss, Inc.
32
UI - 11781837
AU - Fan S; Yuan R; Ma YX; Meng Q; Goldberg ID; Rosen EM
TI -
Mutant BRCA1 genes antagonize phenotype of wild-type BRCA1.
SO - Oncogene 2001 Dec 13;20(57):8215-35
AD - Department of Radiation Oncology, Long Island Jewish Medical Center, The
Long Island Campus for the Albert Einstein College of Medicine, 270-05
76th Avenue, New Hyde Park, NY 11040, USA.
Unregulated expression of wild-type BRCA1 (wtBRCA1) confers an altered
phenotype in cultured human prostate cancer cells, characterized by
chemosensitivity, susceptibility to apoptosis, decreased DNA repair
activity, and alterations of key cell regulatory proteins. We now report
that the expression of truncated or mutant full-length BRCA1 genes can
abrogate certain phenotypic characteristics and/or confer the opposite
phenotype to the wild-type BRCA1 gene. In particular, several
carboxyl-terminal truncated BRCA1 proteins conferred chemoresistance,
decreased susceptibility to apoptosis, and decreased ability to suppress
in vivo tumor growth. These truncated BRCA1 proteins also blocked the
ability of ectopically expressed wtBRCA1 to induce chemosensitivity and
to inhibit estrogen receptor transcriptional activity. Studies using
epitope-tagged truncated proteins confirmed their expression, nuclear
localization, and functionality. On the other hand, in cells with no
endogenous wild-type BRCA1 (HCC1937 human breast cancer cells), the
wtBRCA1 gene enhanced cellular DNA repair activity and rendered the
cells resistant to DNA damage; while truncated BRCA1 proteins blocked
the wtBRCA1-induced chemoresistance. Our findings suggest that truncated
BRCA1 proteins can inhibit the function of wild-type BRCA1. They raise
the possibility that some inherited BRCA1 mutations may actively promote
oncogenesis by blocking the function of the remaining wild-type BRCA1
allele, although this hypothesis remains to be proved.
33
UI - 11737473
AU - Halperin R; Zehavi S; Langer R; Hadas E; Bukovsky I; Schneider D
TI -
Primary peritoneal serous papillary carcinoma: a new epidemiologic
trend? A matched-case comparison with ovarian serous papillary cancer.
SO - Int J Gynecol Cancer 2001 Sep-Oct;11(5):403-8
AD - Department of Obstetrics and Gynecology, Assaf Harofe Medical Center,
Zerifin, Israel.
The aim of the study was to examine the prevalence of primary peritoneal
serous papillary carcinoma (PPSPC) as compared with ovarian serous
papillary cancer (OSPC), and to study the clinicopathologic features and
the frequency of germline BRCA1 and BRCA2 mutations in patients with
PPSPC compared with those with OSPC. The study group included 28 cases
of PPSPC. The comparison group included 35 female patients with OSPC,
matched for stage, grade, and histologic subtype. All tumors were staged
as either IIIB, IIIC or IV according to FIGO criteria. The patient
characteristics, family and personal history of malignancies, the
prevalence of germline BRCA mutations, clinicopathologic findings,
presenting symptoms, pre- and intraoperative findings, and survival were
compared in a matched-case retrospective study comparing patients with
PPSPC vs. those with OSPC. Statistical analysis was made using Student's
t-test, Chi-square, Wilcoxon, Kaplan-Meier and log-rank methods. Women
with PPSPC had a significantly earlier menarche (P = 0.037) and a higher
number or births (P = 0.03) than women with OSPC. No difference was
found with regard to the prevalence of germline BRCA mutations in women
with PPSPC compared with women with OSPC (7.1% vs. 25.7%). There was a
significant increase (P = 0.02) in the incidence of abdominal distension
as reported by PPSPC (64%) vs. OSPC patients (26%). Significantly more
women with PPSPC than with OSPC presented with clinical ascites (P =
0.0001) and without palpable pelvic mass (P = 0.000001). On exploratory
laparotomy, significantly more women with PPSPC than with OSPC had a
minimal disease in the pelvis (P = 0.0087). Three-year survival analysis
demonstrated a significantly worse survival rate for the PPSPC group
than for the OSPC group (P = 0.017). A significant increase in the
prevalence of PPSPC compared with OSPC was observed during the study
years (P = 0.00001). We concluded that PPSPC and OSPC might be two
distinct cancers, presenting a new epidemiologic trend regarding the
increased incidence of PPSPC.
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