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Abramson Cancer CenterNCI CANCERLIT® Search: BRCA1 Gene - April 2002
National Cancer Institute®
Last Modified: April 1, 2002
Table of Contents
1
UI - 11801872
AU - Narod SA; Boyd J
TI -
Current understanding of the epidemiology and clinical implications of
BRCA1 and BRCA2 mutations for ovarian cancer.
SO - Curr Opin Obstet Gynecol 2002 Feb;14(1):19-26
AD - The Centre for Research on Women's Health, Women's College Hospital,
University of Toronto, Toronto, Canada. steven.narod@swchsc.on.ca
Genetic testing for susceptibility to ovarian cancer is rapidly becoming
integrated into the clinical practice of oncology. Genetic testing for
BRCA1 and BRCA2 is now recommended to most women with invasive ovarian
cancer. Approximately 10% of these women will have a positive test,
including 4% of women without a family history of cancer. Currently, the
treatment of hereditary ovarian cancer is the same as for non-hereditary
ovarian cancer. It appears that women with ovarian cancer and a BRCA
mutation experience better survival than women without a mutation,
possibly due to enhanced susceptibility to chemotherapy. Strategies for
prevention of ovarian cancer among carriers include oral contraceptives,
tubal ligation and prophylactic oophorectomy.
2
UI - 11904319
AU - Sobol H; Vey N; Sauvan R; Philip N; Noguchi T; Eisinger F
TI -
Re: familial multiple myeloma: a family study and review of the
literature.
SO - J Natl Cancer Inst 2002 Mar 20;94(6):461-2; discussion 463
3
UI - 11904320
AU - Hemminki K
TI -
Re: familial multiple myeloma: a family study and review of the
literature.
SO - J Natl Cancer Inst 2002 Mar 20;94(6):462-3; discussion 463
4
UI - 11870156
AU - DeMichele A; Weber BL
TI -
Risk management in BRCA1 and BRCA2 mutation carriers: lessons learned,
challenges posed.
SO - J Clin Oncol 2002 Mar 1;20(5):1164-6
5
UI - 11899651
AU - Blanchard DK; Hartmann LC
TI -
Prophylactic surgery for women at high risk for breast cancer.
SO - Clin Breast Cancer 2000 Jul;1(2):127-34; discussion 135
AD - Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA.
Women at high risk for the development of breast cancer have several
options open to them including increased cancer surveillance,
prophylactic mastectomy and/or oophorectomy, and chemoprevention. We
consider high-risk women to be those with known BRCA mutations or a
strong family history characterized by multiple relatives with breast
cancer, early age at diagnosis, and in some families, ovarian cancer. We
present existing data regarding prophylactic surgery for these women.
Essentially, a woman at high risk for breast cancer may choose to
undergo bilateral prophylactic mastectomy, with or without
reconstruction. For patients who have a known breast cancer,
contralateral mastectomy is also an option. Finally, for women in
families with a strong incidence of ovarian cancer, prophylactic
oophorectomy can be considered.
6
UI - 11907939
AU - Pines A
TI -
Management problems. BRCA mutation, prophylactic oophorectomy and HRT.
SO - Climacteric 1998 Dec;1(4):309-10
AD - Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
7
UI - 11777930
AU - Fan W; Jin S; Tong T; Zhao H; Fan F; Antinore MJ; Rajasekaran B; Wu M;
TI -
Zhan Q
BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT
motifs.
SO - J Biol Chem 2002 Mar 8;277(10):8061-7
AD - Department of Radiation Oncology, Cancer Institute, University of
Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
BRCA1, a breast and ovarian cancer susceptibility gene, has been
implicated in gene regulation. Previous studies demonstrate that BRCA1
induces GADD45, a p53-regulated and stress-inducible gene that plays an
important role in cellular response to DNA damage. However, the
mechanism(s) by which BRCA1 regulates GADD45 remains unclear. In this
report, we have shown that BRCA1 activation of the GADD45 promoter is
mediated through the OCT-1 and CAAT motifs located at the GADD45
promoter region. Site-directed mutations of both OCT-1 and CAAT motifs
abrogate induction of the GADD45 promoter by BRCA1. Both OCT-1 and CAAT
motifs are able to confer BRCA1 inducibility in a non-related minimal
promoter. Physical associations of BRCA1 protein with transcription
factors Oct-1 and NF-YA, which directly bind to the OCT-1 and CAAT
motifs, are established by biotin-streptavidin pull-down and
coimmunoprecipitation assays. Such protein interactions are required for
interaction of BRCA1 with the GADD45 promoter because either
immunodepletion of Oct-1 and NF-YA proteins or mutations in the OCT-1
and CAAT motifs disrupt BRCA1 binding to the GADD45 promoter. These
findings indicate that BRCA1 can up-regulate its targeted genes through
protein-protein interactions and provide a novel mechanism by which
BRCA1 participates in transcriptional regulation.
8
UI - 11905804
AU - McCormick F
TI -
Cancer gene therapy: fringe or cutting edge?
SO - Nature Rev Cancer 2001 Nov;1(2):130-41
AD - University of California San Francisco, Cancer Research Institute,
94115, USA. mccormick@cc.ucsf.edu
Direct targeting of cancer cells with gene therapy has the potential to
treat cancer on the basis of its molecular characteristics. But although
laboratory results have been extremely encouraging, many practical
obstacles need to be overcome before gene therapy can fulfil its goals
in the clinic. These issues are not trivial, but seem less formidable
than the challenge of killing cancers selectively and rationally--a
challenge that has been successfully addressed.
9
UI - 11923153
AU - Bosch X
TI -
New test simplifies genetic testing for breast cancer.
SO - BMJ 2002 Mar 30;324(7340):755
10
UI - 11263928
AU - Aziz S; Kuperstein G; Rosen B; Cole D; Nedelcu R; McLaughlin J; Narod SA
TI -
A genetic epidemiological study of carcinoma of the fallopian tube.
SO - Gynecol Oncol 2001 Mar;80(3):341-5
AD - Department of Public Health Sciences, University of Toronto, Toronto,
Ontario, Canada.
OBJECTIVE: The goal of this work was to evaluate the importance of
genetic factors in the etiology of fallopian tube cancer. METHODS: All
pathologically confirmed cases of fallopian tube cancer diagnosed in
Ontario from 1990 to 1998 were identified from the records of the
Ontario Cancer Registry. Living patients were approached to provide
information about their family history and to provide a blood sample for
testing for mutations in BRCA1 and BRCA2. RESULTS: A modest increase in
the risk of ovarian cancer (relative risk (RR) = 2.2; 95% confidence
interval (CI) = 0.4, 6.3) and of early-onset breast cancer (RR = 2.4;
95% CI = 0.6, 6.1) was observed in the first-degree relatives of the
fallopian cancer cases. Five of the forty-four cases were positive for a
mutation in BRCA1 (11%) and two were positive for a BRCA2 mutation (5%).
Five of eighteen women diagnosed at or before age 55 were positive
(28%). Two of the seven mutation carriers had a strong family history of
breast and ovarian cancer, and three carriers had a modest family
history. Three of the forty-four cases were Jewish, and of these, two
carried a founder mutation characteristic of this population.
CONCLUSIONS: Fallopian tube carcinoma should be considered to be a
clinical component of the hereditary breast-ovarian cancer syndrome, and
may be associated with BRCA1 and BRCA2 mutations. Genetic evaluation
should be offered to women who present with fallopian tube carcinoma. It
is important to consider the risk of fallopian tube carcinoma when
prophylactic oophorectomy is performed in high-risk women. Copyright
2001 Academic Press.
11
UI - 9616736
AU - Lynch HT; Fusaro RM; Lynch JF
TI -
Cancer genetics in the new era of molecular biology.
SO - Ann N Y Acad Sci 1997 Dec 29;833():1-28
AD - Department of Preventive Medicine and Public Health, Creighton
University School of Medicine, Omaha, Nebraska 68178, USA.
htlynch@creighton.edu
The role of primary genetic factors in the etiology of cancer has become
of intense interest to the research and clinical community. This
interest has been heightened by recent discoveries that germ-line
mutations such as BRCA1 and BRCA2 in hereditary breast cancer are
responsible for an increasing percentage of common solid tumors. A
potpourri of proto-oncogenes and tumor-suppressor genes has been
identified in hereditary as well as certain common sporadic and rare
cancer types, and new cancer genes will likely be discovered every month
to account for the 5 to 10% of the cases of cancer that can be
attributed to primary genetic factors. Molecular mechanisms in the
pathogenesis of hereditary cancer can result in more-targeted
cancer-control measures. At least four mutator genes (MHS2, MLH1, PMS1
and PMS2) appear to account for 70-80% of hereditary nonpolypoid
colorectal cancer (HNPCC). When one of these germ-line mutations is
present in an HNPCC family, the physician is then able to determine the
patient's lifetime cancer destiny with an accuracy of about 90% (limited
only by the penetrance of the gene). This will enable highly targeted
surveillance to be initiated early, such as colonoscopy beginning at
ages 20 to 25 or prophylactic subtotal colectomy. Also, in multiple
endocrine neoplasia syndromes (MEN 2A and 2B), the identification of the
culprit RET proto-oncogene now enables a secure diagnosis and permits
testing of children who might benefit from prophylactic total
thyroidectomy. Central to translation of these momentous molecular
genetic discoveries into patient care is the necessity of determining
who requires DNA testing. The cancer family history is the linchpin in
making this decision.
12
UI - 11196174
AU - Wang H; Zeng ZC; Bui TA; DiBiase SJ; Qin W; Xia F; Powell SN; Iliakis G
TI -
Nonhomologous end-joining of ionizing radiation-induced DNA
double-stranded breaks in human tumor cells deficient in BRCA1 or BRCA2.
SO - Cancer Res 2001 Jan 1;61(1):270-7
AD - Department of Radiation Oncology, Kimmel Cancer Center, Jefferson
Medical College, Philadelphia, Pennsylvania 19107, USA.
Mutations in the BRCA1 or BRCA2 genes predispose to a wide spectrum of
familial cancers. The functions of the proteins encoded by BRCA1 and
BRCA2 remain to be elucidated, but their interaction and colocalization
with hRAD51 suggest a role in homologous recombination and DNA
double-strand break (DSB) repair. The role of BRCA1 and BRCA2 in the
rejoining of ionizing radiation (IR)-induced DNA DSBs, which may
represent a step in the overall process of repair, remains uncertain
because recent reports provide conflicting results. Because elucidation
of the role of these proteins in DNA DSB rejoining is important for
their functional characterization, we reexamined this end point in cells
with mutations in either BRCA1 or BRCA2. We show that two pancreatic
carcinoma cell lines known to have either wild-type (BxPC3) or mutant
forms (Capan-1) of BRCA2 rejoin IR-induced DNA DSBs to a similar extent
following biphasic kinetics characterized by a fast and a slow
component. Importantly, inactivation of DNA-dependent protein kinase
(DNA-PK) by wortmannin generates similar shifts from the fast to the
slow component of rejoining in BRCA2-proficient and BRCA2-deficient
cells. This suggests that the functioning of either the fast,
DNA-PK-dependent component or the slow, DNA-PK-independent component of
rejoining is not affected by mutations in BRCA2. Also, a human breast
cancer cell line with mutated BRCA1 shows normal rejoining of IR-induced
DNA DSBs and levels of inhibition by wortmannin commensurate with the
degree of DNA-PK inhibition. These observations fail to confirm a direct
role for BRCA1 or BRCA2 in the rejoining of IR-induced DSBs in the
genome of human tumor cells and, as a result, an involvement in
nonhomologous end-joining. They are in line with similar observations
with mutants deficient in genes implicated in homologous recombination
and support the view that the radiosensitivity to killing of cells
deficient in BRCA1 or BRCA2 derives from defects in this repair pathway.
13
UI - 11836499
AU - Yarden RI; Pardo-Reoyo S; Sgagias M; Cowan KH; Brody LC
TI -
BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA
damage.
SO - Nat Genet 2002 Mar;30(3):285-9
AD - Genome Technology Branch, National Human Genome Research Institute,
National Institutes of Health, Bethesda, Maryland 20892, USA.
The breast cancer tumor-suppressor gene, BRCA1, encodes a protein with a
BRCT domain-a motif that is found in many proteins that are implicated
in DNA damage response and in genome stability. Phosphorylation of BRCA1
by the DNA damage-response proteins ATM, ATR and hCds1/Chk2 changes in
response to DNA damage and at replication-block checkpoints. Although
cells that lack BRCA1 have an abnormal response to DNA damage, the exact
role of BRCA1 in this process has remained unclear. Here we show that
BRCA1 is essential for activating the Chk1 kinase that regulates DNA
damage-induced G2/M arrest. Thus, BRCA1 controls the expression,
phosphorylation and cellular localization of Cdc25C and Cdc2/cyclin B
kinase-proteins that are crucial for the G2/M transition. We show that
BRCA1 regulates the expression of both Wee1 kinase, an inhibitor of
Cdc2/cyclin B kinase, and the 14-3-3 family of proteins that sequesters
phosphorylated Cdc25C and Cdc2/cyclin B kinase in the cytoplasm. We
conclude that BRCA1 regulates key effectors that control the G2/M
checkpoint and is therefore involved in regulating the onset of mitosis.
14
UI - 11775450
AU - DeFrias DV; Okonkwo AM; Keh PC; Nayar R
TI -
Cytopathology of the ovary.
SO - Cancer Treat Res 2002;107():185-211
AD - Department of Pathology, Northwestern University Medical School,
Chicago, Illinois 60611, USA.
15
UI - 11775456
AU - Chappuis PO; Foulkes WD
TI -
Risk assessment & genetic testing.
SO - Cancer Treat Res 2002;107():29-59
AD - Division of Medical Genetics, Department of Medicine, McGill University
Health Center, Montreal, QC, Canada.
Ovarian cancer is the fifth most common cause of cancer death in women
in Western countries and family history is one of the strongest known
risk factors. Approximately 5 to 13% of all ovarian cancer cases are
caused by the inheritance of cancer predisposing genes with an autosomal
pattern of transmission. The inherited fraction of ovarian cancer may
differ between populations. Based on analysis of familial ovarian cancer
pedigrees and other epidemiological studies, three hereditary ovarian
cancer syndromes have been defined. The identification of the genes
responsible for most hereditary ovarian cancers has open a new area of
early detection methods and preventive procedures specifically dedicated
to women identified as carrying ovarian cancer predisposing genes.
Predictive oncology is best performed by a dedicated unit with
professionals aware of all the issues surrounding genetic testing.
16
UI - 11925560
AU - Gold ER
TI -
Biotechnology patents: strategies for meeting economic and ethical
concerns.
SO - Nat Genet 2002 Apr;30(4):359
The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.
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