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Abramson Cancer CenterNCI CANCERLIT® Search: BRCA1 Gene - July 2002
National Cancer Institute®
Last Modified: July 1, 2002
- Risk-reduction mastectomy: clinical issues and research needs.
- Benign mental health consequences of screening for mutations of BRCA1/BRCA2.
- What do women really want to know? Motives for attending familial breast cancer clinics.
- Factors affecting genetic testing and decisions about prophylactic surgery.
- 14. Breast cancer prevention.
- Lumpectomy and breast radiotherapy in breast cancer patients with a family history of breast cancer, ovarian cancer, or both.
- [Risk factors for the development of ovarian carcinoma]
- BRCA1 transactivates the cyclin-dependent kinase inhibitor p27(Kip1).
- Peritoneal lavage cytology: an assessment of its value during prophylactic oophorectomy.
- Cell proliferation and apoptosis in BRCA-associated hereditary ovarian cancer.
- Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.
- [Genes and cancer. NBS1 (Nijmegen breakage syndrome). Repair gene]
- Frameshift mutations at coding mononucleotide repeats of the hRAD50 gene in gastrointestinal carcinomas with microsatellite instability.
- Expression of BRCA1 and BRCA2 in different tumor cell lines with various growth status.
- Familial ovarian cancer.
- Cancer gene therapy: fringe or cutting edge?
- Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX.
Table of Contents
1
UI - 11535704
AU - Stefanek M; Hartmann L; Nelson W
TI -
Risk-reduction mastectomy: clinical issues and research needs.
SO - J Natl Cancer Inst 2001 Sep 5;93(17):1297-306
AD - Behavioral Research Program, Division of Cancer Control and Population
Sciences, National Cancer Institute, Bethesda, MD, USA. ms496r@nih.gov
Risk-reduction mastectomy (RRM), also known as bilateral prophylactic
mastectomy, is a controversial clinical option for women who are at
increased risk of breast cancer. High-risk women, including women with a
strong family history of breast cancer and BRCA1/2 mutation carriers,
have several clinical options: risk-reduction surgery (bilateral
mastectomy and bilateral oophorectomy), surveillance (mammography,
clinical breast examination, and breast self-examination), and
chemoprevention (tamoxifen). We review research in a number of areas
central to our understanding of RRM, including recent data on 1) the
effectiveness of RRM in reducing breast cancer risk, 2) the perception
of RRM among women at increased risk and health-care providers, 3) the
decision-making process for follow-up care of women at high risk, and 4)
satisfaction and psychological status after surgery. We suggest areas of
future research to better guide high-risk women and their health-care
providers in the decision-making process.
2
UI - 11840496
AU - Coyne JC; Kruus L; Kagee A; Thompson R; Palmer S; Kruus L
TI -
Benign mental health consequences of screening for mutations of
BRCA1/BRCA2.
SO - Am J Med Genet 2002 Feb 1;107(4):346-9
3
UI - 12070250
AU - Van Asperen CJ; Van Dijk S; Zoeteweij MW; Timmermans DR; De Bock GH;
TI -
Meijers-Heijboer EJ; Niermeijer MF; Breuning MH; Kievit J; Otten W
What do women really want to know? Motives for attending familial breast
cancer clinics.
SO - J Med Genet 2002 Jun;39(6):410-4
4
UI - 11899370
AU - Mahon SM
TI -
Factors affecting genetic testing and decisions about prophylactic
surgery.
SO - Clin J Oncol Nurs 2001 May-Jun;5(3):117-20
AD - St. Louis University, Division of Hematology/Oncology, St. Louis, MO,
USA.
Both of the articles reviewed here as well as the references, suggest
that very little is actually known about the impact of many aspects of
genetic testing. How decision are made about genetic testing in people
who do not have cancer, how the results of testing are used used to
guide care, and ultimately how people adjust to prophylactic surgery,
which is the most effective form of prevention currently available to
those who do have a mutation are not completely clear. This has many
implications for practice in general. Oncology nurses who build
relationships with those diagnosed with cancer and their families may be
one of the best groups of professionals to provide the education and
counseling individuals and families need prior to making any decision
about genetic testing. Just as many responses to cancer exist, so do
many responses to finding out the results of mutation status. Oncology
nurses are challenged to help facilitate adjustment to learning that one
carries a mutation that significantly increases risk of developing
cancer. More nursing research needs to be conducted on how to facilitate
this adjustment. Dealing with the unknown can be a frightening
experience. Little is known about the long-term effectiveness of
prophylactic mastectomy and oophorectomy in unaffected mutation-positive
individuals. Most of what is known is based on retrospective review.
Nurses are challenged to interpret this information, along with its
inherent strengths and weaknesses, to individuals so they can make the
best possible decisions. The psychosocial needs of those who undergo
prophylactic surgery are not clearly understood. Surgery can have many
psychological outcomes, and how individuals adjust to these changes is
not clear. More nursing research is needed not only to understand these
needs but also to design interventions to facilitate and improve
adjustment to not only the information that one is mutation positive but
also to prophylactic surgery. People who do not have cancer but have a
high risk for cancer because of their genetic background need
comprehensive and consistent care by knowledgeable healthcare providers.
Although these individuals have not been diagnosed with cancer, they
have complex psychosocial needs related to their family history and the
decisions being made about prevention strategies. Oncology nurses can
help fill this gap in care and provide the necessary support these
individuals need.
5
UI - 12074209
AU - Salih AK; Fentiman IS
TI -
14. Breast cancer prevention.
SO - Int J Clin Pract 2002 May;56(4):267-71
AD - Hedley Atkins Breast Unit, Guy's Hospital London, UK.
Increased risk of breast cancer may result from potentially modifiable
causes such as endogenous hormone levels, obesity, HRT, and
non-lactation, or non-modifiable factors including genetic
susceptibility and increasing age. The Gail model, based on known
factors, may be useful for estimating lifetime risk in some individuals,
but those risk factors that are easier to modify may have a limited
impact on the totality of breast cancer. Tamoxifen prevention still
remains contentious, with a significant reduction in risk of breast
cancer in women given tamoxifen in the NSABP P1 study but no effect in
the Italian and Royal Marsden trials. Raloxifene, tested in the MORE
trial, reduced the incidence of breast cancer by 65% but this was
restricted to oestrogen receptor positive tumours. Lifestyle factors
such as diet, obesity, exercise and age at first full term pregnancy and
number of pregnancies have a mild to moderate impact on risk, so may
have little effect on the incidence of breast cancer. Reduction of
alcohol intake could lead to a modest reduction in the risk of breast
cancer but possibly adversely affect other diseases. Fat reduction and
GnRH analogue reduce mammographic density but have not yet been shown to
affect risk. For women with BRCA1/2 mutation, options include unproven
surveillance and prophylactic mastectomy with an unquantified risk
reduction. Interesting new candidates for chemoprevention include
aromatase inhibitors, new generation SERMs, demethylating agents,
non-selective COX inhibitors, tyrosine kinase inhibitors and polyamine
synthetic inhibitors.
6
UI - 12047472
AU - Leonard CE; Sedlacek S; Shapiro H; Hey D; Liang X; Howell K; Vernon B;
TI -
Ponce J; Smith L
Lumpectomy and breast radiotherapy in breast cancer patients with a
family history of breast cancer, ovarian cancer, or both.
SO - Breast J 2002 May-Jun;8(3):154-61
AD - Rocky Mountain Cancer Centers; Department of Radiation Oncology, Denver,
Colorado 80110, USA.
This article presents an outcomes review of breast cancer patients
identified from the cancer registries of four area hospitals. These
patients had family histories of breast cancer, ovarian carcinoma, or
both and were treated with conservative surgery and radiation to the
involved breast. Patients were as follows: group 1, one first-degree
relative ( n = 165, one synchronous bilateral breast cancer); group 2, >
or =2 first-degree relatives ( n = 21); group 3, one second-degree
relative ( n = 20); and group 4, > or =2 second-degree relatives ( n =
18). The total of patients and breast cancer events was 224 and 225,
respectively. Group 5 was a subgroup of 53 patients with a substantial
risk (>10%) of a BRCA1 or BRCA2 mutation. After a median follow-up of
3.9 years, 5 patients had local failure (2%), and 5 developed a
contralateral breast cancer (2%). There were no significant differences
in local failure rates between groups (p = 1.0): group 1, 5 of 166 (3%);
group 2, 0 of 21 (0%); group 3, 0 of 20 (0%); and group 4, 0 of 18 (0%).
Local failure for group 5 was 2% (1 of 53). Four of 143 patients (3%)
with a minimum 3 years of follow-up (median, 5.6 years) had local
failure, and 5 (4%) developed a contralateral breast cancer. A
univariate analysis was statistically significant for differentiation
only (well, 0 of 67; moderately, 1 of 57 [1.8%]; poor, 3 of 26 [11.5%],
p = 0.008). Overall survival for groups 1-4 did not differ
significantly. Although follow-up has been relatively short, we have not
found that breast cancer patients with various degrees of family
histories of breast/ovarian carcinoma have had a detrimental outcome
when treated with conservative therapy.
7
UI - 11965725
AU - Malinova M
TI -
[Risk factors for the development of ovarian carcinoma]
SO - Akush Ginekol (Sofiia) 1999;38(1):57-60
8
UI - 12082635
AU - Williamson EA; Dadmanesh F; Koeffler HP
TI -
BRCA1 transactivates the cyclin-dependent kinase inhibitor p27(Kip1).
SO - Oncogene 2002 May 9;21(20):3199-206
AD - Department of Medicine, Cedars-Sinai Medical Center, UCLA School of
Medicine, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
williamsone@cshs.org
The p27(Kip1) is a member of the universal cyclin-dependent kinase
inhibitor family. Previously, immunochemical analysis of a series of
breast cancer cell lines demonstrated a correlation between the
expression of p27(Kip1) and the breast cancer susceptibility gene BRCA1.
BRCA1 has a number of activities including DNA repair, growth inhibition
and as a transcription factor. Here we demonstrate that BRCA1
transactivates expression of p27(Kip1). This transactivation is
dependent on the presence of a functional C-terminal transactivation
domain. Promoter-deletion analysis identified the presence of a putative
BRCA1-responsive element located at position -615 to -511 of the
p27(Kip1) promoter. These results suggest that the transcriptional
regulation of p27(Kip1) by BRCA1 may be a mechanism for BRCA1- induced
growth inhibition.
9
UI - 12051865
AU - Colgan TJ; Boerner SL; Murphy J; Cole DE; Narod S; Rosen B
TI -
Peritoneal lavage cytology: an assessment of its value during
prophylactic oophorectomy.
SO - Gynecol Oncol 2002 Jun;85(3):397-403
AD - Department of Laboratory Medicine and Pathology, Mount Sinai Hospital,
Toronto, Canada. tcolgan@mtsinai.on.ca
OBJECTIVE: Prophylactic oophorectomy (PO) is an accepted treatment
strategy for women who are at high risk for the development of ovarian
carcinoma, particularly women who are BRCA mutation-positive. This study
sought to assess the utility of peritoneal lavage cytology at the time
of PO in detecting occult malignancy in this group of patients. METHODS:
Thirty-five high-risk women, who were not suspected of having any
malignancy or ovarian mass, underwent peritoneal lavage at the time of
PO. Thirty-one of the thirty-five women had undergone BRCA mutation
analysis (BRCA1+, 18; BRCA2+, 10; BRCA-, 3). Intensive histopathologic
examination was used in all 35 cases to identify occult carcinoma.
Lavage specimens were reviewed for the presence of malignant cells and
endosalpingiosis. The cytologic review was conducted without knowledge
of either the histopathologic or BRCA results. RESULTS: In 32 of the 35
lavage specimens no malignancy was detected. In the remaining three
cases malignant cells were detected; in two of these cases
histopathologic examination confirmed an ovarian/tubal occult carcinoma.
Two of these women were BRCA1 mutation positive. Endosalpingiosis was
detected in the peritoneal lavage specimens of 7 of the 32 cases showing
no evidence of malignancy. All of these 7 women were BRCA mutation
positive or unknown. CONCLUSION: Peritoneal lavage cytology can detect
occult carcinoma at the time of PO and should be performed at PO. The
significance of occult carcinoma detected by either histopathologic or
cytopathologic examination is uncertain. Whether the prevalence of
endosalpingiosis detectable by lavage cytology is increased in BRCA
mutation-positive patients requires further study.
10
UI - 12051869
AU - Levine DA; Federici MG; Reuter VE; Boyd J
TI -
Cell proliferation and apoptosis in BRCA-associated hereditary ovarian
cancer.
SO - Gynecol Oncol 2002 Jun;85(3):431-4
AD - Gynecology and Breast Research Laboratory, Memorial Sloan-Kettering
Cancer Center, New York, New York 10021, USA.
OBJECTIVE: The goal was to test the hypothesis that cellular growth
properties differ between hereditary and sporadic ovarian cancers.
METHODS: Cell proliferation and apoptosis were assessed in 67 tumors
associated with deleterious germline BRCA mutations (hereditary) and 69
tumors without BRCA mutations (sporadic). Cell proliferation was
evaluated by immunohistochemical analysis of Ki-67 expression, and
apoptosis was assessed using a TUNEL assay. RESULTS: The mean number of
Ki-67-immunopositive nuclei was significantly higher in ovarian cancers
from the hereditary group compared with those from the sporadic group (P
= 0.017). Cell proliferation did not differ significantly between BRCA1-
and BRCA2-associated hereditary tumors, and apoptosis did not differ
significantly between the hereditary and sporadic tumors. CONCLUSION:
These data indicate that ovarian carcinomas associated with germline
BRCA mutations have a significantly higher growth fraction than sporadic
cancers. This property may contribute to an improved response to
cytotoxic chemotherapy, partially accounting for the longer
recurrence-free interval and overall survival observed in the hereditary
group.
11
UI - 10426999
AU - Zhong Q; Chen CF; Li S; Chen Y; Wang CC; Xiao J; Chen PL; Sharp ZD; Lee
TI -
WH
Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA
damage response.
SO - Science 1999 Jul 30;285(5428):747-50
AD - Department of Molecular Medicine, Institute of Biotechnology, University
of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San
Antonio, TX 78245, USA.
BRCA1 encodes a tumor suppressor that is mutated in familial breast and
ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in
vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon
irradiation, BRCA1 was detected in discrete foci in the nucleus, which
colocalize with hRad50. Formation of irradiation-induced foci positive
for BRCA1, hRad50, hMre11, or p95 was dramatically reduced in HCC/1937
breast cancer cells carrying a homozygous mutation in BRCA1 but was
restored by transfection of wild-type BRCA1. Ectopic expression of
wild-type, but not mutated, BRCA1 in these cells rendered them less
sensitive to the DNA damage agent, methyl methanesulfonate. These data
suggest that BRCA1 is important for the cellular responses to DNA damage
that are mediated by the hRad50-hMre11-p95 complex.
12
UI - 10610129
AU - Soussi T
TI -
[Genes and cancer. NBS1 (Nijmegen breakage syndrome). Repair gene]
SO - Bull Cancer 1999 Oct;86(10):803-4
AD - Institut Curie, Paris.
13
UI - 11196187
AU - Kim NG; Choi YR; Baek MJ; Kim YH; Kang H; Kim NK; Min JS; Kim H
TI -
Frameshift mutations at coding mononucleotide repeats of the hRAD50 gene
in gastrointestinal carcinomas with microsatellite instability.
SO - Cancer Res 2001 Jan 1;61(1):36-8
AD - Department of Pathology, Yonsei University College of Medicine, Seoul,
Korea.
Microsatellite instability (MSI) and frameshift mutations in genes
containing nucleotide repeats have been reported in a subset of
colorectal and gastric carcinomas. This study describes the analysis of
MSI-positive colorectal (39 cases) and gastric carcinomas (36 cases) for
the presence of frameshift mutations of the six genes known to be
involved in DNA repair and containing mononucleotide repeats in their
coding region. Our mutational study of the 75 MSI-positive tumors
revealed frequent mutations in hRAD50 (23 cases, 31%), BLM (16 cases,
21%), and hMSH6 (16 cases, 21%); rare mutations in BRCA1 (1 case, 1%)
and ATM (3 cases, 4%); and no mutation in NBS1. In contrast, no
frameshift mutation was found in 60 MSI-negative colorectal and gastric
carcinomas. The mutation of hRAD50, a gene that is involved in the
response to cellular DNA damage and forms a complex with hMRE11 and
NBS1, has not been reported previously. Our results suggest that
frameshift mutations of hRAD50, BLM, and hMSH6 are selected and play a
role in the tumorigenesis of colorectal and gastric carcinomas with MSI.
The MSI targeting of the hRAD50 and BLM genes represents an additional
link between MSI and DNA repair because alteration of these genes could
accelerate defective DNA repair.
14
UI - 11983207
AU - Vissac C; Peffault De Latour M; Communal Y; Bignon YJ; Bernard-Gallon DJ
TI -
Expression of BRCA1 and BRCA2 in different tumor cell lines with various
growth status.
SO - Clin Chim Acta 2002 Jun;320(1-2):101-10
AD - Laboratoire d'Oncologie Moleculaire, Centre Jean Perrin, 58 rue
Montalembert-B.P. 392-63011, Clermont-Ferrand Cedex 1, France.
BACKGROUND: BRCA1 and BRCA2 are breast cancer susceptibility genes.
Recent studies suggest that BRCA1 interacts with a great variety of
proteins, including BRCA2, cell-cycle regulators, transcriptional
activators and repressors. We investigated the expression of both BRCA1
and BRCA2 during the progression of the cell cycle of human tumor cell
lines from different origins (MCF7, MDA-MB231, PA1 and CCL221) in two
growth status (60% and 100% of confluency). METHODS: First, the growth
status was characterized by determination of the cell cycle by flow
cytometry analysis. At the same time, immunohistochemistry was performed
to follow BRCA1 and BRCA2 protein expression and then, quantification of
BRCA1 and BRCA2 transcripts was realized using real-time quantitative
RT-PCR. RESULTS: We reported in studied tumor cell lines with 60% of
confluency by comparison with 100% of confluency, an increase in the
BRCA1 and BRCA2 expression at the level of proteins and transcripts.
CONCLUSION: Therefore, the expression of both BRCA1 and BRCA2 genes at
the protein and mRNA levels appear to be up-regulated after cell
proliferation in human tumor cell lines from different origins.
15
UI - 12112981
AU - Volm T
TI -
Familial ovarian cancer.
SO - Curr Womens Health Rep 2002 Feb;2(1):34-8
AD - Universitats-Frauenklinik Ulm, Prittwitzstrasse 43, 89075 Ulm, Germany.
tanja.volm@medizin.uni-ulm.de
Women with mutations in the BRCA1 or BRCA2 genes are at increased risk
for the development not only of breast, but of ovarian cancer. The
estimated lifetime risk of contracting ovarian cancer for women bearing
the mutation is 16% for Ashkenazi Jews and up to 60% for high-risk
populations. If a woman is at high familial risk of getting ovarian
cancer, an intense screening with transvaginal ultrasound or
determination of CA 125 can be done, although these methods have not
proved beneficial so far. It is thought by some that the use of the
contraceptive pill can prevent up to 50% of family-associated ovarian
cancers, but the few existing studies have yielded contradictory
results. That prophylactic oophorectomy can prolong the lives of healthy
women with a family history or who bear a germline BRCA mutation is
quite sure, but it is not helpful in preventing peritoneal carcinoma.
The clinicopathologic behavior of mutation-associated ovarian cancer
differs from the growth pattern of sporadic ovarian cancer. The hope is
to develop suitable therapies for both types.
16
UI - 11905804
AU - McCormick F
TI -
Cancer gene therapy: fringe or cutting edge?
SO - Nat 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.
17
UI - 12034884
AU - Bassing CH; Chua KF; Sekiguchi J; Suh H; Whitlow SR; Fleming JC; Monroe
TI -
BC; Ciccone DN; Yan C; Vlasakova K; Livingston DM; Ferguson DO; Scully
R; Alt FW
Increased ionizing radiation sensitivity and genomic instability in the
absence of histone H2AX.
SO - Proc Natl Acad Sci U S A 2002 Jun 11;99(12):8173-8
AD - Howard Hughes Medical Institute, Department of Genetics, Children's
Hospital, Boston, MA 02115, USA.
In mammalian cells, DNA double-strand breaks (DSBs) cause rapid
phosphorylation of the H2AX core histone variant (to form gamma-H2AX) in
megabase chromatin domains flanking sites of DNA damage. To investigate
the role of H2AX in mammalian cells, we generated H2AX-deficient
(H2AX(Delta)/Delta) mouse embryonic stem (ES) cells. H2AX(Delta)/Delta
ES cells are viable. However, they are highly sensitive to ionizing
radiation (IR) and exhibit elevated levels of spontaneous and IR-induced
genomic instability. Notably, H2AX is not required for NHEJ per se
because H2AX(Delta)/Delta ES cells support normal levels and fidelity of
V(D)J recombination in transient assays and also support lymphocyte
development in vivo. However, H2AX(Delta)/Delta ES cells exhibit altered
IR-induced BRCA1 focus formation. Our findings indicate that H2AX
function is essential for mammalian DNA repair and genomic stability.
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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