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Abramson Cancer CenterNCI CANCERLIT® Search: BRCA1 Gene - October 2002
National Cancer Institute®
Last Modified: October 1, 2002
- Cancer. BRCA2 enters the fray.
- Cancer Incidence in BRCA1 mutation carriers.
- Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.
- Inactivation of BRCA1 and BRCA2 in ovarian cancer.
- A rational approach to prenatal screening and intervention.
- BRCA2 T2722R is a deleterious allele that causes exon skipping.
- [Review of risk factors for breast cancer--what's new?]
- Caretaker tumour suppressor genes that defend genome integrity.
- Fighting the battle against breast cancer. So close and yet so far.
- BRCA1 interacts with acetyl-CoA carboxylase through its tandem of BRCT domains.
- Re: Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers.
- The role of p53 mutation in BRCA1-associated ovarian cancer.
- No BRCA1 germline mutation in a family with uterine papillary serous carcinoma: a case report.
- BRCA1-induced apoptosis involves inactivation of ERK1/2 activities.
Table of Contents
1
UI - 12228708
AU - Wilson JH; Elledge SJ
TI -
Cancer. BRCA2 enters the fray.
SO - Science 2002 Sep 13;297(5588):1822-3
AD - Department of Biochemistry and Molecular Biology, Baylor College of
Medicine, Houston, TX 77030, USA.
2
UI - 12237281
AU - Thompson D; Easton DF; Breast Cancer Linkage Consortium
TI -
Cancer Incidence in BRCA1 mutation carriers.
SO - J Natl Cancer Inst 2002 Sep 18;94(18):1358-65
AD - Cancer Research UK, Genetic Epidemiology Unit, University of Cambridge,
United Kingdom.
BACKGROUND: Germline BRCA1 mutations confer a substantial lifetime risk
of breast and ovarian cancer, but whether cancer at other sites is
increased is less clear. To evaluate the risks of other cancers in BRCA1
mutation carriers, we conducted a cohort study of 11 847 individuals
from 699 families segregating a BRCA1 mutation that were ascertained in
30 centers across Europe and North America. METHODS: The observed cancer
incidence was compared with the expected cancer incidence based on
population cancer rates. Relative risks (RRs) of each cancer type in
BRCA1 carriers relative to risks for the general population were
estimated by weighting individuals according to their estimated
probability of being a mutation carrier. All statistical tests were
two-sided. RESULTS: BRCA1 mutation carriers were at a statistically
significantly increased risk for several cancers, including pancreatic
cancer (RR = 2.26, 95% confidence interval [CI] = 1.26 to 4.06, P =.004)
and cancer of the uterine body and cervix (uterine body RR = 2.65, 95%
CI = 1.69 to 4.16, P<.001; cervix RR = 3.72, 95% CI = 2.26 to 6.10,
P<.001). There was some evidence of an elevated risk of prostate cancer
in mutation carriers younger than 65 years old (RR = 1.82, 95% CI = 1.01
to 3.29, P =.05) but not in those 65 years old or older (RR = 0.84, 95%
CI = 0.53 to 1.33, P =.45). Overall, increases in the risk for cancer at
sites other than the breast or ovary were small and evident in women (RR
= 2.30, 95% CI = 1.93 to 2.75, P =.001) but not in men (RR = 0.95, 95%
CI = 0.81 to 1.12, P =.58). CONCLUSIONS: In carriers of BRCA1 mutations,
the overall increased risk of cancer at sites other than breast and
ovary is small and is observed in women but generally not in men. BRCA1
mutations may confer increased risks of other abdominal cancers in women
and increased risks of pancreatic cancer in men and women.
3
UI - 12237282
AU - Brose MS; Rebbeck TR; Calzone KA; Stopfer JE; Nathanson KL; Weber BL
TI -
Cancer risk estimates for BRCA1 mutation carriers identified in a risk
evaluation program.
SO - J Natl Cancer Inst 2002 Sep 18;94(18):1365-72
AD - Department of Medicine and Abramson Family Cancer Research Institute,
University of Pennsylvania Cancer Center, Philadelphia 19104, USA.
BACKGROUND: Increasing numbers of BRCA1 mutation carriers are being
identified in cancer risk evaluation programs. However, no estimates of
cancer risk specific to a clinic-based population of mutation carriers
are available. These data are clinically relevant, because estimates
based on families ascertained for linkage studies may overestimate
cancer risk in mutation carriers, and population-based series may
underestimate it. Wide variation in risk estimates from these disparate
ascertainment groups makes counseling in risk evaluation programs
difficult. The purpose of this study was to estimate BRCA1-related
cancer risks for individuals ascertained in a breast cancer risk
evaluation clinic. METHODS: Cumulative observed and age-adjusted cancer
risk estimates were determined by analyzing 483 BRCA1 mutation carriers
in 147 families identified in two academic breast and ovarian cancer
risk evaluation clinics. Cancer risks were computed from the proportion
of individuals diagnosed with cancer during a 10-year age interval from
among the total number of individuals alive and cancer-free at the
beginning of that interval. Age-of-diagnosis comparisons were made using
two-sided Student's t tests. RESULTS: By age 70, female breast cancer
risk was 72.8% (95% confidence interval [CI] = 67.9% to 77.7%) and
ovarian cancer risk was 40.7% (95% CI = 35.7% to 45.6%). The risk for a
second primary breast cancer by age 70 was 40.5% (95% CI = 34.1% to
47.0%). We also identified an increased risk of cancer of the colon
(twofold), pancreas (threefold), stomach (fourfold), and fallopian tube
(120-fold) in BRCA1 mutation carriers as compared with Surveillance,
Epidemiology, and End Results (SEER) Program population-based estimates.
CONCLUSION: The estimates for breast and ovarian cancer risk in BRCA1
mutation carriers is higher than population-based estimates but lower
than estimates based on families ascertained for linkage studies. These
cancer risk estimates may most closely approximate those faced by BRCA1
mutation carriers identified in risk evaluation clinics.
4
UI - 12237285
AU - Hilton JL; Geisler JP; Rathe JA; Hattermann-Zogg MA; DeYoung B; Buller
TI -
RE
Inactivation of BRCA1 and BRCA2 in ovarian cancer.
SO - J Natl Cancer Inst 2002 Sep 18;94(18):1396-406
AD - Department of Obstetrics and Gynecology, Division of Gynecologic
Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA.
BACKGROUND: Although BRCA1 and BRCA2 play important roles in hereditary
ovarian cancers, the extent of their role in sporadic ovarian cancers
and their mechanisms of inactivation are not yet well understood. Our
goal was to characterize BRCA2 mutations and mRNA expression in a group
of ovarian tumors previously evaluated for BRCA1 mutations and mRNA
expression. METHODS: The tumors of 92 unrelated women with "ovarian"
cancer (i.e., ovarian, peritoneal, or fallopian tube cancer) were
screened for BRCA2 null mutations using a protein truncation test.
Methylation-specific polymerase chain reaction (PCR) was used to examine
the BRCA2 promoter for hypermethylation in tumors that did not express
BRCA2 mRNA. All statistical tests were two-sided. RESULTS: Nine tumors
had a germline (n = 5) or somatic (n = 4) BRCA2 mutation; each was
associated with loss of heterozygosity. All of the somatic (1445delC,
E880X, 4286del8, and 5783delT) and one of the germline (5984ins4)
mutations were unique to this study. One tumor had somatic mutations in
both BRCA1 and BRCA2. Two tumors are, to our knowledge, the first cases
of germline BRCA2-associated peritoneal cancer. Twelve additional tumors
lacked detectable BRCA2 mRNA, but the BRCA2 promoter was hypermethylated
in only one of them, suggesting that other mechanisms effect
transcriptional silencing of BRCA2. Tumors lacking BRCA1 mRNA were more
likely to lack BRCA2 mRNA than tumors expressing BRCA1 mRNA (P<.001).
Overall, 82% (95% confidence interval [CI] = 74% to 90%) of the tumors
contained alterations in BRCA1, BRCA2, or both genes. Of 41 informative
tumors with some alteration in BRCA2, 36 also had an alteration in
BRCA1. The frequency, but not the mechanism, of BRCA1 or BRCA2
dysfunction in ovarian cancer was independent of family history.
CONCLUSIONS: Multiple mechanisms cause nearly universal dysfunction of
BRCA1 and/or BRCA2 in hereditary and sporadic ovarian carcinoma. Ovarian
cancers with BRCA2 dysfunction often have simultaneous BRCA1
dysfunction.
5
UI - 9647530
AU - Yagel S; Anteby E
TI -
A rational approach to prenatal screening and intervention.
SO - Hum Reprod 1998 May;13(5):1126-8
AD - Department of Obstetrics and Gynecology, Hadssah Mt Scopus, Jerusalem,
Israel.
6
UI - 12145750
AU - Fackenthal JD; Cartegni L; Krainer AR; Olopade OI
TI -
BRCA2 T2722R is a deleterious allele that causes exon skipping.
SO - Am J Hum Genet 2002 Sep;71(3):625-31
AD - Center for Clinical Cancer Genetics, Department of Medicine, University
of Chicago Medical Center, Chicago, IL, 60637, USA.
Patients with a strong family history of breast cancer are often
counseled to receive genetic screening for BRCA1 and BRCA2 mutations,
the strongest known predictors of breast cancer. A major limitation of
genetic testing is the number of inconclusive results due to
unclassified BRCA1 and BRCA2 sequence variants. Many known deleterious
BRCA1 and BRCA2 mutations affect splicing, and these typically lie near
intron/exon boundaries. However, there are also potential internal
exonic mutations that disrupt functional exonic splicing enhancer (ESE)
sequences, resulting in exon skipping. Using previously established
sequence matrices for the scoring of putative ESE motifs, we have
systematically examined several BRCA2 mutations for potential ESE
disruption mutations. These predictions revealed that BRCA2 T2722R
(8393C-->G), which segregates with affected individuals in a family with
breast cancer, disrupts three potential ESE sites. Reverse-transcriptase
polymerase chain reaction analysis confirms that this mutation causes
exon skipping, leading to an out-of-frame fusion of BRCA2 exons 17 and
19. This represents the first BRCA2 missense mutation shown to be a
predicted deleterious protein-truncating mutation and suggests a
potentially useful method for determining the clinical significance of a
subset of the many unclassified variants in BRCA1 and BRCA2.
7
UI - 12222134
AU - Haimov-Kochman R; Lavy Y; Hochner-Celinkier D
TI -
[Review of risk factors for breast cancer--what's new?]
SO - Harefuah 2002 Aug;141(8):702-8, 761
AD - Center for Education and Advancement of Women's Health in Menopause,
Hadassah University Hospital, Mt. Scopus, Hebrew University, Jerusalem.
Breast cancer is the most common malignancy in women and constitutes 18%
of all cancers in women. Female gender, age and country of birth are the
strongest determinants of disease risk. Family history and mutations in
tumor suppressor genes BRCA1 and BRCA2 are important correlates of
lifetime risk. Genetic polymorphisms associated with estrogen synthesis
and metabolism are viewed as major factors in breast cancer prevalence
in specific populations. Atypical hyperplasia and ductal/lobular
carcinoma in situ although uncommon, are considered as pre-malignant
conditions as well as markers for invasive breast cancer. Lately,
increased bone density and high breast tissue density on mammogram in
postmenopausal women have been reported in association with increased
risk of breast carcinoma, probably attributable to increased levels of
endogenous estrogen. Serum estrogen levels are higher in breast cancer
cases as compared with controls. Current use of oral contraceptives and
prolonged, current or recent use of postmenopausal hormonal replacement
therapy are also considered as risk factors for breast cancer. Tamoxifen
and raloxifene, selective estrogen receptor modulators, were shown to
reduce breast cancer risk among high-risk women. Various nutrients were
evaluated for their possible effect on breast cancer risk but further
studies are needed. High socioeconomic status is found to be associated
with increased risk of breast malignancy for as yet unestablished
reasons. Studying breast cancer risk factors and further research into
the molecular etiology of the disease will enable early diagnosis and
detection of high-risk women and ultimately improve prognosis.
8
UI - 11927276
AU - Levitt NC; Hickson ID
TI -
Caretaker tumour suppressor genes that defend genome integrity.
SO - Trends Mol Med 2002 Apr;8(4):179-86
AD - Cancer Research UK Laboratories, Weatherall Institute of Molecular
Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK OX3
9DS.
Cancers arise as a result of genetic changes that impact upon cell
proliferation through promoting cell division and/or inhibiting cell
death. Tumour suppressor (TS) genes are the targets for many of these
genetic changes. In general, both alleles of TS genes must be disrupted
to observe a phenotypic effect. Broadly speaking, there are two types of
TS gene: 'gatekeepers' and 'caretakers'. In contrast to gatekeepers,
caretaker genes do not directly regulate proliferation, but act to
prevent genomic instability. Thus, mutation of caretaker genes leads to
accelerated conversion of a normal cell to a neoplastic cell. Many
caretaker genes are required for the maintenance of genome integrity.
This review focuses on those caretaker genes that play a role, directly
or indirectly, in the repair of DNA strand breaks by the homologous
recombination pathway, and that are associated with cancer-prone
clinical syndromes, in particular ataxia telangiectasia, hereditary
breast cancer, Bloom's syndrome and Werner's syndrome.
9
UI - 10463080
AU - Warner E
TI -
Fighting the battle against breast cancer. So close and yet so far.
SO - Can Fam Physician 1999 Aug;45():1849-54
10
UI - 12360400
AU - Magnard C; Bachelier R; Vincent A; Jaquinod M; Kieffer S; Lenoir GM;
TI -
Venezia ND
BRCA1 interacts with acetyl-CoA carboxylase through its tandem of BRCT
domains.
SO - Oncogene 2002 Oct 3;21(44):6729-39
AD - Laboratoire de Genetique, CNRS UMR 5641, Universite Claude Bernard Lyon
I, Faculte de Medecine Rockefeller, 8 Avenue Rockefeller, 69373 Lyon
cedex 08, France.
Germ-line alterations in BRCA1 are associated with an increased
susceptibility to breast and ovarian cancer. BRCA1 is a 220-kDa protein
that contains a tandem of two BRCA1 C-Terminal (BRCT) domains. Among
missense and nonsense BRCA1 mutations responsible for family breast
cancer, some are located into the BRCT tandem of BRCA1 coding sequence.
In an attempt to understand how BRCT is critical for BRCA1 function, we
search for partners of this BRCT tandem of BRCA1. Using a
glutathione-S-transferase (GST) pull-down assay with murine cells, we
isolated only one major BRCA1-interacting protein, further identified as
Acetyl Coenzyme A (CoA) Carboxylase alpha (ACCA). We showed that this
interaction is conserved through murine and human species. We also
delineated the minimum interacting region as being the whole tandem of
BRCT domains. We demonstrated that BRCA1 interacts in vitro and in vivo
with ACCA. This interaction is completely abolished by five distinct
germline BRCA1 deleterious mutations affecting the BRCT tandem of BRCA1.
Interestingly, ACCA originally known as a rate-limiting enzyme for fatty
acids biosynthesis, has been recently shown to be over-expressed in
breast cancers and considered as a potential target for anti-neoplastic
therapy. Furthermore, our observation is making a bridge between the
genetic factors involved in susceptibility to breast and ovarian
cancers, and environmental factors such as nutrition considered as key
elements in the etiology of those cancers.
11
UI - 12359861
AU - Bertucci F; Eisinger F; Tagett R; Sobol H; Birnbaum D
TI -
Re: Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic
ovarian cancers.
SO - J Natl Cancer Inst 2002 Oct 2;94(19):1506-7
12
UI - 12063435
AU - Rose SL; Buller RE
TI -
The role of p53 mutation in BRCA1-associated ovarian cancer.
SO - Minerva Ginecol 2002 Jun;54(3):201-9
AD - Division of Gynecologic Oncology, Department of Obstetrics and
Gynecology, Holden Comprehensive Cancer Center, University of Iowa
Hospitals and Clinics, Iowa City, IA, USA. stephen-rose@uiowa.edu
Ovarian cancer remains the most deadly gynecologic malignancy, resulting
in an estimated 23,300 new cases and 13,900 deaths in the United States
in the year 2002. The discovery of the BRCA1 gene in 1994 has proven to
be of great interest to the study of hereditary ovarian cancer. BRCA1
gene mutation confers a 16-42% lifetime risk of the development of
ovarian cancer in those affected. Although BRCA1 functions as a tumor
suppressor gene, conflicting studies have shown that BRCA1 dysfunction
alone may not be sufficient for tumorigenesis. p53 is a tumor suppressor
gene found to be dysfunctional in nearly 50% of all human cancers and in
up to 80% of ovarian malignancies. The p53 protein product plays a
crucial role in DNA surveillance and repair at the Gap 1-synthesis
(G1-S) cell cycle checkpoint. Studies exhibiting the interaction of
BRCA1 and p53 and the role of this interaction in DNA damage response
led many investigators to suggest that p53 gene mutation is required for
BRCA1-associated tumor development. This review explores the evidence
for BRCA1 and p53 interplay, and outlines the crucial role p53 may play
in BRCA1-related ovarian cancer.
13
UI - 11766733
AU - Pejovic T; Koul A; Olsen D; Chambers JT
TI -
No BRCA1 germline mutation in a family with uterine papillary serous
carcinoma: a case report.
SO - Eur J Gynaecol Oncol 2001;22(5):336-8
AD - Department of Gynecologic Oncology, Yale School of Medicine, New Haven,
CT 06520, USA.
The purpose of the study was to examine BRCA1 germline mutation and its
relationship to BRCA1 expression in two patients, a mother and a
daughter, both diagnosed with uterine papillary serous carcinoma (UPSC).
DNA was screened for BRCA1 and BRCA2 germline mutations common in the
Jewish population (185delAG, 5382insC, and 6174delT) by PCR-based assay
and with a protein truncation test (PTT) to detect mutation in exon 11
of BRCA1 and exons 10 and 11 of BRCA2. BRCA1 expression in fixed tumor
tissues was assessed by immunocytochemistry (IHC). No germline mutation
in either BRCAI or BRCA2 gene was found in the two patients. Both
samples showed reduced levels of BRCAI expression. Taken together, these
results suggest that undetected or unscreened for germline mutation may
be associated with occurrence of this rare tumor type in two members of
the same family. Alternatively, an epigenetic mechanism such as BRCA1
promoter hypermethylation may be responsible for reduced expression of
BRCA1 in the absence of DNA mutations.
14
UI - 12082091
AU - Yan Y; Haas JP; Kim M; Sgagias MK; Cowan KH
TI -
BRCA1-induced apoptosis involves inactivation of ERK1/2 activities.
SO - J Biol Chem 2002 Sep 6;277(36):33422-30
AD - Eppley Institute for Research in Cancer and Allied Diseases, University
of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Mutation in the BRCA1 gene is associated with an increased risk of
breast and ovarian cancer. Recent studies have shown that the BRCA1 gene
product may be important in mediating responses to DNA damage and
genomic instability. Previous studies have indicated that overexpression
of BRCA1 can induce apoptosis or cell cycle arrest at the G(2)/M border
in various cell types. Although the activation of JNK kinase has been
implicated in BRCA1-induced apoptosis, the role of other members of the
mitogen-activated protein kinase family in mediating the cellular
response to BRCA1 has not yet been examined. In this study, we monitored
the activities of three members of the MAPK family (ERK1/2, JNK, p38) in
MCF-7 breast cancer cells and U2OS osteosarcoma cells after their
exposure to a recombinant adenovirus expressing wild type BRCA1
(Ad.BRCA1). Overexpression of BRCA1 in MCF-7 cells resulted in arrest at
the G(2)/M border; however, BRCA1 expression in U2OS cells induced
apoptosis. Although BRCA1 induced JNK activation in both cell lines,
there were marked differences in ERK1/2 activation in response to BRCA1
expression in these two cell lines. BRCA1-induced apoptosis in U2OS
cells was associated with no activation of ERK1/2. In contrast, BRCA1
expression in MCF-7 cells resulted in the activation of both ERK1/2 and
JNK. To directly assess the role of ERK1/2 in determining the cellular
response to BRCA1, we used dominant negative mutants of MEK1 as well as
MEK1/2 inhibitor PD98059. Our results indicate that inhibition of ERK1/2
activation resulted in increased apoptosis after BRCA1 expression in
MCF-7 cells. Furthermore, BRCA1-induced apoptosis involved activation of
JNK, induction of Fas-L/Fas interaction, and activation of caspases 8
and 9. The studies presented in this report indicate that the response
to BRCA1 expression is determined by the regulation of both the JNK and
ERK1/2 signaling pathways in cells.
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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