National Cancer Institute®
Last Modified: October 1, 2002
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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. email@example.com
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.
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.
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.
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