National Cancer Institute®
Last Modified: April 1, 2002
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. email@example.com
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.
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
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
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.
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.
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. firstname.lastname@example.org
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.
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.
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. email@example.com
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.
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.
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.
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.
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.
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