Table of Contents
1
UI - 11778984
AU - Burke W; Pinsky LE; Press NA
TI -
Categorizing genetic tests to identify their ethical, legal, and social
implications.
SO - Am J Med Genet 2001 Fall;106(3):233-40
AD - Department of Medical History and Ethics, University of Washington,
Seattle 98195, USA. wburke@u.washington.edu
Practice standards in medical genetics provide an implicit guide to the
ethical, legal, and social implications (ELSI) of genetic tests. The
common use of nondirective counseling reflects the principle that many
testing decisions should be determined by personal values. Yet
geneticists make test recommendations in some circumstances, e.g., RET
mutation testing for MEN2 and newborn screening for phenylketonuria
(PKU). Conversely, many geneticists recommend against testing for
Apolipoprotein E (ApoE) alleles to predict Alzheimer disease (AD) risk.
Taken together, these examples suggest that genetic tests can be
categorized by a joint consideration of clinical validity and
availability of effective treatment for persons who test positive. For
genetic tests with high clinical validity/no treatment (e.g.,
presymptomatic testing for Huntington disease), the predominant concern
is adequate nondirective counseling to ensure an informed, autonomous
decision. By contrast, the predominant concern for tests with high
clinical validity/effective treatment (e.g., PKU) is assuring access to
care for eligible persons. For tests with limited clinical validity/no
treatment (e.g., ApoE), recommending against test use can be justified
on the principle of avoiding harm. For a fourth category, tests with
limited clinical validity/effective treatment (e.g., HFE mutation
testing for hereditary hemochromatosis), net benefit is the issue: the
balance between potential benefits of treatment and potential harms of
genetic labeling must be weighed. Where uncertainty exists concerning
both clinical validity and effectiveness of treatment, as in the case of
BRCA 1/2 mutation testing, the value of testing may vary according to
different testing contexts. This approach to test categorization allows
a rapid determination of the predominant ELSI concerns for different
kinds of genetic tests and identifies the data most urgently needed for
test evaluation.
2
UI - 11873549
AU - Fries MH; Holt C; Carpenter I; Carter CL; Daniels J; Flanagan J; Murphy
TI -
K; Hailey BJ; Martin L; Hume R; Hudson G; Cadman M; Weatherly R; Nunes
ME
Guidelines for evaluation of patients at risk for inherited breast and
ovarian cancer: recommendations of the Department of Defense Familial
Breast/Ovarian Cancer Research Project.
SO - Mil Med 2002 Feb;167(2):93-8
AD - Air Force Medical Genetics Center, Keesler Air Force Base, MS 39534,
USA.
Patients at high risk for inherited breast and/or ovarian cancer are
frequently encountered in all medical specialties. Department of
Defense, Health Affairs funding as part of the Breast Cancer Education
and Awareness Program was used to develop a comprehensive program for
the identification, counseling, genetic testing, and long-term follow-up
of such high-risk patients. This article reports the recommendations for
high-risk patient management based on 4 years of evaluation and care,
including discussions of the approach to counseling, indications for
genetic testing, post-testing counseling, patient surveillance with
examination, imagining, and laboratory testing, and suggested options
for surgical and chemoprophylaxis as well as lifestyle modifications.
3
UI - 11873550
AU - Fries MH; Holt C; Carpenter I; Carter CL; Daniels J; Flanagan J; Murphy
TI -
K; Hailey BJ; Martin L; Hume R; Hudson G; Cadman M; Weatherly R; Nunes
ME
Diagnostic criteria for testing for BRCA1 and BRCA2: the experience of
the Department of Defense Familial Breast/Ovarian Cancer Research
Project.
SO - Mil Med 2002 Feb;167(2):99-103
AD - Air Force Medical Genetics Center, Keesler Air Force Base, MS 39534,
USA.
The Department of Defense Familial Breast/Ovarian Cancer Research
Project has offered genetic counseling and testing for BRCA1 and BRCA2
on a research basis to patients meeting specific diagnostic criteria,
with risk for BRCA1 and BRCA2 mutations calculated based on the Couch
model. In 2.5 years, 250 patients were evaluated and 101 patients met
criteria requirements, including 33 who met criteria in more than one
category. Ninety patients elected to undergo DNA testing. In this group
of 90 patients, 14 mutations (15.5%) and 16 unclassified variants
(17.7%) were identified. The most common inclusion criteria were onset
of breast/ovarian cancer before age 45 years (n = 32) and onset of
breast/ovarian cancer before age 45 years with strong family history (n
= 21). However, when number of mutations and unclassified variants found
were compared separately across all diagnostic criteria (including those
of more than one capacity) using the chi 2 statistic, no significant
differences were seen among the categories to suggest that one criterion
was more predictive of mutations or variants than another. Couch risk
values for patients with mutations showed a mean of 14% and ranged from
3.2 to 43.5% (range for all patients, 1.2-69.7%). These findings
emphasize the importance of using multiple diagnostic criteria and
suggest that a Couch risk value of > 3% may be useful in selecting
patients for testing. The data also underscore the necessity of genetic
counseling in the testing process, particularly given the large number
of unclassified variants diagnosed and their uncertain status for
disease predisposition.
4
UI - 11966837
AU - Ardern-Jones A; Eeles R
TI -
Forum for Applied Cancer Education and Training (FACET).
SO - Eur J Cancer Care (Engl) 2002 Mar;11(1):63-8
AD - The Royal Marsden NHS Trust, London, UK.
5
UI - 11890937
AU - Trenz K; Rothfuss A; Schutz P; Speit G
TI -
Mutagen sensitivity of peripheral blood from women carrying a BRCA1 or
BRCA2 mutation.
SO - Mutat Res 2002 Mar 20;500(1-2):89-96
AD - Universitatsklinikum Ulm, Abteilung Humangenetik, D-89070 Ulm, Germany.
We are studying the induction and repair of DNA damage in lymphocytes of
women from families with familial breast cancer and a heterozygous
mutation in the breast cancer susceptibility genes BRCA1 or BRCA2.
Besides various other functions, BRCA proteins seem to be involved in
DNA repair processes like transcription-coupled and double-strand break
(dsb) repair. Our previous results indicated a close relationship
between the presence of a BRCA1 mutation and sensitivity for the
induction of micronuclei (MN) by gamma irradiation and hydrogen peroxide
(H2O2). In contrast to the results with the micronucleus assay, we found
no significant individual difference between women with and without a
BRCA1 mutation with respect to the induction and repair of DNA damage in
the alkaline comet assay. We now investigated further cases heterozygous
for a BRCA1 mutation and cases heterozygous for a BRCA2 mutation and
show that enhanced micronucleus formation after gamma irradiation and
H2O2-treatment is also a feature of lymphocytes carrying a BRCA2
mutation. Investigations with the comet assay did not reveal clear
differences with regard to the induction of DNA damage on the individual
level. There were also no significant differences between blood samples
carrying a BRCA1 or BRCA2 mutation and blood samples from normal
controls when the repair capacities (i.e. the kinetics of the removal of
radiation-induced DNA effects in the comet assay) were compared. Our
results indicate that mutagen sensitivity of lymphocytes heterozygous
for a BRCA2 mutation is similar to that of cells with a BRCA1 mutation
and BRCA1 and BRCA2 cannot be differentiated at present with the
micronucleus test (MNT) or the comet assay.
6
UI - 11964925
AU - Hartge P; Chatterjee N; Wacholder S; Brody LC; Tucker MA; Struewing JP
TI -
Breast cancer risk in Ashkenazi BRCA1/2 mutation carriers: effects of
reproductive history.
SO - Epidemiology 2002 May;13(3):255-61
AD - Division of Cancer Epidemiology and Genetics, National Cancer Institute,
Bethesda, MD 20892-7246, USA. hartgep@exchange.nih.gov
BACKGROUND: Younger age at first birth and greater parity generally
reduce the risk of developing breast cancer, but whether this reduced
risk holds in women with a mutation in the BRCA1 or BRCA2 gene is
unknown. METHODS: In a Washington DC community-based study conducted in
1996, we tested 5318 Ashkenazi Jews for three BRCA1/2 founder mutations
and identified 120 mutation carriers. Applying an extension of the
"kin-cohort" analysis, we compared the effects of reproduction on breast
cancer risk in carriers and noncarriers. We also used a case-case
analysis among 288 participants who had been diagnosed with breast
cancer. RESULTS: In noncarriers, the estimated relative risk (RR) of
breast cancer rose 5% with each 5-year increment in age at first birth
(RR = 1.05; 95% confidence interval [CI] = 0.97-1.15). By contrast, the
estimated risk in mutation carriers fell with each 5-year increment in
age (RR = 0.65; 95% CI = 0.37-1.16). Among the 288 participants who were
breast cancer survivors themselves, the comparison of carriers with
noncarriers also showed no protection associated with early birth in the
presence of a mutation in BRCA1 or BRCA2. CONCLUSIONS: It is not yet
clear whether the recognized breast cancer risk factors operate in the
same way in women who carry a mutation in the BRCA1 or BRCA2 genes.
7
UI - 11996364
AU - Wang J; Kawde AN
TI -
Amplified label-free electrical detection of DNA hybridization.
SO - Analyst 2002 Mar;127(3):383-6
AD - Department of Chemistry and Biochemistry, New Mexico State University,
Las Cruces 88003, USA.
A new protocol is described for amplifying label-free electrochemical
measurements of DNA hybridization based on the enhanced accumulation of
purine nucleobases in the presence of copper ions . Such electrical DNA
assays involve hybridization of the target to inosine-substituted
oligonucleotide probes (captured on magnetic beads), acidic
dipurinization of the hybrid DNA, and adsorptive chronopotentiometric
stripping measurements of the free nucleobases in the presence of copper
ions. Both amplified adenine and guanine peaks can be used for detecting
the DNA hybridization. The dramatic signal amplification advantage of
this type of detection has been combined with efficient magnetic removal
of non-complementary DNA, use of microliter sample volumes and
disposable transducers. Factors influencing the signal enhancement were
assessed and optimized. A detection limit of 40 fmol (250 pg) was
obtained with 10 min hybridization and 5 min adsorptive-accumulation
times. The advantages of this procedure were demonstrated by its
application in the detection of DNA segments related to the BRCA1 breast
cancer gene. The copper enhancement holds great promise not only for the
detection of DNA hybridization, but also for trace measurement of
nucleic acids.
8
UI - 12023992
AU - Kauff ND; Satagopan JM; Robson ME; Scheuer L; Hensley M; Hudis CA; Ellis
TI -
NA; Boyd J; Borgen PI; Barakat RR; Norton L; Castiel M; Nafa K; Offit K
Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2
mutation.
SO - N Engl J Med 2002 May 23;346(21):1609-15
AD - Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New
York 10021, USA.
BACKGROUND: Risk-reducing salpingo-oophorectomy is often considered by
carriers of BRCA mutations who have completed childbearing. However,
there are limited data supporting the efficacy of this approach. We
prospectively compared the effect of risk-reducing salpingo-oophorectomy
with that of surveillance for ovarian cancer on the incidence of
subsequent breast cancer and BRCA-related gynecologic cancers in women
with BRCA mutations. METHODS: All women with BRCA1 or BRCA2 mutations
identified during a six-year period were offered enrollment in a
prospective follow-up study. A total of 170 women 35 years of age or
older who had not undergone bilateral oophorectomy chose to undergo
either surveillance for ovarian cancer or risk-reducing
salpingo-oophorectomy. Follow-up involved an annual questionnaire,
telephone contact, and reviews of medical records. The time to cancer in
the two groups was compared by Kaplan-Meier analysis and a Cox
proportional-hazards model. RESULTS: During a mean follow-up of 24.2
months, breast cancer was diagnosed in 3 of the 98 women who chose
risk-reducing salpingo-oophorectomy and peritoneal cancer was diagnosed
in 1 woman in this group. Among the 72 women who chose surveillance,
breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal
cancer in 1. The time to breast cancer or BRCA-related gynecologic
cancer was longer in the salpingo-oophorectomy group, with a hazard
ratio for subsequent breast cancer or BRCA-related gynecologic cancer of
0.25 (95 percent confidence interval, 0.08 to 0.74). CONCLUSIONS:
Salpingo-oophorectomy in carriers of BRCA mutations can decrease the
risk of breast cancer and BRCA-related gynecologic cancer.
9
UI - 12023993
AU - Rebbeck TR; Lynch HT; Neuhausen SL; Narod SA; Van't Veer L; Garber JE;
TI -
Evans G; Isaacs C; Daly MB; Matloff E; Olopade OI; Weber BL; The
Prevention and Observation of Surgical End Points Study Group
Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations.
SO - N Engl J Med 2002 May 23;346(21):1616-22
AD - Center for Clinical Epidemiology and Biostatistics, University of
Pennsylvania School of Medicine, Philadelphia 19104-6021, USA.
trebbeck@cceb.med.upenn.edu
BACKGROUND: Data concerning the efficacy of bilateral prophylactic
oophorectomy for reducing the risk of gynecologic cancer in women with
BRCA1 or BRCA2 mutations are limited. We investigated whether this
procedure reduces the risk of cancers of the coelomic epithelium and
breast in women who carry such mutations. METHODS: A total of 551 women
with disease-associated germ-line BRCA1 or BRCA2 mutations were
identified from registries and studied for the occurrence of ovarian and
breast cancer. We determined the incidence of ovarian cancer in 259
women who had undergone bilateral prophylactic oophorectomy and in 292
matched controls who had not undergone the procedure. In a subgroup of
241 women with no history of breast cancer or prophylactic mastectomy,
the incidence of breast cancer was determined in 99 women who had
undergone bilateral prophylactic oophorectomy and in 142 matched
controls. The length of postoperative follow-up for both groups was at
least eight years. RESULTS: Six women who underwent prophylactic
oophorectomy (2.3 percent) received a diagnosis of stage I ovarian
cancer at the time of the procedure; two women (0.8 percent) received a
diagnosis of papillary serous peritoneal carcinoma 3.8 and 8.6 years
after bilateral prophylactic oophorectomy. Among the controls, 58 women
(19.9 percent) received a diagnosis of ovarian cancer, after a mean
follow-up of 8.8 years. With the exclusion of the six women whose cancer
was diagnosed at surgery, prophylactic oophorectomy significantly
reduced the risk of coelomic epithelial cancer (hazard ratio, 0.04; 95
percent confidence interval, 0.01 to 0.16). Of 99 women who underwent
bilateral prophylactic oophorectomy and who were studied to determine
the risk of breast cancer, breast cancer developed in 21 (21.2 percent),
as compared with 60 (42.3 percent) in the control group (hazard ratio,
0.47; 95 percent confidence interval, 0.29 to 0.77). CONCLUSIONS:
Bilateral prophylactic oophorectomy reduces the risk of coelomic
epithelial cancer and breast cancer in women with BRCA1 or BRCA2
mutations.
10
UI - 12024000
AU - Haber D
TI -
Prophylactic oophorectomy to reduce the risk of ovarian and breast
cancer in carriers of BRCA mutations.
SO - N Engl J Med 2002 May 23;346(21):1660-2
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