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Abramson Cancer CenterNCI CANCERLIT® Search: Genetic Counseling and Screening - February 2002
National Cancer Institute®
Last Modified: February 1, 2002
Table of Contents
1
UI - 11732490
AU - Aktan-Collan K; Haukkala A; Mecklin JP; Uutela A; Kaariainen H
TI -
Comprehension of cancer risk one and 12 months after predictive genetic
testing for hereditary non-polyposis colorectal cancer.
SO - J Med Genet 2001 Nov;38(11):787-92
2
UI - 11746496
AU - Yarden RI; Brody LC
TI -
Identification of proteins that interact with BRCA1 by Far-Western
library screening.
SO - J Cell Biochem 2001;83(4):521-31
AD - Genetics and Molecular Biology Branch, National Human Genome Research
Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Protein-protein interactions control numerous biological processes. In
the case of a protein with no known function, identification of
interacting proteins may lend insight into its cellular function.
Protein-protein interactions are often detected by yeast two-hybrid
screening which is based on a transcriptional read-out. One limitation
of this technique is that transcription factors, when used as bait,
frequently impair the effectiveness of this screen because they give
rise to high levels of false positives. The carboxyl terminus of the
breast cancer tumor suppressor gene, BRCA1, contains two BRCT motifs, a
motif found in several DNA repair and cell cycle checkpoint proteins.
This region of BRCA1 also exhibits an intrinsic transcriptional
transactivation activity when bound to DNA as a fusion protein, thereby
limiting its use in yeast two-hybrid screen. In order to isolate
proteins that interact with this domain of BRCA1, we utilized a
Far-Western screen, a method based on direct protein binding. We used
recombinant histidine-tagged BRCT as the primary protein probe. We
isolated eight cDNAs that bind to the BRCT domain of BRCA1. Further
analysis demonstrated that two of the clones encode for proteins that
interact directly with the BRCT domain of BRCA1. Copyright 2001
Wiley-Liss, Inc.
3
UI - 11788724
AU - Liu Q; Sommer SS
TI -
Pyrophosphorolysis-activatable oligonucleotides may facilitate detection
of rare alleles, mutation scanning and analysis of chromatin structures.
SO - Nucleic Acids Res 2002 Jan 15;30(2):598-604
AD - Departments of Molecular Genetics, City of Hope National Medical Center,
1500 East Duarte Road, Duarte, CA 91010-3000, USA.
Pyrophosphorolysis-activated polymerization (PAP) was initially
developed to enhance the specificity of allele-specific PCR for
detection of known mutations in the presence of a great excess of
wild-type allele. The high specificity of PAP derives from the serial
coupling of pyrophosphorolysis-mediated activation of a
pyrophosphorolysis-activatable oligonucleotide (P*) followed by
extension of the activated oligonucleotide. Herein, we demonstrate that
genetically engineered DNA polymerases greatly improve the efficiency of
PAP, making it a practical technique for detection of rare mutations. We
also show that P* oligonucleotides have the novel and unexpected
property of high sensitivity to mismatches throughout at least the 16
3'-terminal nucleotides. Thus, PAP constitutes a technology platform of
potential utility whenever high specificity is required along the length
of an oligonucleotide.
4
UI - 11788729
AU - Wilhelmsson LM; Norden B; Mukherjee K; Dulay MT; Zare RN
TI -
Genetic screening using the colour change of a PNA-DNA hybrid-binding
cyanine dye.
SO - Nucleic Acids Res 2002 Jan 15;30(2):E3
AD - Department of Physical Chemistry, Chalmers University of Technology,
S-412 96 Gothenburg, Sweden.
As the relationship between human genes and various malfunctions and
diseases becomes revealed at an ever-increasing pace, the need arises
for the development of rapid genetic screening methods for diagnostic
purposes. Genetic diseases show great diversity. Some are caused by a
few characteristic localised mutations, while others arise from a large
number of variations. Hence, it is unlikely that a single, general
diagnostic method that applies to all cases will ever exist. Instead, a
combination of methods is frequently applied. Here we propose the use of
a dramatic colour change that a cyanine dye,
3,3'-diethylthiadicarbocyanine, displays upon binding to DNA-PNA
duplexes. This method could become an inexpensive, fast and simple
genetic screening test by visual inspection, with no need for
complicated equipment. Our results demonstrate that this diagnostic
method may be sufficiently sensitive to discriminate between even a
fully complementary and a single mutation DNA sequence.
5
UI - 11521793
AU - Olopade OI; Pichert G
TI -
Cancer genetics in oncology practice.
SO - Ann Oncol 2001 Jul;12(7):895-908
AD - University of Chicago Pritzker School of Medicine, Illinois, USA.
folopade@medicine.bsd.uchicago.edu
Cancer is a genetic disease caused by the progressive accumulation of
mutations in critical genes that control cell growth and
differentiation. Completion of the Human Genome Project promises to
revolutionize the practice of Medicine, especially Oncology care. The
tremendous gains in the knowledge of the structure and function of human
genes will surely impact the diagnosis, prognosis and treatment of
cancer. Moreover, it will lead to more effective cancer control through
the use of genetics to quantify individual cancer risks. This article
reviews the current status of genetic testing and counseling for cancer
risk assessment and will suggest a framework for integrating such
counseling into oncology practice.
6
UI - 11720736
AU - Hussain SP; Hofseth LJ; Harris CC
TI -
Tumor suppressor genes: at the crossroads of molecular carcinogenesis,
molecular epidemiology and human risk assessment.
SO - Lung Cancer 2001 Dec;34 Suppl 2():S7-15
AD - Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, 37
Convent Drive, MSC 4255, Bethesda, MD 20892, USA.
The p53 tumor suppressor gene is mutated in about half of all human
cancer cases. The p53 protein modulates multiple cellular functions,
such as gene transcription, DNA synthesis and repair, cell cycle arrest,
senescence, and apoptosis. Mutations in the p53 gene can abrogate these
functions and may lead to genetic instability and progress to cancer.
The molecular archeology of the p53 mutation spectrum generates
hypotheses concerning the etiology and molecular pathogenesis of cancer.
The spectrum of somatic mutations in the p53 gene implicates
environmental carcinogens and endogenous processes in the etiology of
human cancer. The presence of a characteristic p53 mutation also can
manifest a molecular link between exposure to a particular carcinogen
and a specific type of human cancer, e.g. aflatoxin B1 (AFB1) exposure
and codon 249ser mutations in hepatocellular carcinoma, ultraviolet (UV)
exposure and CC to TT tandem mutations in skin cancer, and cigarette
smoke and the prevalence of G to T transversions in lung cancer.
Although several different exogenous carcinogens have been shown to
selectively target p53, evidence supporting the endogenous insult of p53
from oxyradical and nitrogen-oxyradicals is accumulating. p53 mutations
can be a biomarker of carcinogen effect. Determining the characteristic
p53 mutation load in nontumorous tissue, with a highly sensitive
mutation assay, can indicate a specific carcinogen exposure and also may
help in identifying individuals at an increased risk of cancer.
7
UI - 11706616
AU - Royal Australian College of General Practitioners. National Preventive
TI -
and Community Medicine Committee.
Guidelines for preventive activities in general practice.
SO - Aust Fam Physician 2001 Oct;Spec No():S1i-xvi, S1-1-61
8
UI - 10885351
AU - Meijers-Heijboer EJ; Verhoog LC; Brekelmans CT; Seynaeve C;
TI -
Tilanus-Linthorst MM; Wagner A; Dukel L; Devilee P; van den Ouweland AM;
van Geel AN; Klijn JG
Presymptomatic DNA testing and prophylactic surgery in families with a
BRCA1 or BRCA2 mutation.
SO - Lancet 2000 Jun 10;355(9220):2015-20
AD - Department of Clinical Genetics, Erasmus University, Rotterdam, The
Netherlands.
BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes highly
predispose to breast and ovarian cancer. In families with BRCA1 or BRCA2
mutations, identification of mutation carriers is clinically relevant in
view of the options for surveillance and prevention. METHODS: We
assessed presymptomatic DNA testing and prophylactic surgery in 53
consecutive families presenting to the Rotterdam Family Cancer Clinic
with a known BRCA1 or BRCA2 mutation. We identified predictors for DNA
testing and prophylactic surgery with univariate and multivariate
analysis. FINDINGS: 682 unaffected individuals with a 50% risk (275
women and 271 men) or with a 25% risk (136 women) for carrying a
mutation were identified and offered a DNA test. Presymptomatic DNA
testing was requested by 48% (198 of 411) of women and 22% (59 of 271)
of men (odds ratio for difference between sexes 3.21 [95% CI 2.27-4.51];
p<0.001). In women, DNA testing was significantly more frequent at young
age, in the presence of children, and at high pre-test genetic risk for
a mutation. Of the unaffected women with an identified mutation who were
eligible for prophylactic surgery, 51% (35 of 68) opted for bilateral
mastectomy and 64% (29 of 45) for oophorectomy. Parenthood was a
predictor for prophylactic mastectomy but not for prophylactic
oophorectomy. Age was significantly associated with prophylactic
oophorectomy, but not with prophylactic mastectomy, although there was a
tendency towards mastectomy at younger ages. INTERPRETATION: In a
clinical setting, we show a high demand for BRCA1 and BRCA2 testing by
unaffected women at risk, and of prophylactic surgery by unaffected
women with the mutation. Young women with children especially opt for
DNA testing and prophylactic mastectomy.
9
UI - 11499060
AU - Frank TS; Critchfield GC
TI -
Identifying and managing hereditary risk of breast and ovarian cancer.
SO - Clin Perinatol 2001 Jun;28(2):395-406
AD - Myriad Genetic Laboratories, Salt Lake City, Utah, USA.
tfrank@myriad.com
In the past, all women with a family history of breast or ovarian cancer
were considered to be at increased risk of cancer themselves. The
discovery of BRCA1 and BRCA2 demonstrated that susceptibility to breast
and ovarian cancer can be inherited by women as a single-gene autosomal
dominant disorder. For such women, evaluation of family history is an
important screening tool to identify the possibility of hereditary
cancer risk but only genetic testing can provide definitive,
individualized risk assessment. Women who have inherited mutations in
BRCA1 or BRCA2 now have several medical management options to address
their increased risk of cancer. A well-educated community of health care
providers and patients can use hereditary risk assessment, including
genetic testing, to improve health care.
10
UI - 11499063
AU - McCabe LL; McCabe ER
TI -
Postgenomic medicine. Presymptomatic testing for prediction and
prevention.
SO - Clin Perinatol 2001 Jun;28(2):425-34
AD - Departments of Human Genetics and Pediatrics, UCLA School of Medicine,
Los Angeles, California, USA.
Significant changes are occurring in genetic screening paradigms.
Genetic screening is moving from traditional analytes, such as small
molecules and proteins, to molecular genetic testing involving DNA and
RNA. There are significant consequences to these changes, involving
issues for the family unit, such as misattribution of parentage, and
concerns regarding discrimination, confidentiality, and privacy.
Although these latter issues have broader concerns for medicine and
medical information, in the context of genetic testing, information
derived from one individual can have a significant impact on others
within their family. Screening is also changing from mendelian disease
ascertainment to predictive testing. Issues that arise involve
appropriate age at testing for adult-onset disorders, the clinical
validity and clinical use of genetic testing for complex diseases, and
the efficacy of interventions following genetic testing. We are also
learning that the phenotypes of even simple mendelian disorders are
influenced by complex genetic and environmental factors. The
observations that genotypes rarely predict phenotypes absolutely have
significant ramifications for counseling based on mutation analysis, for
example in neonates who have not yet manifested symptoms and in older
children and in adults undergoing predictive testing. Molecular genetic
testing often proceeds rapidly from the research laboratory to the
clinical setting. We must recognize that for single-gene disorders with
high penetrance, the information derived from such testing may be
relatively easy to interpret and apply. For complex diseases, however,
the populations studied and their demographic characteristics are
extremely important for extrapolation to counseling of individual
patients. The value of population-based predictive testing is
exemplified by newborn screening. It is clear that the Human Genome
Project, and the information and technologies from it, will have a much
broader impact on public health by presymptomatic prediction and
prevention of disease.
11
UI - 11209389
AU - Skirton H; Patch C
TI -
The 'new genetics' and nursing: what does it have to do with me?
SO - Nurs Stand 2000 Jan 26-Feb 1;14(19):42-6
AD - Clinical Genetics Unit Taunton and Somerset NHS Trust.
Recent developments in genetics mean that this previously specialised
subject is now essential knowledge for all nurses. Heather Skirton and
Christine Patch describe how fundamental knowledge of the new genetics
will enable nurses to help patients through the maze of choices open to
them.
12
UI - 11677941
AU - Kobayashi S; Ochiai T; Hori S; Suzuki T; Shimizu T; Gunji Y; Shimada H;
TI -
Yamamoto S; Ogawa A; Kohno Y; Sunaga M; Shimazu M; Tanaka K
Copper metabolism after living donor liver transplantation for hepatic
failure of Wilson's disease from a gene mutated donor.
SO - Hepatogastroenterology 2001 Sep-Oct;48(41):1259-61
AD - Department of Academic Surgery, Graduate School of Medicine, Chiba
University, 1-8-1 Inohana, Chuoh-ku, Chiba 260-8670, Japan.
kobayasi@med.m.chiba-u.ac.jp
There is a genetic problem in living donor liver transplantation,
involving Wilson's disease, because the majority of donors have a
kinship relationship. Recently, it was reported that the serum
ceruloplasmin level is insufficient in some persons with one allele
mutation. The recipient was a 13-year-old male child, and the donor was
a 22-year-old woman, who was his sister by a different father. The gene
analysis for Wilson's disease (ATP7B gene) was preoperatively carried
out by the amplification refractory mutation system-PCR. Homozygous and
heterozygous deletion of 2871 cytosine (C) were detected in the
recipient and donor, respectively, in the ATP7B gene. Serum
ceruloplasmin level was sufficient in the donor. The right hepatic lobe
graft was transplanted to the recipient. Immediately after the liver
transplantation, the copper metabolism improved to increase the serum
ceruloplasmin levels up to the normal range, and decrease the urinary
copper excretion. However, the serum ceruloplasmin levels gradually
decreased below the normal base line, although the urine copper levels
continued to be low without any clinical symptoms. We should perform
gene analyses and confirm the serum ceruloplasmin levels in donors
before living donor liver transplantation for Wilson's disease, to
screen for their impairment of copper metabolism. After living donor
liver transplantation for Wilson's disease, we should carefully
follow-up the transition of serum ceruloplasmin levels in the recipient.
13
UI - 11753744
AU - Yildiz Y; Matern S; Lammert F
TI -
[Screening for hereditary pancreatic carcinoma]
SO - Dtsch Med Wochenschr 2001 Dec 21;126(51-52):1479-80
AD - Medizinische Klinik III, Universitatsklinikum der RWTH Aachen.
14
UI - 11787135
AU - Kaariainen H
TI -
[Risks and adverse effects of genetic screening]
SO - Duodecim 2000;116(8):909-13
AD - Vaestoliiton perinnollisyysklinikka PL 849, 00101 Helsinki.
helena.kaariainen@vaestoliitto.fi
15
UI - 11789512
AU - Gevers S
TI -
Medical examinations preceding employment and/or private insurance: a
proposal for European guidelines.
SO - Eur J Health Law 2000 Jun;7(2):145-72
AD - University of Amsterdam.
16
UI - 11789513
AU - Bottis MC
TI -
Comment on a view favoring ignorance of genetic information:
confidentiality, autonomy, beneficence and the right not to know.
SO - Eur J Health Law 2000 Jun;7(2):173-83
AD - Ionian University, Greece.
17
UI - 11789514
AU - Laurie GT
TI -
Protecting and promoting privacy in an uncertain world: further defences
of ignorance and the right not to know.
SO - Eur J Health Law 2000 Jun;7(2):185-91
AD - Faculty of Law, University of Edinburgh, Scotland.
18
UI - 11802208
AU - de la Hoya M; Osorio A; Godino J; Sulleiro S; Tosar A; Perez-Segura P;
TI -
Fernandez C; Rodriguez R; Diaz-Rubio E; Benitez J; Devilee P; Caldes T
Association between BRCA1 and BRCA2 mutations and cancer phenotype in
Spanish breast/ovarian cancer families: implications for genetic
testing.
SO - Int J Cancer 2002 Feb 1;97(4):466-71
AD - Laboratory of Molecular Oncology, Hospital Universitario San Carlos,
Madrid, Spain.
Index cases from a clinically relevant cohort of 102 Spanish families
with at least 3 cases of breast and/or ovarian cancer (at least 1 case
diagnosed before age 50) in the same lineage were screened for germline
mutations in the entire coding sequence and intron boundaries of the
breast cancer susceptibility genes BRCA1 and BRCA2. Overall, the
prevalence of mutations was 43% in female breast/ovarian cancer
families, 15% in female breast cancer families and 100% in male breast
cancer families. Three recurrent mutations (185delAG, 589delCT and
A1708E) explained 63% of BRCA1-related families. Early age at diagnosis
of breast cancer, ovarian cancer, bilateral breast cancer, concomitant
breast/ovarian cancer in a single patient and prostate cancer but not
unilateral breast cancer were associated with BRCA1 and BRCA2 mutations.
Male breast cancer was associated with BRCA2 mutations. The presence of
male breast cancer was the only cancer phenotype that distinguished
BRCA2- from BRCA1-related families. We have developed a logistic
regression model for predicting the probability of harbouring a mutation
in either BRCA1 or BRCA2 as a function of the cancer phenotype present
in the family. The predictive positive and negative values of this model
were 77.4% and 79%, respectively (probability cutoff of 30%). The
findings of our work may be a useful tool for increasing the
cost-effectiveness of genetic testing in familial cancer clinics.
Copyright 2001 Wiley-Liss, Inc.
19
UI - 11802209
AU - Meindl A; German Consortium for Hereditary Breast and Ovarian Cancer
TI -
Comprehensive analysis of 989 patients with breast or ovarian cancer
provides BRCA1 and BRCA2 mutation profiles and frequencies for the
German population.
SO - Int J Cancer 2002 Feb 1;97(4):472-80
AD - Department of Medical Genetics, Ludwig-Maximilians University, Munich,
Germany. alfons@pedgen.med.uni-muenchen.de
The main focus of this German-wide multi-center study was to establish a
BRCA1/2 mutation profile and to determine family types with high
frequencies of mutations in these genes. In a comprehensive study, the
entire coding sequences of the breast cancer genes BRCA1 and BRCA2 were
analyzed in 989 unrelated patients from German breast/ovarian cancer
families. A total of 77 BRCA1 and 63 BRCA2 distinct deleterious
mutations were found in 302 patients. More than (1/3) of these mutations
are novel and might be specific for the German population. Eighteen
common mutations were found in 68% of cases in BRCA1 and 13 recurrent
mutations in 44% of cases in BRCA2, facilitating prescreening
approaches. Haplotype analysis indicate that 14 out of 20 recurrent
mutations are likely originating from a common founder. An additional 50
different rare sequence variants with unknown relevance for
tumorigenesis were found in 72 families. Correlation of BRCA1/BRCA2
detection rates with family history identified families with both breast
and ovarian cancer to be at highest risk for BRCA1/BRCA2 mutations (43%
and 10%, respectively), followed by families with at least 2
premenopausal cases of breast cancer (24% BRCA1 and 13% BRCA2
mutations). These data provide strong evidence for further predisposing
genes in the German population. In breast cancer families with 2 or 3
affected females but only a single or no premenopausal case, mutations
were detected with low frequencies (about 10% or less for both genes).
The decision for or against molecular diagnosis is now aided by
considering the expected mutation detection rates that greatly depend on
family history and structure. Copyright 2001 Wiley-Liss, Inc.
20
UI - 11826460
AU - Levin T; Reichelt J; Heimdal K; Moller P
TI -
[Information to families with hereditary breast and ovarian cancer]
SO - Tidsskr Nor Laegeforen 2001 Nov 20;121(28):3292-4
AD - Seksjon for genetisk veiledning Avdeling for kreftgenetikk Det Norske
Radiumhospital 0310 Oslo. pal.moller@klinmed.uio.no
BACKGROUND: Under Norwegian legislation, persons at risk should make the
initial contact with the proper health personnel, and not vice versa. It
may be argued that the physician should be allowed to make contact with
persons at risk of preventable or curable disorders. MATERIAL AND
METHODS: We identified all first-degree relatives of all 75 BRCA1
mutation carriers diagnosed within a given period of time and asked them
whether or not they had been informed by their relatives. RESULTS: After
two years, 60/63 (95%) adult sisters and daughters had made contact with
us; the remaining three (5%) had been informed. In comparison, 18/45
(40%) adult brothers and sons had contacted us. INTERPRETATION: The
legislation constituted no barrier to offering health services to the
target group. Information on our services had reached all close
relatives who could benefit from them. This may be representative for
curable inherited disorders. We examined inherited cancer limited to
females; similar studies on inherited cancers in males and on other
curable inherited disorders should be performed. Outside the framework
of the present study, we are aware of rare examples of distant cousins
who have not been properly informed through their families. One legally
acceptable way of identifying mutation carrier families is to test all
patients with breast or ovarian cancer for causative mutations. Health
services should be monitored to make future decisions based on empirical
evidence.
21
UI - 11810084
AU - Hebert-Blouin MN; Koufogianis V; Gillett P; Foulkes WD
TI -
Fallopian tube cancer in a BRCA1 mutation carrier: rapid development and
failure of screening.
SO - Am J Obstet Gynecol 2002 Jan;186(1):53-4
AD - Department of Medicine, McGill University Health Centre, McGill
University, Montreal, Quebec, Canada.
We report a case of fallopian tube cancer that developed in a woman with
a germ-line BRCA1 mutation. The notable feature of this case was the
extremely rapid growth of the cancer, which precluded early diagnosis.
Preventive gynecologic surgery in BRCA1/2 mutation carriers should
probably always include bilateral salpingectomy.
22
UI - 11795428
AU - Hittelman WN
TI -
Genetic instability in epithelial tissues at risk for cancer.
SO - Ann N Y Acad Sci 2001 Dec;952():1-12
AD - Department of Experimental Therapeutics, The University of Texas M. D.
Anderson Cancer Center, Houston 77030, USA. whittelm@mdanderson.org
Epithelial tumors develop through a multistep process driven by genomic
instability frequently associated with etiologic agents such as
prolonged tobacco smoke exposure or human papilloma virus (HPV)
infection. The purpose of the studies reported here was to examine the
nature of genomic instability in epithelial tissues at cancer risk in
order to identify tissue genetic biomarkers that might be used to assess
an individual's cancer risk and response to chemopreventive
intervention. As part of several chemoprevention trials, biopsies were
obtained from risk tissues (i.e., bronchial biopsies from chronic
smokers, oral or laryngeal biopsies from individuals with premalignancy)
and examined for chromosome instability using in situ hybridization.
Nearly all biopsy specimens show evidence for chromosome instability
throughout the exposed tissue. Increased chromosome instability was
observed with histologic progression in the normal to tumor transition
of head and neck squamous cell carcinomas. Chromosome instability was
also seen in premalignant head and neck lesions, and high levels were
associated with subsequent tumor development. In bronchial biopsies of
current smokers, the level of ongoing chromosome instability correlated
with smoking intensity (e.g., packs/day), whereas the chromosome index
(average number of chromosome copies per cell) correlated with
cumulative tobacco exposure (i.e., pack-years). Spatial chromosome
analyses of the epithelium demonstrated multifocal clonal outgrowths. In
former smokers, random chromosome instability was reduced; however,
clonal populations appeared to persist for many years, perhaps
accounting for continued lung cancer risk following smoking cessation.
23
UI - 11807889
AU - Hughes C; Lerman C; Schwartz M; Peshkin BN; Wenzel L; Narod S; Corio C;
TI -
Tercyak KP; Hanna D; Isaacs C; Main D
All in the family: evaluation of the process and content of sisters'
communication about BRCA1 and BRCA2 genetic test results.
SO - Am J Med Genet 2002 Jan 15;107(2):143-50
AD - Department of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, USA. chanita@mail.med.upenn.edu
Despite the potential importance of family communication, little is
known about the process and content of communicating BRCA1/2 test
results to relatives. The objectives of this observational study were to
describe the process and content of communicating BRCA1/2 test results
to sisters, and to evaluate whether the proband's carrier status
influenced communication outcomes. Participants were 43 women who were
the first family member to have genetic testing (probands). Probands
reported on communication outcomes for 81 sisters. Process and content
variables were evaluated 1-month after receipt of BRCA1/2 test results
using the Family Communication Questionnaire (FCQ). Overall, BRCA1/2
test results were communicated to 85% of sisters, and carriers
communicated their results to significantly more sisters compared to
uninformative (96% vs. 76%, FET = 0.02). The most important reason for
communicating results was to provide genetic risk information; however,
compared to uninformatives, carriers communicated their results to
significantly more sisters to obtain emotional support (74%) and to get
advice about medical decisions (42%) (FET = 0.001). Carriers also
discussed the possibility of discrimination and recommendations for
cancer management with significantly more sisters. Among sisters to whom
BRCA1/2 test results were not communicated, the most important reason
for not sharing test results was because of emotionally distant
relationships. The results of this study suggest that probands are
likely to quickly communicate their BRCA1/2 test results to relatives
and that although needs for social support may motivate family
communication, emotionally distant relationships may be a barrier to
communication with relatives. Copyright 2001 Wiley-Liss, Inc.
24
UI - 11682322
AU - Surbone A
TI -
Ethical implications of genetic testing for breast cancer
susceptibility.
SO - Crit Rev Oncol Hematol 2001 Nov;40(2):149-57
AD - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New
York, NY, USA. surbonea@aol.com
The identification of gene mutations involved in hereditary breast
cancer is a major recent scientific discovery, enabling us to identify
women at very high risk, and also providing the means to understand the
biology of breast cancer and to explore novel preventive strategies.
Yet, it carries medical, psychological, ethical and social implications.
This paper is a review of all the ethical implications of genetic
testing for breast cancer predisposition, as well as an attempt to
discuss the more philosophical questions of women facing BRCA testing.
To what extent does the individual benefit from genetic knowledge? Some
women look with trepidation upon the potential of planning their life in
view of a risk, while others believe that only through knowledge and
awareness we can improve control of our life. The risk of breast cancer
may be qualitatively so important to justify all the potential risks of
finding out about it.
25
UI - 11809257
AU - Ahr A; Karn T; Solbach C; Seiter T; Strebhardt K; Holtrich U; Kaufmann M
TI -
Identification of high risk breast-cancer patients by gene expression
profiling.
SO - Lancet 2002 Jan 12;359(9301):131-2
We previously used DNA array analyses in the molecular profiling of
breast cancers. By cluster analysis of 55 patients, we identified a
subpopulation of breast cancers-designated class A-that contained a high
number of nodal-positive tumours and that had frequently developed
distant metastases at the time of diagnosis. We have now analysed
follow-up data from these patients. We found that, despite a median of
only 23.5 months of follow-up, 11 of 22 patients in class A progressed
to metastatic disease, and three of five patients classified as having a
nodal status of N0 in this subpopulation developed distant metastases.
Our analysis identifies breast-cancer patients with a high risk of
disease recurrence, and could act as a first step towards improved
patient-adapted therapy.
26
UI - 11813762
AU - Hailey BJ; Carter CL; Burnett DR
TI -
Breast cancer attitudes, knowledge, and screening behavior in women with
and without a family history of breast cancer.
SO - Health Care Women Int 2000 Dec;21(8):701-15
AD - Department of Psychology, The University of Southern Mississippi,
Hattiesburg 39406-5025, USA. j.hailey@usm.edu
Women volunteers with or without a first-degree relative with breast
cancer (FDR) were compared on several measures. Relative to the
comparison group, women in the FDR group had more negative attitudes
about breast cancer (including more anxiety about breast cancer), viewed
their risk for getting breast cancer as greater (although they
underestimated the actual risk), and were more likely to engage in
appropriate screening behavior. A high percentage of women in both
groups stated that they would want to have a genetic test for breast
cancer if it were generally available.
27
UI - 10606060
AU - Pasquini P
TI -
Does assessment of family history of melanoma provide valid information?
SO - Arch Dermatol 1999 Dec;135(12):1527-8
28
UI - 11786931
AU - Majores M; Kolsch H; Bagli M; Papassotiropoulos A; Lohmann PL; Schmitz
TI -
S; Rao ML; Maier W; Heun R
Cathepsin D: screening for new polymorphisms using single-strand
conformation polymorphism analysis.
SO - Int J Mol Med 2002 Feb;9(2):185-7
AD - Department of Psychiatry, University of Bonn, D-53105 Bonn, Germany.
Cathepsin D (CTSD) is a lysosomal protease involved in the pathogenesis
of several diseases such as breast cancer and possibly Alzheimer's
disease (AD). Previous findings revealed a significant association
between the T allele of the 224 C/T (A58V) polymorphism in exon 2 of the
CTSD gene and late onset AD. The exonic regions of the CTSD gene were
screened for further polymorphic variations using polymerase chain
reaction and single-strand conformation polymorphism analysis. In
addition to the known 224 C/T polymorphism and two silent mutations in
exons 3 and 4 we detected two new polymorphisms in introns 5 and 8.
Combination of these sequence variations results in three different
haplotypes; one of these haplotypes is due to the new polymorphism in
intron 5. We detected no further missense mutations except for the known
224 C/T polymorphism in exon 2. Thus, if sequence variations within the
CTSD gene influence the risk for various diseases, the pathogenic
mechanism is likely to be linked to the amino acid substitution in the
profragment of CTSD.
29
UI - 11817609
AU - Neumann E; Kullmann F; Judex M; Justen HP; Wessinghage D; Gay S;
TI -
Scholmerich J; Muller-Ladner U
Identification of differentially expressed genes in rheumatoid arthritis
by a combination of complementary DNA array and RNA arbitrarily
primed-polymerase chain reaction.
SO - Arthritis Rheum 2002 Jan;46(1):52-63
AD - University of Regensburg, Germany.
OBJECTIVE: There is increasing evidence that T cell-independent
pathways, such as the up-regulation of protooncogenes and the production
of growth factors and matrix-degrading enzymes, lead to progressive
destruction of affected joints. Therefore, identification of
differentially regulated genes restricted to rheumatoid arthritis (RA)
synovial fibroblasts is essential. A combination of RNA arbitrarily
primed-polymerase chain reaction (RAP-PCR) and complementary DNA (cDNA)
array with defined genes was used for a highly sensitive differential
screening using small amounts of RNA. METHODS: RNA was extracted from
cultured synovial fibroblasts obtained from 6 patients with RA and 6
patients with osteoarthritis (OA). RAP-PCR was performed using different
arbitrary primers for first- and second-strand synthesis. PCRs were
hybridized to cDNA array membranes. RA samples were compared with OA
samples for differentially expressed genes. RESULTS: In contrast to
standard cDNA array, the identification of 12 differentially expressed
genes in RA compared with OA (approximately 6%) was possible.
Differentially expressed genes of interest were confirmed using
semiquantitative RT-PCR and in situ hybridization. CONCLUSION: Numerous
variants of the differential display method and continuous improvements,
including RAP-PCR, have proven to be both efficient and reliable for
examining differentially regulated genes. Our results show that RAP-PCR
combined with cDNA arrays is a suitable method for identifying
differentially expressed genes in rheumatoid synovial fibroblasts, using
very small amounts of RNA.
30
UI - 11822793
AU - Cappelli M; Surh L; Humphreys L; Verma S; Logan D; Hunter A; Allanson J
TI -
Measuring women's preferences for breast cancer treatments and
BRCA1/BRCA2 testing.
SO - Qual Life Res 2001;10(7):595-607
AD - Children's Hospital of Eastern Ontario, Ottawa, Canada.
cappelli@cheo.on.ca
In establishing decision models in the treatment and prevention of
breast cancer, it is important to evaluate patients' preferences for
such interventions. The objectives of the present study were: (i) to
characterize women's preferences for breast cancer treatments and
BRCA1/BRCA2 testing, using the rating scale and standard gamble
techniques; and (ii) to identify factors associated with these quality
of life indices. Data were collected from women with breast cancer (n =
60), high-risk relatives of women with breast cancer (n = 58), and women
in the general population (n = 51). Regardless of group membership,
participants favoured treatment and prevention options that involved
minimal physical invasiveness. Women with breast cancer rated lumpectomy
and radiation treatment more highly than high-risk relatives and women
in the general population. Preferences did not differ according to
participants' intentions to undergo BRCA testing. Age was the only
demographic variable associated with health state preferences. These
findings hold implications for the application of patient preferences to
clinical decision making.
31
UI - 11822419
AU - European Group on Ethics in Science and New Technologies
TI -
Citizens' rights and the new technologies: a European challenge.
SO - Biomed Ethics 2000;5(2):52-63
32
UI - 11822420
AU - Merle JC; European Group on Ethics in Science and New Technologies
TI -
The weakness of the intention to be uncontroversial on controversial
issues.
SO - Biomed Ethics 2000;5(2):64-9
AD - Faculty of Philosophy, University of Tuebingen.
33
UI - 10714658
AU - Brassat D; Camuzat A; Vidailhet M; Feki I; Jedynak P; Klap P; Agid Y;
TI -
Durr A; Brice A
Frequency of the DYT1 mutation in primary torsion dystonia without
family history.
SO - Arch Neurol 2000 Mar;57(3):333-5
AD - Federation de Neurologie, INSERM U289, Hopital de la Salpetriere, Paris,
France.
BACKGROUND: Idiopathic torsion dystonia is a clinically and genetically
heterogeneous movement disorder. A GAG deletion at position 946 of the
DYT1 gene was the first mutation found, in early-onset dystonia, with an
autosomal dominant transmission and reduced penetrance. OBJECTIVE: To
evaluate the frequency of the DYT1 mutation in patients with idiopathic
torsion dystonia but without a family history. DESIGN: Prospective
cohort study. SETTING: Four botulinum toxin clinics in the Paris,
France, area. PATIENTS: A French population of 100 patients with
dystonia. MAIN OUTCOME: Frequency of the DYT1 mutation tested by
polymerase chain reaction and enzyme restriction analysis for the 946
GAG deletion, and genotype-to-phenotype correlation. RESULTS: Only 5
mutation carriers were identified, 4 of whom were part of a group of 10
patients with generalized dystonia. Onset was between ages 5 and 12
years as in typical early-onset dystonia. All 4 patients had cranial
muscle involvement, which is atypical for DYT1 mutation carriers. One
had segmental dystonia. Molecular analysis of relatives in 2 families
demonstrated that the lack of family history was due to reduced
penetrance. CONCLUSIONS: For accurate diagnosis and genetic counseling,
screening for the DYT1 deletion is of great interest in cases with
generalized dystonia without a family history. In other cases, positive
results are rare.
34
UI - 11426564
AU - Einsiedel HG; Taube T; Beyermann B; Dragon S; Moricke A;
TI -
Kebelmann-Betzig C; Kochling J; Henze G; Seeger K
Absence of mutations in the CDKN2 binding site of CDK4 in childhood
acute lymphoblastic leukemia.
SO - Leuk Lymphoma 2001 Jan;40(3-4):413-7
AD - Department of Pediatric Oncology/Hematology, Charite Campus Virchow
Klinikum, Humboldt-University Berlin, Germany.
The cell cycle regulatory circuit resulting in phosphorylation of the
retinoblastoma protein (pRB) is frequently altered in human cancers.
Several mechanisms of disruption are known in that pathway. In childhood
acute lymphoblastic leukemia (ALL), the main disrupting mechanism is the
homozygous deletion of the CDKN2 (cyclin dependent kinase inhibitor 2)
genes: p16CDKN2a, p15CDKN2b, and p19ARF. Another pRB pathway disturbance
is a previously described point mutation in the exon 2 of CDK4, a pRB
phosphorylating enzyme, which abrogates binding of the latter to its
inhibitors, p16CDKN2a and p15CDKN2b. Here we report the absence of point
mutations in the CDKN2-binding site of CDK4 in 100 cases of childhood
ALL, 2 cases of childhood chronic myeloid leukemia and 9 hematologic
cell lines screened by PCR-SSCP (polymerase chain reaction single
stranded conformational polymorphism gel electrophoresis), thereby
minimizing the possibility of the existence of these specific CDK4
mutations in childhood ALL.
35
UI - 11705864
AU - Ikonen T; Matikainen M; Mononen N; Hyytinen ER; Helin HJ; Tommola S;
TI -
Tammela TL; Pukkala E; Schleutker J; Kallioniemi OP; Koivisto PA
Association of E-cadherin germ-line alterations with prostate cancer.
SO - Clin Cancer Res 2001 Nov;7(11):3465-71
AD - Laboratory of Cancer Genetics, Institute of Medical Technology,
University of Tampere, P.O. Box 607, FIN-33101 Tampere, Finland.
tarja.ikonen@uta.fi
In our recent cancer registry-based study, the incidence of gastric
carcinoma was increased up to 5-fold in male relatives of early-onset
prostate cancer (PCA) patients. This association may reflect the
influence of genetic factors predisposing individuals to both tumor
types. Germ-line mutations of the CDH1 gene at 16q have recently been
associated with familial gastric cancer. Furthermore, two genome-wide
linkage studies of PCA recently reported positivity at 16q. We therefore
identified families and individual patients with both gastric and PCA
and investigated whether the CDH1 gene mutations were involved in cancer
predisposition in these cases. Fifteen of the 180 Finnish hereditary PCA
families (8.3%) had one or more gastric cancer cases. No truncating or
splice site CDH1 mutations were identified by PCR single-strand
conformational polymorphism in these families or in eight individual
patients who had both prostate and gastric cancer. However, a novel
S270A missense mutation in exon 6 of the CDH1 gene was seen in a single
family with four prostate and two gastric cancers. A large-scale
population-based survey indicated a higher prevalence of S270A among
both familial PCA cases (3.3%; n = 120; P = 0.01) and unselected PCA
patients (1.5%; n = 472; P = 0.12) as compared with blood donors serving
as population controls (0.5%; n = 923). We conclude that individual rare
mutations and polymorphisms in the CDH1 gene, such as S270A, may
contribute to the onset of PCA and warrant further investigations in
other populations. However, the CDH1 gene does not appear to explain the
link between prostate and gastric cancer.
36
UI - 11730630
AU - Roman R; Colomer A; Erill N; Puig X; Guix M
TI -
[Importance of 5569G/A polymorphism in intron 4 of HFE gene in the
diagnosis of hereditary hemochromatosis]
SO - Med Clin (Barc) 2001 Dec 1;117(18):690-1
AD - BIOPAT, Biopatologia Molecular, Grup Assistencia, Hospital de Barcelona,
Barcelona, Spain.
BACKGROUND: The presence of the 5569A polymorphism may lead to
misdiagnosis of patients susceptible of hereditary hemochromatosis (HH).
For that reason, samples containing the Cys282Tyr mutation were revised
and the frequency of this polymorphism in our environment was assessed.
PATIENTS AND METHOD: Twenty samples were retested and 56 controls were
included. The study was performed by PCR-RFLP. RESULTS: The diagnosis
was confirmed in 8 cases susceptible of error. However, an amplification
deficiency of normal alleles was detected in 2 heterozygous (17%). The
allelic frequency of the 5569A polymorphism in the control population
was 14.3%. CONCLUSIONS: Although misdiagnosis was not committed, we
recommend changing to any primer that does not include the 5569G/A
polymorphism in the study of HH.
37
UI - 11796012
AU - He J; Zhou G; Liu KD; Qin XY
TI -
Construction and preliminary screening of a human phage single-chain
antibody library associated with gastric cancer.
SO - J Surg Res 2002 Feb;102(2):150-5
AD - Department of Surgery, Fudan University, Shanghai 200032, People's
Republic of China.
BACKGROUND: The aim of this study was to construct a phage library of
human single-chain antibodies associated with gastric cancer and screen
such a library for CEA binding scFv. MATERIALS AND METHODS: The cDNA
library of antibody variable regions was constructed using mRNA from
metastatic lymph nodes or spleen of patients with stomach cancer by
RT-PCR. These cDNA were assembled into a single-chain format and cloned
into phagemid pCANTAB-5 and then transformed into Escherichia coli TG1.
The scFv gene library was rescued by M13KO7 helper phage. CEA and the
viable CEA-positive gastric cancer cell line MKN-28 were used to screen
the phage antibody library. Indirect and tumor cell ELISA was used to
determine the specificity of phage antibody. Fixed cell
immunofluorescence and live cell FACS analysis were used to further
characterize the binding of phage scFv. RESULTS: After transformation
into E. coli TG1, 2.5 x 10(7) cfu/microg ampicillin-resistant clones
grew. Sequences of tho
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