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Abramson Cancer CenterNCI CANCERLIT® Search: Genetic Counseling and Screening - March 2002
National Cancer Institute®
Last Modified: March 1, 2002
Table of Contents
1
UI - 11551099
AU - Rivers CA; Barton JC; Acton RT
TI -
A rapid PCR-SSP assay for the hemochromatosis-associated Tyr250Stop
mutation in the TFR2 gene.
SO - Genet Test 2001 Summer;5(2):131-4
AD - Department of Microbiology, University of Alabama at Birmingham, 35294,
USA.
Several genes associated with hemochromatosis and primary iron overload
have been identified. Mutations in the HFE gene have been detected in
60-100% of hemochromatosis patients of northern, central, and western
European descent, although the frequencies of these mutations vary among
racial and ethnic groups. Recently, a mutation in the gene encoding
transferrin receptor-2 (exon 6, nucleotide 750 C --> G; Y250X) was
detected by a PCR-restriction fragment length polymorphism (RFLP) method
in Sicilians with hemochromatosis. We describe a modification of the
original assay in which the sequence-specific priming PCR assay does not
require the use of restriction endonuclease. The modified assay is
robust and cost-efficient, and may be more useful for large-scale
population studies because it can be performed rapidly on DNA extracted
from buccal swabs.
2
UI - 11551100
AU - Hegde MR; Fawkner M; Chong B; McGaughran J; Gilbert D; Love DR
TI -
Compound heterozygosity at the FMR1 gene.
SO - Genet Test 2001 Summer;5(2):135-8
AD - School of Biological Sciences, University of Auckland, and Auckland
Hospital, New Zealand.
Individuals affected with Fragile X syndrome are usually characterized
at the DNA level by the presence of at least 200 CGG repeats in the 5'
untranslated region of the FMR1 gene; this number of repeats is defined
as a full mutation. Repeats that number 50-200 usually define those with
premutations and are termed unaffected carriers. We report here a
compound heterozygous female who carried CGG repeats in the FMR1 gene
that fall within the premutation and full mutation ranges. The former
appears to have been inherited from the father, whereas the latter is an
expansion of the premutation carried by the proband's mother. Therefore,
the offspring of the proband will carry a significant risk of being
affected with Fragile X syndrome, and the paternal uncle and any cousins
should be counselled for being at risk for this syndrome.
3
UI - 11551107
AU - Gilbert F
TI -
Familial dysautonomia and the expansion of the Ashkenazi Jewish carrier
screening panel.
SO - Genet Test 2001 Summer;5(2):83-5
4
UI - 11551108
AU - Wang ZH; Zeng B; Pastores GM; Raksadawan N; Ong E; Kolodny EH
TI -
Rapid detection of the two common mutations in Ashkenazi Jewish patients
with mucolipidosis type IV.
SO - Genet Test 2001 Summer;5(2):87-92
AD - Department of Neurology, New York University School of Medicine, NY
10016, USA.
Among Ashkenazi Jewish individuals with mucolipidosis IV (ML IV), two
mutations in the ML IV gene, IVS3-1A --> G and delEX1-EX7, account for
more than 95% of disease alleles. The reported method of genotyping for
the delEX1-EX7 mutation involves a cumbersome multistep procedure. In
the present study, a new simplified one-step procedure is described that
detects this mutation in both patients and carriers. An improved
procedure is also described for detection of the IVS3-1A --> G mutation.
Using these improved procedures, we have characterized the ML IV mutant
alleles in 27 patients and 95 of their relatives from 22 families, and
in 123 unrelated and unaffected Ashkenazi Jewish controls. Of the 27 ML
IV patients, 16 patients (59.3%) were found to be homozygous for the
IVS3-1A --> G mutation and 1 patient (3.7%) homozygous for the
delEX1-EX7 mutation. Additionally, 9 patients (33.3%) were compound
heterozygotes for IVS3-1A --> G/delEX1-EX7. Among the 123 Ashkenazi
Jewish controls, two individuals were identified as heteroallelic with
one IVS3-1A --> G mutation (carrier frequency: approximately 1 in 61);
none showed the delEX1-EX7 mutation. The modifications described here
provide a more facile means of genotyping patients and carriers and
expand the possibilities for screening at-risk populations.
5
UI - 11660561
AU - Pokorski RJ
TI -
Insurance underwriting in the genetic era.
SO - Cancer 1997 Aug;80(3 Suppl):587-99
6
UI - 11748358
AU - Chung WB; Hong SH; Kim JA; Sohn YK; Kim BW; Kim JW
TI -
Hypermethylation of tumor-related genes in genitourinary cancer cell
lines.
SO - J Korean Med Sci 2001 Dec;16(6):756-61
AD - Department of Dental Microbiology, College of Dentistry, Kyungpook
National University, Taegu, Korea. jwkim@knu.ac.kr
Hypermethylation of CpG island is a common mechanism for the
inactivation of tumor-related genes. In the present study, we analyzed
13 genitourinary cancer cell lines for aberrant DNA methylation of 5
tumor-related genes using methylation- specific polymerase chain
reaction (MSP). GSTP1 was methylated in 5 (38.5%), E-cadherin in 1 (8%),
VHL in 1 (8%), and MGMT and hMLH1 in none (0%). Six out of thirteen
genitourinary cancer cell lines had methylation of at least one of five
genes; 5 had one gene methylated, and, 1 had two genes methylated.
Methylation of these 5 genes was not detected in any of the bladder
cancer cell lines. GSTP1 was methylated in all of the 3 prostate cancer
cell lines. We conclude that aberrant hypermethylation may be an
important mechanism for the inactivation of cancer-related genes in
kidney and prostate cancer cell lines.
7
UI - 11793470
AU - Herman GE; Kopacz K; Zhao W; Mills PL; Metzenberg A; Das S
TI -
Characterization of mutations in fifty North American patients with
X-linked myotubular myopathy.
SO - Hum Mutat 2002 Feb;19(2):114-21
AD - Children's Research Institute and the Department of Pediatrics, The Ohio
State University, Columbus, Ohio, USA. hermang@pediatrics.ohio-state.edu
X-linked myotubular myopathy (MTM1) is a rare developmental disorder of
skeletal muscle that is characterized by the presence of abnormal
central nuclei in biopsy specimens taken from affected individuals. To
date 133 different mutations have been identified in the MTM1 gene
worldwide. We report here mutations detected in 50 additional U.S.
families with biopsy-proven MTM1. Forty-one of the patients have not
been described previously, including 18 with novel mutations.
Eighty-eight percent of the mothers of sporadic cases that were studied
were identified as carriers, extending the previously reported
high-carrier frequency for this disorder. Clinical information collected
on the majority of patients helps to further correlate genotype with
phenotype, and implications of these data for genetic counseling in
families are discussed. Copyright 2002 Wiley-Liss, Inc.
8
UI - 11793471
AU - Yamaguchi N; Kobayashi K; Yasuda T; Nishi I; Iijima M; Nakagawa M; Osame
TI -
M; Kondo I; Saheki T
Screening of SLC25A13 mutations in early and late onset patients with
citrin deficiency and in the Japanese population: Identification of two
novel mutations and establishment of multiple DNA diagnosis methods for
nine mutations.
SO - Hum Mutat 2002 Feb;19(2):122-30
AD - Department of Biochemistry, Faculty of Medicine, Kagoshima University,
Kagoshima, Japan.
We have recently identified SLC25A13 on chromosome 7q21.3 as the gene
responsible for adult-onset type II citrullinemia (CTLN2) and found
seven mutations in the SLC25A13 gene of CTLN2 patients. Most recently,
the SLC25A13 mutations have been detected in neonatal/infantile patients
with a type of neonatal hepatitis associated with cholestasis (NICCD).
In the present study, we identified a novel mutation, E601X, in the
SLC25A13 gene and established multiple DNA diagnosis methods for eight
mutations by using a genetic analyzer with GeneScan and the single
primer extension procedure (SNaPshot). An additional novel missense
mutation (variation), E601K, was detected by SNaPshot analysis and was
indistinguishable from the mutation E601X detected by the PCR/RFLP
method. Multiple DNA diagnoses for the nine mutations revealed that 100
(male/female: 70/30) out of 115 CTLN2 and 38 (14/24) out of 45 NICCD
patients tested were homozygotes or compound heterozygotes. The
frequency of homozygotes carrying SLC25A13 mutations in both alleles is
estimated to be minimally 1 in 21,000 from carrier detection (18 in
1,315 individuals tested) in the Japanese population. The differences in
the gender ratio and in mutation types between CTLN2 and NICCD patients
are significant. It is, however, unknown whether all homozygotes with
mutated SLC25A13 in both alleles suffer from NICCD, CTLN2, both, or
neither. Copyright 2002 Wiley-Liss, Inc.
9
UI - 11793473
AU - Dakeishi M; Shioya T; Wada Y; Shindo T; Otaka K; Manabe M; Nozaki J;
TI -
Inoue S; Koizumi A
Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local
community in the northern part of Japan.
SO - Hum Mutat 2002 Feb;19(2):140-8
AD - Department of Hygiene, Akita University School of Medicine, Akita,
Japan. koizumi@pbh.med.kyoto-u.ac.jp
Hereditary hemorrhagic telangiectasia (HHT or Rendu-Osler-Weber
syndrome) is an autosomal dominant disorder characterized by aberrant
vascular development. We report here a genetic epidemiologic study in a
county, A, in the Akita prefecture (population 1.2 million) located in
northern Japan. Nine HHT patients who had been referred to tertiary-care
hospitals were located in and near the study county. A total of 137
pedigree members were traced of which 81 were alive and 32 were affected
by HHT. Complications associated with cerebral or pulmonary
arteriovenous malformations were proven in six out of seven families.
Linkage analysis in two large families revealed a weak yet suggestive
linkage to the HHT1 locus (encoding endoglin; ENG). Three novel
mutations were found in four families, all of which led to a frameshift:
a G to C transversion at the splicing donor site of intron 3 (Inv3+1
G>C) in one family, one base pair insertion (A) at nucleotide 828 (exon
7) of the endoglin cDNA in two large families (c.828-829 ins A), and a
four base pair deletion (AAAG) beginning with nucleotide 1120 (exon 8)
of the endoglin cDNA (c.1120-1123 delAAAG) in one family. The insertion
of A in exon 11 (c.1470-1471 insA) mutation found in one family has also
been reported in a European family. No endoglin gene mutations were
found in two families. The population prevalence of HHT in the county
was estimated to be 1:8,000 approximately 1:5,000, roughly comparable
with those reported in European and U.S. populations, which is
contradictory to the traditional view that HHT is rare among Asians. We
recommend that families with HHT be screened for gene mutations in order
that high-risk individuals receive early diagnosis and treatment
initiation that will substantially alter their clinical course and
prognosis. Copyright 2002 Wiley-Liss, Inc.
10
UI - 11793475
AU - Kahmann S; Herter P; Kuhnen C; Muller KM; Muhr G; Martin D; Soddemann M;
TI -
Muller O
A non-radioactive protein truncation test for the sensitive detection of
all stop and frameshift mutations.
SO - Hum Mutat 2002 Feb;19(2):165-72
AD - Max-Planck-Institut fur molekulare Physiologie, Dortmund, Germany.
A new method for mutation detection is described, which is a technical
advancement of the protein truncation test. The new technique is
non-radioactive and highly sensitive for detection of virtually all
sequence mutations, which lead to a stop signal or to the shift of the
translation frame. The method includes four steps: 1) capture of the
interesting sequence copies out of the sample by binding to an
immobilized complementary sequence, 2) PCR amplification of the gene
fragment to be analyzed with primers coding both for amino- and
carboxy-terminal tags, 3) in vitro transcription and translation, and 4)
analysis of the translation products by Western blot. As an evaluation
of the new method, we detected mutated gene copies at a dilution of 1 to
40 compared to the non-mutated gene. Using the method, we were able to
detect a mutation in the adenomatous polyposis coli tumor suppressor
gene (APC) in a stool sample of a colorectal cancer patient. This
mutation could not be detected by direct sequencing of the amplified APC
gene fragment. Copyright 2002 Wiley-Liss, Inc.
11
UI - 11793476
AU - Sodha N; Houlston RS; Williams R; Yuille MA; Mangion J; Eeles RA
TI -
A robust method for detecting CHK2/RAD53 mutations in genomic DNA.
SO - Hum Mutat 2002 Feb;19(2):173-7
AD - Royal Marsden NHS Trust, Surrey, UK. nayanta@icr.ac.uk
While screening for germline CHK2 mutations in cancer cases by
heteroduplex CSGE, we observed that additional PCR fragments were
generated from the 3' end region of the gene that includes exons 11-14.
Direct sequencing of these fragments suggested that homologous loci
(possibly pseudogenes) were concomitantly being amplified. Searches of
public sequence databases showed that a number of areas of the genome
show a high degree of homology to exons 10-14 of the CHK2 gene. The
presence of these homologous regions means that standard screening
methods for detecting mutations in CHK2, based on PCR of genomic DNA,
are prone to error. To circumvent this problem, we have developed a
strategy, based on long-range PCR, to screen the functional copy of
CHK2. Using this approach it is possible to carry out a comprehensive
mutational analysis of CHK2 from genomic DNA. Copyright 2002 Wiley-Liss,
Inc.
12
UI - 11793482
AU - Nuchprayoon I; Sanpavat S; Nuchprayoon S
TI -
Glucose-6-phosphate dehydrogenase (G6PD) mutations in Thailand: G6PD
Viangchan (871G>A) is the most common deficiency variant in the Thai
population.
SO - Hum Mutat 2002 Feb;19(2):185
AD - Department of Pediatrics, Faculty of Medicine, Chulalongkorn University,
Bangkok 10330, Thailand.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common
hereditary disorder in humans. Through a population study for G6PD
deficiency using a cord blood quantitative G6PD assay in Bangkok,
Thailand, we found that the prevalence of G6PD deficiency is 11.1% in
Thai male (N=350) and 5.8% in female (N=172) cord blood samples. Among
the neonates with hyperbilirubinemia, the prevalence of G6PD deficiency
is 22.1% in males (N=140) and 10.1% in females (N=89). We developed a
PCR-restriction enzyme-based method to identify G6PD Viangchan (871G>A),
and searched for this and 9 other mutations in DNA from G6PD deficient
blood samples. G6PD Viangchan (871G>A) was the most common mutation
identified (54%), followed by G6PD Canton (1376G>T; 10%), G6PD Mahidol
(487G>A; 8%), G6PD Kaiping (1388G>A; 5%), G6PD Union (1360C>T; 2.6%) and
"Chinese-5" (1024C>T; 2.6%). Among 20 neonates with hyperbilirubinemia,
G6PD Viangchan was also most frequently identified (60%), followed by
G6PD Canton (10%), G6PD Mahidol, G6PD Union, and G6PD Kaiping (5% each).
G6PD Viangchan appears from this study to be the most common G6PD
mutation in the Thai population, bringing into question previous reports
that G6PD Mahidol is most prevalent. G6PD Viangchan, together with G6PD
Mahidol and G6PD Canton, are responsible for over 70% of G6PD deficiency
in this study of Thais. With the data from other Southeast Asian ethnic
groups such as Laotians, G6PD Viangchan (871G>A) is probably the most
common variant in non-Chinese Southeast Asian population.Copyright 2002
Wiley-Liss, Inc.
13
UI - 11793484
AU - Okubo M; Horinishi A; Kim DH; Yamamoto TT; Murase T
TI -
Seven novel sequence variants in the human low density lipoprotein
receptor related protein 5 (LRP5) gene.
SO - Hum Mutat 2002 Feb;19(2):186
AD - Department of Endocrinology and Metabolism, Okinaka Memorial Institute
for Medical Research and Toranomon Hospital, Tokyo, Japan.
QFG00550@nifty.ne.jp
We identified seven novel polymorphisms in the human low density
lipoprotein receptor related protein 5 (LRP5) gene. Two of them are
predicted to replace amino acid in LRP5 protein (c.314A>G: Q89R and
c.4037T>C: V1330A), whereas three are silent mutations in the coding
region (c.2268T>C: N740N, c.3405A>G: V1119V, and c.4137C>T: D1363D) and
two are polymorphisms in introns (IVS10+6T>C and IVS17-30G>A). Since
LRP5 recognizes apolipoprotein E and is genetically linked with type 1
diabetes, these novel polymorphisms will be useful in genetic studies of
hyperlipoproteinemia and diabetes. To our knowledge, this is the first
report in the literature of sequence variants in the human LRP5 gene.
Copyright 2002 Wiley-Liss, Inc.
14
UI - 11793485
AU - El-Hakeh J; Rosenzweig S; Oleastro M; Basack N; Berozdnik L; Molina F;
TI -
Rivas EM; Zelazko M; Danielian S
Wiskott-Aldrich syndrome in Argentina: 17 unique, including nine novel,
mutations.
SO - Hum Mutat 2002 Feb;19(2):186-7
AD - Molecular Biology Laboratory, Hospital Nacional de Pediatria "J.P
Garrahan", Buenos Aires, Argentina.
Wiskott-Aldrich syndrome (WAS), is an X-linked immunodeficiency disease
caused by mutations of the WAS protein (WASP) gene, characterized by
thrombocytopenia, eczema and recurrent infections. X-linked
thrombocytopenia (XLT) is a milder form with only platelet
abnormalities. Cumulative mutation data have revealed that WASP
genotypes are highly variable among WAS patients. By SSCP analysis, we
determined the location of the mutation in 23 WAS patients from 17
unrelated families with variable clinical phenotypes. Direct sequence
analysis of genomic DNA showed 9 novel mutations (Q52H, G70W, 393del7,
Ex 7 Ex11del, IVS 8+1G-->C, 925delG, 959ins38, 1380del8, and IVS
2+2T-->C) and 8 known mutations distributed throughout the WAS gene.
This is the first report of WAS gene mutations from a Latin American
country. Copyright 2002 Wiley-Liss, Inc.
15
UI - 11808679
AU - Parker M
TI -
Genetics and the interpersonal elaboration of ethics.
SO - Theor Med Bioeth 2001 Sep;22(5):451-9
AD - The Ethox Centre, University of Oxford, Institute of Health Sciences,
UK. michael.parker@ethics-and-communication-in-health.oxford.ac.uk
Confidentiality in genetic testing poses important ethical challenges to
the current primacy of respect for autonomy and patient choice in health
care. It also presents a challenge to approaches to decision-making
emphasising the ethical importance of the consequences of health care
decisions. In this paper a case is described in which respect for
confidentiality calls both for disclosure and non-disclosure, and in
which respect for patient autonomy and the demand to avoid causing harm
each appear to call both for testing without consent, and testing only
with consent. This creates problems not only for clinicians, families
and patients, but also for those who propose clinical bioethics as a
tool for the resolution of such dilemmas. In this paper I propose some
practical ways in which ethical issues in clinical genetics and
elsewhere, might be addressed. In particular I call for a closer
relationship between ethics and communication in health care
decision-making and describe an approach to the ethics consultation that
places particular emphasis on the value of interpersonal deliberation in
the search for moral understanding. I reach these conclusions through an
analysis of the concept of 'moral development' in which I argue that the
achievement of moral understanding is a necessarily intersubjective
project elaborated by moral persons.
16
UI - 11808680
AU - Bennett R
TI -
Antenatal genetic testing and the right to remain in ignorance.
SO - Theor Med Bioeth 2001 Sep;22(5):461-71
AD - School of Law, The University of Manchester, UK.
rebecca.bennett@man.ac.uk
As knowledge increases about the human genome, prenatal genetic testing
will become cheaper, safer and more comprehensive. It is likely that
there will be a great deal of support for making prenatal testing for a
wide range of genetic disorders a routine part of antenatal care. Such
routine testing is necessarily coercive in nature and does not involve
the same standard of consent as is required in other health care
settings. This paper asks whether this level of coercion is ethically
justifiable in this case, or whether pregnant women have a right to
remain in ignorance of the genetic make-up of the fetus they are
carrying. While information gained by genetic testing may be useful for
pregnant women when making decisions about their pregnancy, it does not
prevent harm to future children. It is argued that as this kind of
testing provides information in the interests of the pregnant women and
not in the interests of any future child, the same standards of consent
that are normally required for genetic testing should be required in
this instance.
17
UI - 11861430
AU - Spencer K
TI -
Point-of-care screening for chromosomal anomalies in the first trimester
of pregnancy.
SO - Clin Chem 2002 Mar;48(3):403-4
18
UI - 11866650
AU - Verlinsky Y; Rechitsky S; Verlinsky O; Masciangelo C; Lederer K; Kuliev
TI -
A
Preimplantation diagnosis for early-onset Alzheimer disease caused by
V717L mutation.
SO - JAMA 2002 Feb 27;287(8):1018-21
AD - Reproductive Genetics Institute, Chicago, IL, USA. rgi@flash.net
CONTEXT: Indications for preimplantation genetic diagnosis (PGD) have
recently been expanded to include disorders with genetic predisposition
to allow only embryos free of predisposing genes to be preselected for
transfer back to patients, with no potential for pregnancy termination.
OBJECTIVE: To perform PGD for early-onset Alzheimer disease (AD),
determined by nearly completely penetrant autosomal dominant mutation in
the amyloid precursor protein (APP) gene. DESIGN: Analysis undertaken in
1999-2000 of DNA for the V717L mutation (valine to leucine substitution
at codon 717) in the APP gene in the first and second polar bodies,
obtained by sequential sampling of oocytes following in vitro
fertilization, to preselect and transfer back to the patient only the
embryos that resulted from mutation-free oocytes. SETTING: An in vitro
fertilization center in Chicago, Ill. PATIENTS: A 30-year-old
AD-asymptomatic woman with a V717L mutation that was identified by
predictive testing of a family with a history of early-onset AD. MAIN
OUTCOME MEASURES: Results of mutation analysis; pregnancy outcome.
RESULTS: Four of 15 embryos tested for maternal mutation in 2 PGD
cycles, originating from V717L mutation--free oocytes, were preselected
for embryo transfer, yielding a clinical pregnancy and birth of a
healthy child free of predisposing gene mutation according to chorionic
villus sampling and testing of the neonate's blood. CONCLUSION: This is
the first known PGD procedure for inherited early-onset AD resulting in
a clinical pregnancy and birth of a child free of inherited
predisposition to early-onset AD.
19
UI - 11873798
AU - Lewin T
TI -
Boom in gene testing raises questions on sharing results.
SO - NY Times (Print) 2000 Jul 21;():A1,16
20
UI - 11873799
AU - Pollack A
TI -
Company seeking donors of DNA for a 'gene trust'.
SO - NY Times (Print) 2000 Aug 1;():A1,C10
21
UI - 11742676
AU - Abuin A; Holt KH; Platt KA; Sands AT; Zambrowicz BP
TI -
Full-speed mammalian genetics: in vivo target validation in the drug
discovery process.
SO - Trends Biotechnol 2002 Jan;20(1):36-42
AD - Lexicon Genetics Incorporated, 4000 Research Forest Drive, The
Woodlands, TX 77381, USA.
The completion of the Human Genome Project has signaled the beginning of
the post-genome era, with a corresponding shift in focus from the
sequencing and identification of genes to the exploration of gene
function. A rate-limiting step in deriving value from this gene sequence
information is determining the potential pharmaceutical applications of
genes and their encoded proteins. This validation step is crucial for
focusing efforts and resources on only the most promising targets.
Strategies using reverse mouse genetics provide excellent methods for
validating potential targets and therapeutic proteins in vivo in a
mammalian model system.
22
UI - 11748846
AU - Elanko N; Sibbring JS; Metcalfe KA; Clayton-Smith J; Donnai D; Temple
TI -
IK; Wall SA; Wilkie AO
A survey of TWIST for mutations in craniosynostosis reveals a variable
length polyglycine tract in asymptomatic individuals.
SO - Hum Mutat 2001 Dec;18(6):535-41
AD - Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford,
UK.
The human TWIST gene encodes a 202 amino acid transcription factor
characterized by a highly conserved basic-helix-loop-helix motif in the
C-terminal half, and a less conserved N-terminal half that has binding
activity toward the histone acetyltransferase p300. Between these
domains is a repeat region of unknown function that encodes the
glycine-rich sequence (Gly)5Ala(Gly)5. Heterozygous mutations of TWIST
were previously described in Saethre-Chotzen craniosynostosis syndrome
[El Ghouzzi et al., 1997; Howard et al., 1997]. During a search for
TWIST mutations in patients with craniosynostosis, we identified, in
addition to 11 novel and one previously described bona fide mutations,
several individuals with rearrangements of the glycine-rich region,
involving either deletion of 18 nucleotides or insertion of three, 15,
or 21 nucleotides. None of these rearrangements was consistently
associated with clinical disease and we conclude that they are at most
weakly pathogenic. The glycine stretch may serve as a flexible linker
between the functional domains of the TWIST protein, and as such may be
subject to reduced evolutionary constraint. Copyright 2001 Wiley-Liss,
Inc.
23
UI - 11748305
AU - Eng C; Brody LC; Wagner TM; Devilee P; Vijg J; Szabo C; Tavtigian SV;
TI -
Nathanson KL; Ostrander E; Frank TS; Steering Committee of the Breast
Cancer Information Core (BIC) Consortium
Interpreting epidemiological research: blinded comparison of methods
used to estimate the prevalence of inherited mutations in BRCA1.
SO - J Med Genet 2001 Dec;38(12):824-33
AD - Clinical Cancer Genetics and Human Cancer Genetics Programs,
Comprehensive Cancer Center, and Division of Human Genetics, Department
of Internal Medicine, The Ohio State University, Columbus, OH 43210,
USA. eng-1@medctr.osu.edu
While sequence analysis is considered by many to be the most sensitive
method of detecting unknown mutations in large genes such as BRCA1, most
published estimates of the prevalence of mutations in this gene have
been derived from studies that have used other methods of gene analysis.
In order to determine the relative sensitivity of techniques that are
widely used in research on BRCA1, a set of blinded samples containing 58
distinct mutations were analysed by four separate laboratories. Each
used one of the following methods: single strand conformational
polymorphism analysis (SSCP), conformation sensitive gel electrophoresis
(CSGE), two dimensional gene scanning (TDGS), and denaturing high
performance liquid chromatography (DHPLC). Only the laboratory using
DHPLC correctly identified each of the mutations. The laboratory using
TDGS correctly identified 91% of the mutations but produced three
apparent false positive results. The laboratories using SSCP and CSGE
detected abnormal migration for 72% and 76% of the mutations,
respectively, but subsequently confirmed and reported only 65% and 60%
of mutations, respectively. False negatives therefore resulted not only
from failure of the techniques to distinguish wild type from mutant, but
also from failure to confirm the mutation by sequence analysis as well
as from human errors leading to misreporting of results. These findings
characterise sources of error in commonly used methods of mutation
detection that should be addressed by laboratories using these methods.
Based upon sources of error identified in this comparison, it is likely
that mutations in BRCA1 and BRCA2 are more prevalent than some studies
have previously reported. The findings of this comparison provide a
basis for interpreting studies of mutations in susceptibility genes
across many inherited cancer syndromes.
24
UI - 11768386
AU - Fokstuen S; Myring J; Evans C; Harper PS
TI -
Presymptomatic testing in myotonic dystrophy: genetic counselling
approaches.
SO - J Med Genet 2001 Dec;38(12):846-50
25
UI - 11768389
AU - Eccles D; Harvey J; Bateman A; Ross F
TI -
A novel 3' mutation in the APC gene in a family presenting with a
desmoid tumour.
SO - J Med Genet 2001 Dec;38(12):861-3
26
UI - 11748308
AU - Fokstuen S; Myring J; Meredith L; Ravine D; Harper PS
TI -
Eight years' experience of direct molecular testing for myotonic
dystrophy in Wales.
SO - J Med Genet 2001 Dec;38(12):E42
27
UI - 11748310
AU - Akrami SM; Winter RM; Brook JD; Armour JA
TI -
Detection of a large TBX5 deletion in a family with Holt-Oram syndrome.
SO - J Med Genet 2001 Dec;38(12):E44
28
UI - 11748311
AU - Gong W; Gottlieb S; Collins J; Blescia A; Dietz H; Goldmuntz E;
TI -
McDonald-McGinn DM; Zackai EH; Emanuel BS; Driscoll DA; Budarf ML
Mutation analysis of TBX1 in non-deleted patients with features of
DGS/VCFS or isolated cardiovascular defects.
SO - J Med Genet 2001 Dec;38(12):E45
29
UI - 11773283
AU - Geisler JP; Hatterman-Zogg MA; Rathe JA; Buller RE
TI -
Frequency of BRCA1 dysfunction in ovarian cancer.
SO - J Natl Cancer Inst 2002 Jan 2;94(1):61-7
AD - Division of Gynecologic Oncology, Department of Obstetrics and
Gynecology, Holden Comprehensive Cancer Center, University of Iowa, Iowa
City 52242, USA.
BACKGROUND: Ovarian cancer is one of the most common hereditary cancers
in women. Mutations in the BRCA1 gene increase a woman's risk of ovarian
cancer. Testing for BRCA1 mutations is cumbersome and impractical for
large populations. Therefore, we developed an efficient strategy to
detect various types of BRCA1 dysfunction and also determined the
relative frequency of BRCA1 dysfunction in ovarian cancer. METHODS:
Tumors from 221 patients with epithelial ovarian cancer were screened
for loss of heterozygosity (LOH) at the BRCA1 locus. BRCA1 complementary
DNA (cDNA) and genomic DNA from all cancers with BRCA1 LOH (106 tumors)
or noninformative status (15 tumors) were polymerase chain reaction
(PCR) amplified and analyzed for protein truncation in a coupled
transcription/translation test. When truncated BRCA1 protein was
detected, the BRCA1 gene from both the tumor and a paired blood sample
was sequenced. When BRCA1 expression in tumor cDNA was not detected with
a protein truncation test, a methylation-specific PCR was used to
determine whether the promoter region of BRCA1 was methylated and thus
inactivated. All statistical tests were two-sided. RESULTS: Fifty-one
(23.1%) of 221 tumors had BRCA1 dysfunction, including 18 with germline
mutations, 15 with somatic mutations, and 18 with monoallelic or
biallelic hypermethylated promoters. By the consideration of only tumors
with LOH or that were noninformative, the efficiency for detecting BRCA1
dysfunction improved to 45 (37.2%) of 121 tumors. Therefore,
LOH/noninformative was a strong predictor of mutation status (Fisher's
exact test, P<.001). However, this subset of tumors did not include
those with BRCA1 missense mutations (estimated at six [2.7%] of 221 not
detected by our method) or biallelic promoter methylation (estimated at
six [2.7%] of 221). CONCLUSIONS: BRCA1 dysfunction in ovarian cancer is
common and occurs via multiple mechanisms. The use of LOH, rather than a
family history of ovarian cancer, as a first step in a screening
strategy, followed by protein truncation testing, appears to increase
the chance of identifying tumors with BRCA1 dysfunction.
30
UI - 11857010
AU - Bish A; Sutton S; Jacobs C; Levene S; Ramirez A; Hodgson S
TI -
Changes in psychological distress after cancer genetic counselling: a
comparison of affected and unaffected women.
SO - Br J Cancer 2002 Jan 7;86(1):43-50
AD - Department of Clinical Genetics, Guy's Hospital, St Thomas's Street,
London SE1 9RT, UK. alison.bish@kcl.ac.uk
This study sought to examine changes in psychological distress following
cancer genetic counselling. Women attending a family cancer clinic
completed questionnaires before their appointment and at 2 weeks, 6
months and 12 months after their appointment. Twenty-six women were at
low risk of developing breast or ovarian cancer, 76 were at moderate
risk, 46 were at high risk and 46 women had previously had breast or
ovarian cancer. All groups were compared with regard to measures of
anxiety, depression, general psychological distress, worry about
developing breast and ovarian cancer, and perceived risk of developing
breast/ovarian cancer and perceived likelihood of carrying a genetic
mutation. General psychological distress did not change over the course
of the study and the groups did not differ on these measures. Worry
about developing breast cancer and perceptions of the likelihood of
carrying a genetic mutation significantly reduced following genetic
counselling. On the whole women who had already had breast/ovarian
cancer showed more concerns about ovarian cancer and raised perceptions
of risk in comparison with the other groups, indicating the need for
sensitive counselling of such women.
31
UI - 11838716
AU - Calzone KA; Biesecker BB
TI -
Genetic testing for cancer predisposition.
SO - Cancer Nurs 2002 Feb;25(1):15-25; quiz 26-7
AD - University of Pennsylvania Cancer Center, Philadelphia 19104, USA.
The onslaught of genetic innovations in the past decade has resulted in
the ongoing identification of a spectrum of genes, some of which, when
mutated, result in cancer susceptibility. The impact of these
discoveries on healthcare provides an opportunity to enhance health
promotion and long-term health outcomes by identifying at-risk
individuals before cancer develops. This provides the healthcare
provider with the potential to intervene much earlier to either reduce
the risk or diagnose a cancer early when the chances for effective
treatment are greatest. Even though genetic testing is increasingly
being employed clinically, there remains a gap between the technology
and effective interventions. Genetic tests also provide information that
is distinct from other tests used routinely in health promotion, because
of the personal and family nature of the information. This results in
unique clinical, ethical, legal, and social issues that further affect
the effective diffusion of this technology clinically. This article
provides an overview of the distinguishing characteristics of genetic
testing, outlines the essential components of informed consent, and
discusses the potential implications of testing on individuals' lives
and the nurse's role in offering genetic testing.
32
UI - 11838717
AU - Weinrich S; Royal C; Pettaway CA; Dunston G; Faison-Smith L; Priest JH;
TI -
Roberson-Smith P; Frost J; Jenkins J; Brooks KA; Powell I
Interest in genetic prostate cancer susceptibility testing among african
American men.
SO - Cancer Nurs 2002 Feb;25(1):28-34
AD - School of Nursing, University of Louisville, KY 40292, USA.
sally.weinrich@louisville.edu
Six regions for prostate cancer genes have been identified, and it is
anticipated that prostate cancer susceptibility testing will be
available in the future. This correlational study identified predictors
for interest in prostate cancer susceptibility testing among African
American men. Participants were 320 African American men from the
African American Hereditary Prostate Cancer Study and the South Carolina
Prostate Cancer Education and Screening Study participated. Two
questions measured interest in genetic prostate cancer susceptibility
testing and family history of prostate cancer. Chi-square analyses by
family history as well as demographics (age, education, marital status)
were performed. Most of the men (277 [87%]) indicated an interest in
genetic prostate cancer susceptibility testing. Interest in undergoing
testing did not vary by family history, age, or education. Marital
status was the only significant demographic predictor. Men who were
married were significantly more likely to respond with a "yes" to
interest in prostate cancer susceptibility testing than were men who
were not married. The high "yes" response rate and the men's confusion
between the genetic prostate cancer susceptibility testing and prostate
cancer screening highlight the need for public education once prostate
cancer genes are identified and available for public testing.
33
UI - 11295836
AU - Kamarinos M; McGill J; Lynch M; Dahl H
TI -
Identification of a novel COCH mutation, I109N, highlights the similar
clinical features observed in DFNA9 families.
SO - Hum Mutat 2001 Apr;17(4):351
AD - The Murdoch Childrens Research Institute, Royal Children's Hospital,
Melbourne, Australia. kamarinm@cryptic.rch.unimelb.edu.au
Hereditary hearing loss is a heterogeneous condition at both the genetic
and clinical levels. We have recruited an Australian family with
dominant sensorineural nonsyndromic late onset hearing loss. The hearing
loss typically begins in the second or third decade of life as a high
frequency loss which progresses to a severe to profound loss by the
sixth to seventh decade. All affected family members presented with
concomitant vestibular dysfunction. Vertigo is a less common feature.
The causative gene in this family was identified as COCH which lies
within the DFNA9 interval. We identified a new point mutation, 253 T>A,
in the coding region of the COCH gene, changing the isoleucine 109 to an
asparagine (I109N). This is a non-conservative change of an amino acid
that is identical in the human, mouse and chicken sequences. The
mutation was identified in all affected individuals (n=13) and all were
heterozygotes. Hearing loss in this family is clinically similar to that
observed in ten other DFNA9 families. However, there are some
differences in the age of onset and the extent of vestibular
involvement. The remarkable clinical uniformity observed between DFNA9
families is intriguing especially in light of the great phenotypic
variability observed with some of the other hearing loss genes. Hum
Mutat 117:351, 2001. Copyright 2001 Wiley-Liss, Inc.
34
UI - 11826017
AU - Kanavakis E; Traeger-Synodinos J
TI -
Preimplantation genetic diagnosis in clinical practice.
SO - J Med Genet 2002 Jan;39(1):6-11
AD - Medical Genetics, University of Athens, Aghia Sophia Children's
Hospital, Athens 11527, Greece. ekanavak@cc.uoa.gr
Preimplantation genetic diagnosis (PGD) represents an alternative to
prenatal diagnosis and allows selection of unaffected IVF embryos for
establishing pregnancies in couples at risk for transmitting a genetic
disorder.
35
UI - 11870512
AU - Brain K; Norman P; Gray J; Rogers C; Mansel R; Harper P
TI -
A randomized trial of specialist genetic assessment: psychological
impact on women at different levels of familial breast cancer risk.
SO - Br J Cancer 2002 Jan 21;86(2):233-8
AD - Institute of Medical Genetics, University of Wales College of Medicine,
Heath Park, Cardiff CF14 4XN, UK.
The aim was to compare the psychological impact of a multidisciplinary
specialist genetics service with surgical provision in women at high
risk and those at lower risk of familial breast cancer. Women (n=735)
were randomized to a surgical consultation with (trial group) or without
(control group) specialist genetic risk assessment and the possible
offer of presymptomatic genetic testing. Participants completed
questionnaires before and immediately after the consultation to assess
anxiety, cancer worry, perceived risk, interest in genetic testing and
satisfaction. Responses of subgroups of women stratified by clinicians
as low, moderate, or high risk were analyzed. There were no significant
main effects of study intervention on any outcome variable. Regardless
of risk information, there was a statistically significant reduction in
state anxiety (P<0.001). Reductions in cancer worry and perceived risk
were significant for women at low or moderate risk (P<0.001) but not
those at high risk, and satisfaction was significantly lower in the high
risk group (P<0.001). In high risk women who received specialist genetic
input, there was a marginally significant trend towards increased
perceived risk. The effect of risk information on interest in genetic
testing was not significant. Breast care specialists other than
geneticists might provide assessments of breast cancer risk, reassuring
women at reduced risk and targeting those at high risk for specialist
genetic counselling and testing services. These findings are discussed
in relation to the existing UK Calman-Hine model of service delivery in
cancer genetics. DOI: 10.1038/sj/bjc/6600051 www.bjcancer.comCopyright
2002 The Cancer Research Campaign
36
UI - 11480785
AU - Curuk MA; Arpaci A; Attila G; Tuli A; Kilinc Y; Aksoy K; Yuregir GT
TI -
Genetic heterogeneity of beta-thalassemia at Cukurova in southern
Turkey.
SO - Hemoglobin 2001 May;25(2):241-5
AD - Institute of Molecular Medicine and Genetics, Medical College of
Georgia, Augusta 30912, USA. mcuruk@mail.mcg.edu
Beta-thalassemia is the most common genetic abnormality causing health
problems worldwide. Cukurova, in the southern part of Turkey, being on
the Mediterranean, is in the thalassemic belt. Since there is no cure
for the disease at present, the frequency of the mutation types of
beta-thalassemia must first be identified to aid in clinical follow-up
and prenatal diagnosis. Carriers identified during a screening survey
and patients referred to our laboratory were studied for this purpose.
After routine hematological analysis molecular screening was performed
by the amplification refractory mutation system and DNA sequencing. The
frequency of the common mutations were: IVS-I-110 (G-->A) 57.3%, IVS-I-1
(G-->A) 8.3%, codon 39 (C-->T) 6.4%, IVS-I-6 (T-->C) 5.7%, frameshift
codon 8 (-AA) 5.7%, -30 (T-->A) 4.7%, IVS-II-1 (G-->A) 3.4%, IVS-II-745
(G-->C) 2.8%, and frameshift codon 5 (-CT) 1.1%. Some rare mutations
(1%) such as frameshift codon 44 (-C) 0.7%, frameshift codons 74/75 (-C)
0.7%, IVS-1-5 (G-->C) 0.7%, frameshift codons 8/9 (+G) 0.4%, frameshift
codons 36/37 (-T) 0.4%, frameshif
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