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Abramson Cancer CenterNCI CANCERLIT® Search: Breast Cancer, Hereditary - March 2002
National Cancer Institute®
Last Modified: March 1, 2002
Table of Contents
1
UI - 10995814
AU - Pirnia F; Breuleux M; Schneider E; Hochmeister M; Bates SE; Marti A;
TI -
Hotz MA; Betticher DC; Borner MM
Uncertain identity of doxorubicin-resistant MCF-7 cell lines expressing
mutated p53.
SO - J Natl Cancer Inst 2000 Sep 20;92(18):1535-6
2
UI - 11805588
AU - Vachon CM; Mink PJ; Janney CA; Sellers TA; Cerhan JR; Hartmann L; Folsom
TI -
AR
Association of parity and ovarian cancer risk by family history of
breast or ovarian cancer in a population-based study of postmenopausal
women.
SO - Epidemiology 2002 Jan;13(1):66-71
AD - Department of Health Sciences Research, Mayo Clinic and Mayo Foundation,
Rochester, MN 55905, USA. vachon@mayo.edu
Although parity is associated with a decreased risk of ovarian cancer in
the general population, this association among women with a family
history is less clear. We examined this question in a prospective cohort
of 31,377 Iowa women 55-69 years of age at baseline. Relative risks
(RRs) and 95% confidence intervals (CIs) were estimated through Cox
regression. We identified 181 incident epithelial ovarian cancers
through 13 years of follow-up. At baseline, 14% of the women reported
breast or ovarian cancer in a first-degree relative, and an additional
12% reported a family history in a second-degree relative. Among women
without a family history of breast or ovarian cancer in a first-degree
relative, nulliparous women were at slightly increased risk of ovarian
cancer (RR = 1.4, 95% CI = 0.9-2.4) compared with parous women, whereas
among women with a family history, nulliparous women were at a much
higher risk (RR = 2.7, 95% CI = 1.1-6.6) than parous women. Similar
results were seen when family history included first- or second-degree
relatives with breast or ovarian cancer or a first- or second-degree
relative with ovarian cancer only. Nulliparity may be more strongly
associated with an increased risk of ovarian cancer among women with a
family history of breast or ovarian cancer, compared with women who do
not have a family history of those cancers.
3
UI - 11793480
AU - Tereschenko IV; Basham VM; Ponder BA; Pharoah PD
TI -
BRCA1 and BRCA2 mutations in Russian familial breast cancer.
SO - Hum Mutat 2002 Feb;19(2):184
AD - Department of Prevention, Cancer Research Institute, Tomsk Scientific
Centre, Tomsk, Russia. tivru@yahoo.com
We have screened index cases from 25 Russian breast/ovarian cancer
families for germ-line mutations in all coding exons of the BRCA1 and
BRCA2 genes, using multiplex heteroduplex analysis. In addition we
tested 22 patients with breast cancer diagnosed before age 40 without
family history and 6 patients with bilateral breast cancer. The
frequency of families with germline mutations in BRCA was 16% (4/25).
One BRCA1 mutation, 5382insC, was found in three families. The results
of present study, and those of a separate study of 19 breast-ovarian
cancer families, suggest that BRCA1 5382insC is a founder mutation in
the Russian population. Three BRCA2 mutations were found in patients
with breast cancer without family history: two in young patients and one
in patients with bilateral breast cancer. Four novel BRCA2 mutations
were identified: three frameshift (695insT, 1528del4, 9318del4) and one
nonsense (S1099X). Copyright 2002 Wiley-Liss, Inc.
4
UI - 11840334
AU - Montagna C; Andrechek ER; Padilla-Nash H; Muller WJ; Ried T
TI -
Centrosome abnormalities, recurring deletions of chromosome 4, and
genomic amplification of HER2/neu define mouse mammary gland
adenocarcinomas induced by mutant HER2/neu.
SO - Oncogene 2002 Jan 31;21(6):890-8
AD - Genetics Branch, Center for Cancer Research, National Cancer
Institute/NIH, Bldg. 9, Rm. 1N105, 9 Memorial Drive, Bethesda, MD 20892,
USA.
The conditional expression of activated HER2/neu gene under its
endogenous promoter in the mammary epithelium of the mouse results in
accelerated lobular development and focal mammary tumors.
Carcinogenesis, however, requires amplification and considerably
increased expression levels of oncogenic neu. Deducing from the multiple
genetic aberrations required for human breast cancer to develop, we
hypothesized that in addition to the over-expression of an activated
HER2/neu, secondary aberrations would occur. We have therefore conducted
a genomic screen for chromosomal imbalances and translocations using
comparative genomic hybridization and spectral karyotyping. The results
reveal a moderate degree of chromosomal instability and micronuclei
formation in short-term cultures established from primary tumors.
Genomic instability appears to be linked to the amplification of
functional centrosomes, a phenomenon that we frequently observed in
other tumor types. Seventy per cent of the tumors revealed genomic
amplification of HER2/neu, often in the form of double minute
chromosomes, which correlated with recurring loss of mouse chromosome
4D-E, a region that is orthologous to distal human chromosome 1p. It is
likely that this region contains putative tumor suppressor genes whose
inactivation is required for tumor formation in this model of human
breast cancer.
5
UI - 11830541
AU - Bange J; Prechtl D; Cheburkin Y; Specht K; Harbeck N; Schmitt M;
TI -
Knyazeva T; Muller S; Gartner S; Sures I; Wang H; Imyanitov E; Haring
HU; Knayzev P; Iacobelli S; Hofler H; Ullrich A
Cancer progression and tumor cell motility are associated with the FGFR4
Arg(388) allele.
SO - Cancer Res 2002 Feb 1;62(3):840-7
AD - Department of Molecular Biology, Max-Planck-Institute of Biochemistry,
Am Klopferspitz 18a, D-82152 Martinsried, Germany.
Expression analysis of genes encoding components of the phosphotyrosine
signaling system by cDNA array hybridization revealed elevated levels of
FGFR4 transcripts in several mammary carcinoma cell lines. In the FGFR4
gene transcript from MDA-MB-453 mammary carcinoma cells, a G to A
conversion was discovered that results in the substitution of glycine by
arginine at position 388 in the transmembrane domain of the receptor.
The Arg(388) allele was also found in cell lines derived from a variety
of other tumor types as well as in the germ-line of cancer patients and
healthy individuals. Analysis of three geographically separated groups
indicated that it occurs in approximately 50% of the human population.
Investigation of the clinical data of 84 breast cancer patients revealed
that homo- or heterozygous carriers of the Arg(388) allele had a
significantly reduced disease-free survival time (P = 0.01) within a
median follow-up of 62 months. Moreover, the FGFR4 Arg(388) allele was
associated with early lymph node metastasis and advanced
tumor-node-metastasis (TNM) stage in 82 colon cancer patients.
Consistent with this finding, MDA-MB-231 mammary tumor cells expressing
FGFR4 Arg(388) exhibited increased motility relative to cells expressing
the FGFR4 Gly(388) isotype. Our results support the conclusion that the
FGFR4 Arg(388) allele represents a determinant that is innocuous in
healthy individuals but predisposes cancer patients for significantly
accelerated disease progression.
6
UI - 11836363
AU - Robson M; Scheuer L; Nafa K; Ellis N; Offit K
TI -
Unique de novo mutation of BRCA2 in a woman with early onset breast
cancer.
SO - J Med Genet 2002 Feb;39(2):126-8
7
UI - 11748848
AU - Machackova E; Damborsky J; Valik D; Foretova L
TI -
Novel germline BRCA1 and BRCA2 mutations in breast and breast/ovarian
cancer families from the Czech Republic.
SO - Hum Mutat 2001 Dec;18(6):545
AD - Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer
Institute, Zluty kopec 7, Brno 656 53, Czech Republic.
Germline mutations in breast cancer susceptibility genes, BRCA1 and
BRCA2, are responsible for a substantial proportion of high-risk breast
and breast/ovarian cancer families. To characterize the spectrum of
BRCA1 and BRCA2 mutations, we screened Czech families with
breast/ovarian cancer using the non-radioactive protein truncation test,
heteroduplex analysis and direct sequencing. In a group of 100 high-risk
breast and breast/ovarian cancer families, four novel frame shift
mutations were identified in BRCA1 and BRCA2 genes. In BRCA1, two novel
frame shift mutations were identified as 3761-3762delGA and
2616-2617ins10; in BRCA2, two novel frame shift mutations were
identified as 5073-5074delCT and 6866delC. Furthermore, a novel missense
substitution M18K in BRCA1 gene in a breast/ovarian cancer family was
identified which lies adjacent just upstream of the most highly
conserved C3HC4 RING zinc finger motif. To examine the tertiary
structure of the RING zinc finger domain and possible effects of M18K
substitution on its stability, we used threading techniques according to
the crystal structure of RAG1 dimerization domain of the DNA-binding
protein. Copyright 2000 Wiley-Liss, Inc.
8
UI - 11810042
AU - Siegelmann-Danieli N; Buetow KH
TI -
Significance of genetic variation at the glutathione S-transferase M1
and NAD(P)H:quinone oxidoreductase 1 detoxification genes in breast
cancer development.
SO - Oncology 2002;62(1):39-45
AD - Division of Population Science, Fox Chase Center, Philadelphia, PA, USA.
n_siegelmann@asaf.health.gov.il
This work examined the role of constitutional genetic variation at the
glutathione S-transferase M1 (GSTM1) and NAD(P)H:quinone oxidoreductase
1 (NQO1) detoxification loci in breast cancer development. Methods
included contrasting patterns of genetic variations at these loci
between cases with breast cancer and healthy controls and assessing the
association of genotypes with tumor characteristics. Participants were
Caucasian women living in the Greater Philadelphia region, recruited
from 1988 to 1994, with recently diagnosed women attending breast cancer
clinics at Fox Chase Cancer Center (FCCC) and network affiliated
hospitals as cases, and FCCC employees or women attending noncancer
clinics as controls. The GSTM1 locus was determined for 402 cases and
238 controls, NQO1 for 346 cases and 235 controls. Results show that
neither locus was associated with breast cancer occurrence, with the
GSTM1 null genotype occurring at frequencies of 0.560 and 0.563 in cases
and controls, respectively [odds ratio (OR) 0.98, 0.95 confidence
interval (CI) 0.70-1.38] and the NQO1 wild-type allele at frequencies of
0.808 and 0.845, respectively (OR 0.77, 0.95 CI 0.55-1.06). The GSTM1
null genotype, however, was significantly overrepresented among larger
(T3 and T4) primary tumors (OR 7.61, 0.95 CI 1.05-333) and with the
occurrence of axillary lymph node metastases (OR 1.62, 0.95 CI
0.98-2.69). NQO1 results revealed that homozygotes for the wild type
allele were more likely to have ductal carcinoma and poor histologic
grade when compared with individuals carrying one or two mutated alleles
(OR 3.50, 0.95 CI 1.41-9.0, and OR 2.26, 0.95 CI 1.18-4.35 for histology
type and grade, respectively). We conclude that while these loci are not
associated with breast cancer occurrence, the GSTM1 locus is likely
associated with tumor progression. NQO1 results suggest that different
quinones (possibly estrogenic quinone metabolites) might affect the
histological development of breast tumors. Copyright 2002 S. Karger AG,
Basel
9
UI - 11857015
AU - Antoniou AC; Pharoah PD; McMullan G; Day NE; Stratton MR; Peto J; Ponder
TI -
BJ; Easton DF
A comprehensive model for familial breast cancer incorporating BRCA1,
BRCA2 and other genes.
SO - Br J Cancer 2002 Jan 7;86(1):76-83
AD - CRC Genetic Epidemiology Unit, Institute of Public Health, Strangeways
Research Laboratory, Worts Causeway, University of Cambridge, Cambridge
CB1 8RN, UK.
In computing the probability that a woman is a BRCA1 or BRCA2 carrier
for genetic counselling purposes, it is important to allow for the fact
that other breast cancer susceptibility genes may exist. We used data
from both a population based series of breast cancer cases and high risk
families in the UK, with information on BRCA1 and BRCA2 mutation status,
to investigate the genetic models that can best explain familial breast
cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence
for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the
simultaneous effects of BRCA1, BRCA2, a third hypothetical gene 'BRCA3',
and a polygenic effect using segregation analysis. The hypergeometric
polygenic model was used to approximate polygenic inheritance and the
effect of risk modifiers. BRCA1 and BRCA2 could not explain all the
observed familial clustering. The best fitting model for the residual
familial breast cancer was the polygenic, although a model with a single
recessive allele produced a similar fit. There was also significant
evidence for a modifying effect of other genes on the risks of breast
cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the
frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021-0.125%) and
of BRCA2 0.068% (95% CI: 0.033-0.141%). The breast cancer risk by age 70
years, based on the average incidence over all modifiers was estimated
to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian
cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings
suggest that several common, low penetrance genes with multiplicative
effects on risk may account for the residual non-BRCA1/2 familial
aggregation of breast cancer. The modifying effect may explain the
previously reported differences between population based estimates for
BRCA1/2 penetrance and estimates based on high-risk families.
10
UI - 11857075
AU - Sullivan A; Yuille M; Repellin C; Reddy A; Reelfs O; Bell A; Dunne B;
TI -
Gusterson BA; Osin P; Farrell PJ; Yulug I; Evans A; Ozcelik T; Gasco M;
Crook T
Concomitant inactivation of p53 and Chk2 in breast cancer.
SO - Oncogene 2002 Feb 21;21(9):1316-24
AD - Ludwig Institute for Cancer Research, Imperial College Faculty of
Medicine, St Mary's Campus, Norfolk Place, London W2 1PG, UK.
The structure and expression of the human Rad53 homologue Chk2 was
analysed in breast cancer. The previously described silent polymorphism
at nucleotide 252 in codon 84 (GAA>GAG) was observed in 5/141 cases.
Somatic Chk2 coding mutations were detected in 7/141 cases, these
occurring in 4/18 BRCA1-associated breast cancers, 1/78 sporadic breast
cancers and 2/25 typical medullary carcinomas. Each of the
BRCA1-associated cancers with Chk2 mutations also contained mutations in
p53, whereas the single sporadic cancer with Chk2 mutation was wild-type
for p53. Expression of Chk2 was ubiquitously detected in normal ductal
epithelium of the breast, but there was loss of expression in a
significant proportion of breast carcinomas, and this occurred in
cancers both with and without p53 mutation. A CpG island was identified
5' of the Chk2 transcriptional start site, but there was no evidence of
cytosine methylation in any of the cancers with down-regulated Chk2
expression. Analysis of the germ-line of 45 individuals with hereditary
or early onset breast cancer revealed wild-type Chk2 sequence in all
cases. Thus, despite the rarity of somatic mutations in Chk2 in sporadic
breast carcinomas, our results nevertheless reveal that concomitant loss
of function in Chk2 (via down-regulation of expression) and p53 (via
mutation) occurs in a proportion of sporadic cases. However, consistent
with other studies, we show that germ-line mutations in Chk2 are
unlikely to account for a significant proportion of non BRCA1-, non
BRCA2-associated hereditary breast cancers.
11
UI - 11857408
AU - Lei H; Sjoberg-Margolin S; Salahshor S; Werelius B; Jandakova E;
TI -
Hemminki K; Lindblom A; Vorechovsky I
CDH1 mutations are present in both ductal and lobular breast cancer, but
promoter allelic variants show no detectable breast cancer risk.
SO - Int J Cancer 2002 Mar 10;98(2):199-204
AD - Karolinska Institute, Department of Biosciences at NOVUM, Huddinge,
Sweden.
Mutations and diminished expression of the E-cadherin gene (CDH1) have
been identified in a number of epithelial malignancies. Although somatic
CDH1 mutations were detected in lobular breast cancer with a frequency
ranging from 10-56%, CDH1 alterations in more frequent ductal tumors
appear to be rare. Here we have analyzed the coding region of CDH1 for
mutations using denaturing high performance liquid chromatography and
found 4 mutations in 83 ductal carcinomas (5%) and 3 mutations in 25
lobular carcinomas (12%). The germline of 13 patients with familial
lobular tumors was also analyzed for mutations, but none were detected.
In a case-control study, we also tested whether a variant adenine allele
in the promoter polymorphism -161C-->A with a putative influence on the
transcriptional activity of CDH1 in vitro confers any detectable risk of
breast cancer. No significant difference in the allelic frequency
between patients with breast cancer (326/1,152, 28.3%) and controls
(190/696, 27.3%, p > 0.05; relative risk 1.05, 95% confidence interval
0.85-1.30) was found. A novel promoter polymorphism was identified at
position -152, but the frequency of the variant cytosine allele was also
similar in patients with breast cancer and controls (0.71% vs. 0.21%, p
= 0.23). Transient transfection experiments using reporter constructs
containing the nucleotide substitutions -161C/-152C and -161A/-152T
showed only a slight decrease in the transcription activity compared to
the wild-type construct. These results do not support CDH1 as a
prominent low-penetrance cancer susceptibility gene, but indicate that
CDH1 mutations contribute to the progression of both lobular and ductal
tumors. Copyright 2001 Wileyb Liss, Inc.
12
UI - 11857409
AU - Johnson SM; Shaw JA; Walker RA
TI -
Sporadic breast cancer in young women: prevalence of loss of
heterozygosity at p53, BRCA1 and BRCA2.
SO - Int J Cancer 2002 Mar 10;98(2):205-9
AD - Breast Cancer Research Unit, Clinical Sciences, Glenfield General
Hospital, Leicester, United Kingdom.
Previous studies have shown that breast cancers have more aggressive
pathologic features in young women. In order to examine genetic
alterations associated with early-onset breast cancer, 31 patients with
no known family history, aged 26-35 years at diagnosis, were examined
for loss of heterozygosity (LOH) at 3 key chromosomal intervals: 17p
(p53), 17q 21 (BRCA1) and 13q12-13 (BRCA2) using polymerase chain
reaction analysis of polymorphic microsatellite markers. These were
compared with 31 patients aged 55-72 years that were matched for size,
type and grade. All young breast cancer cases exhibited LOH for at least
1 marker and 20 cases (64.5%) exhibited LOH at 1 or more markers from
each interval. The frequency of LOH detected for each of the markers was
as follows 17p: p534N (33.3%), D17S796 (36.7%), D17S799 (63.3%) and
D17S513 (59.3%); 17q: D17S855 (64.5%), THRA1 (46.7%) and D17S579
(33.3%); and 13q: D13S260 (74.2%), D13S171 (47.6%) and D13S267 (40.0%).
These frequencies are higher than those observed at the 3 markers
studied in the matched postmenopausal patients: D17S799 (41.4%), D17S855
(35.5%), D13S260 (30.0%). These differences in frequency of LOH were
statistically significant for the D17S855 and D13S260 markers (p < 0.025
and p < 0.001 respectively). Although there were more grade III
carcinomas (21 of 31 cases), there was no correlation between number of
alterations and high grade in younger cases. These data suggest that LOH
at these regions could be related to early-onset sporadic breast cancer.
Copyright 2001 Wiley-Liss, Inc.
13
UI - 11873935
AU - Eggerston L
TI -
Ontario defies US firm's genetic patent, continues cancer screening.
SO - CMAJ 2002 Feb 19;166(4):494
14
UI - 10995812
AU - Eisinger F; Juliain-Reynier C; Sobol H
TI -
Re: Biologic characteristics of interval and screen-detected breast
cancers.
SO - J Natl Cancer Inst 2000 Sep 20;92(18):1533-4
15
UI - 11872285
AU - Formenti SC; Spicer D; Skinner K; Cohen D; Groshen S; Bettini A;
TI -
Naritoku W; Press M; Salonga D; Tsao-Wei D; Danenberg K; Danenberg P
Low HER2/neu gene expression is associated with pathological response to
concurrent paclitaxel and radiation therapy in locally advanced breast
cancer.
SO - Int J Radiat Oncol Biol Phys 2002 Feb 1;52(2):397-405
AD - Radiation Oncology and Medicine, New York University School of Medicine,
New York, NY 10016, USA. silvia.formenti@med.nyu.edu
PURPOSE: The objective of this study was twofold: first, to identify
patients with locally advanced breast cancer (LABC) who will achieve a
pathological response to a preoperative regimen of concurrent paclitaxel
and radiation; and second, to explore associations between molecular
markers from the original tumors and pathological response. METHODS AND
MATERIALS: Patients with previously untreated LABC were eligible to
receive a regimen of preoperative concurrent paclitaxel, 30 mg/m(2)
twice a week for a total of 8 weeks, and radiation delivered Weeks 2--6,
45 Gy at 1.8 Gy per fraction to the breast, ipsilateral axilla, and
supraclavicular nodes. At mastectomy, pathologic findings were
classified as pathological complete response (pCR) = no residual
invasive cells in the breast and axillary contents; pathological partial
response (pPR) = presence of < or = 10 microscopic foci of invasive
cells; no pathological response (pNR) = pathological persistence of
tumor. For each patient, pretreatment breast cancer biopsies were
prospectively analyzed by immunohistochemistry (IHC) for estrogen and
progesterone (ER/PR) hormonal receptors, HER2/neu and p53
overexpression. Estrogen receptor (ER), HER2/neu, metablastin,
beta-tubulin III and IV, microtubule-associated protein-4 (MAP-4),
bcl-2, bax, and cyclooxygenase-2 (COX-2) gene expression were measured
using real-time quantitative polymerase chain reaction (PCR). RESULTS: A
total of 36 patients had pretreatment biopsies and were evaluable for
the analysis of the association of molecular markers with pathological
response. Pathological response in the mastectomy specimen was achieved
in 12 of these 36 patients (33%). Only HER2/neu and ER gene expression
were found to be significantly associated with the extent of
pathological response to the regimen, i.e., tumors with low HER2/neu
gene expression and negative estrogen receptors were more likely to
respond to the tested regimen (p = 0.009 and p = 0.006, respectively).
Conversely, p53 protein expression measured by IHC did not appear to be
associated with pathological response (p = 0.67). CONCLUSION: Further
studies in LABC should assess whether patient selection for treatment
based on the original tumor molecular characteristics could affect their
chance to achieve a pathological response.
16
UI - 11831227
AU - Caldas C; Aparicio SA
TI -
The molecular outlook.
SO - Nature 2002 Jan 31;415(6871):484-5
17
UI - 11823860
AU - van 't Veer LJ; Dai H; van de Vijver MJ; He YD; Hart AA; Mao M; Peterse
TI -
HL; van der Kooy K; Marton MJ; Witteveen AT; Schreiber GJ; Kerkhoven RM;
Roberts C; Linsley PS; Bernards R; Friend SH
Gene expression profiling predicts clinical outcome of breast cancer.
SO - Nature 2002 Jan 31;415(6871):530-6
AD - Division of Diagnostic Oncology, The Netherlands Cancer Institute, 121
Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
Breast cancer patients with the same stage of disease can have markedly
different treatment responses and overall outcome. The strongest
predictors for metastases (for example, lymph node status and
histological grade) fail to classify accurately breast tumours according
to their clinical behaviour. Chemotherapy or hormonal therapy reduces
the risk of distant metastases by approximately one-third; however,
70-80% of patients receiving this treatment would have survived without
it. None of the signatures of breast cancer gene expression reported to
date allow for patient-tailored therapy strategies. Here we used DNA
microarray analysis on primary breast tumours of 117 young patients, and
applied supervised classification to identify a gene expression
signature strongly predictive of a short interval to distant metastases
('poor prognosis' signature) in patients without tumour cells in local
lymph nodes at diagnosis (lymph node negative). In addition, we
established a signature that identifies tumours of BRCA1 carriers. The
poor prognosis signature consists of genes regulating cell cycle,
invasion, metastasis and angiogenesis. This gene expression profile will
outperform all currently used clinical parameters in predicting disease
outcome. Our findings provide a strategy to select patients who would
benefit from adjuvant therapy.
18
UI - 11826021
AU - Kristiansen M; Langerod A; Knudsen GP; Weber BL; Borresen-Dale AL;
TI -
Orstavik KH
High frequency of skewed X inactivation in young breast cancer patients.
SO - J Med Genet 2002 Jan;39(1):30-3
AD - Institute of Medical Genetics, University of Oslo, Oslo, Norway.
INTRODUCTION: Patients with invasive ovarian cancer were recently shown
to have a higher frequency of skewed X chromosome inactivation in
peripheral blood cells compared to patients with borderline cancer and
controls. In this study, we analysed the X inactivation pattern in
peripheral blood from 216 breast cancer patients. METHODS: X
inactivation analysis was performed using HpaII predigestion of DNA
followed by PCR of the highly polymorphic CAG repeat of the androgen
receptor gene (AR), which amplifies the undigested inactive X chromosome
only. The X inactivation pattern was classified as skewed when 90% or
more of the cells preferentially used one X chromosome. RESULTS: Young
breast cancer patients (27-45 years) had a higher frequency of skewed X
inactivation than young controls (13 and 1%, respectively) (p=0.009),
whereas no difference was found for middle aged and older patients
compared to controls of a similar age. CONCLUSIONS: A germline mutation
in an X linked tumour suppressor gene may give a proliferative advantage
to cells with this mutation on the active X chromosome, thus causing
skewed X inactivation and an increased risk for developing cancer.
Another possible explanation could be that females with a
constitutionally skewed X inactivation pattern are more susceptible to
develop breast cancer because of an X linked low penetrance
susceptibility allele that is affected by the inactivation pattern.
19
UI - 11848488
AU - Hadjisavvas A; Neuhausen SL; Hoffman MD; Adamou A; Newbold RF; Kyriacou
TI -
KC; Christodoulou CG
BRCA1 germline mutations in Cypriot breast cancer patients from 26
families with family history.
SO - Anticancer Res 2001 Sep-Oct;21(5):3307-11
AD - Department of Electron Microscopy and Molecular Pathology, The Cyprus
Institute of Neurology and Genetics, Nicosia.
Germline mutations in the BRCA1 gene are causative for a variable number
of hereditary breast/ovarian cancers. The data presented in this study
are based on genetic analysis of the BRCA1 gene in 49 DNA samples from
breast cancer patients with a positive family history. A combination of
manual direct DNA sequencing and SSCP analysis was used to screen the
entire coding region of BRCA1. Overall 13 variants were detected which
included 5 missense mutations, 3 polymorphisms and 5 intronic changes.
Further genetic analysis of the 13 variants was carried out using 50
control DNA samples. Our results showed that 12 out of the 13 variants
detected in the DNA of the patients group, were also present in the
control group. It appears that the Greek Cypriot families studied so far
have an unexpectebly low frequency of deleterious mutations in the BRCA1
gene. This is the first report on BRCA1 mutation analysis in Cyprus.
20
UI - 11870509
AU - Duffy SW; Nixon RM
TI -
Estimates of the likely prophylactic effect of tamoxifen in women with
high risk BRCA1 and BRCA2 mutations.
SO - Br J Cancer 2002 Jan 21;86(2):218-21
AD - Department of Mathematics, Statistics and Epidemiology, Imperial Cancer
Research Fund, 61 Lincoln's Inn Fields, London WC2A 3PX, UK.
s.duffy@icrf.icnet.uk
The development of breast cancer control strategies in women at high
genetic risk of breast cancer is an important issue. The likely benefit
of chemopreventive approaches is of particular interest. Tamoxifen tends
to be more effective in both prevention and treatment of oestrogen
receptor positive tumours than oestrogen receptor negative. In this
study, we combine the oestrogen-receptor specific effects of tamoxifen
from randomized preventive or therapeutic trials with the oestrogen
receptor status of tumours in BRCA1 and BRCA2 mutation positive women
from published tumour surveys to obtain estimates of the likely effect
of tamoxifen administration in mutation carriers. We used a simple
two-stage procedure to estimate the benefit as a weighted average of the
effect on oestrogen receptor positive tumours and oestrogen receptor
negative, and using a more complex hierarchical modelling approach.
Using the simple procedure and deriving the estimates of benefit from
both primary prevention and therapeutic trials, we obtain an estimated
reduction in risk of breast cancer from administration of tamoxifen in
BRCA1 mutation positive women of 13% (RR=0.87, 95% CI 0.68--1.11). The
corresponding estimated reduction in BRCA2 mutation positive women was
27% (RR=0.73, 95% CI 0.59--0.90). Using the more complex models gave
essentially the same results. Using only the primary prevention trials
gave smaller estimates of benefit in BRCA1 carriers but larger estimates
in BRCA2, in both cases with wider confidence intervals. The benefit of
prophylactic use of tamoxifen in BRCA1 mutation carriers is likely to be
modest, and the effect in BRCA2 mutation carriers somewhat greater.
Copyright 2002 The Cancer Research Campaign
21
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
22
UI - 11871866
AU - Nicoletto MO; Donach M; De Nicolo A; Artioli G; Banna G; Monfardini S
TI -
BRCA-1 and BRCA-2 mutations as prognostic factors in clinical practice
and genetic counselling.
SO - Cancer Treat Rev 2001 Oct;27(5):295-304
AD - Department of Medical Oncology, Padua City Hospital, Padova, Italy.
Women in general have a 10% risk of developing breast cancer and a 2-3%
chance of ovarian cancer in their life-times. Mutations in BRCA-1 and
BRCA-2 are present in only a small portion (5-10%) of all breast
cancers. Carriers of mutations in these genes have a greater risk of
cancer, especially before menopause in the case of BRCA-1 carriers. In
addition, their risk of contralateral breast cancer is significantly
higher than for the general population (4.2-53% vs. 2%). The grade of
contralateral tumours in these patients is more aggressive. BRCA-2
hereditary breast cancer seems more heterogeneous than the BRCA-1
phenotype, and not clearly different from sporadic forms. However, since
20-30% of carriers of BRCA mutations never develop breast or ovarian
cancer, there must be other 'risk modifiers'. Survival is better for
carriers of hereditary ovarian cancer. Patients with these mutations are
referred for genetic counselling, a complex process which includes: an
informative dialogue between the proband and the geneticist, drawing up
a family history, informed consent, evaluation of risk, genetic testing
and possible involvement of healthy family members. Copyright 2001
Harcourt Publishers Ltd.
23
UI - 11815410
AU - Keshava C; Frye BL; Wolff MS; McCanlies EC; Weston A
TI -
Waf-1 (p21) and p53 polymorphisms in breast cancer.
SO - Cancer Epidemiol Biomarkers Prev 2002 Jan;11(1):127-30
AD - Toxicology and Molecular Biology Branch, Health Effects Laboratory
Division, National Institute for Occupational Safety and Health, Centers
for Disease Control and Prevention, 1095 Willowdale Road, Morgantown, WV
26505, USA.
p53 is a transcription factor for Waf-1/p21, a cyclin-dependent kinase
inhibitor. Certain polymorphic variants of Waf-1 and p53 have been
evaluated for their association with cancer risk. Previous studies
indicated that certain p53 polymorphisms confer an increased risk of
breast cancer [odds ratios (ORs) and 95% confidence intervals (CIs) =
2.9, 1.4-6.3 Carcinogenesis (Lond.), 17: 1313, 1996; 2.5, 1.3-4.8 Cancer
Epidemiol. Biomark. Prev., 6: 105, 1997; and 1.5, 1.1-2.0, Anticancer
Res., 18: 2095, 1998). The primary objectives of this study were to test
the hypotheses that the serine variant (codon 31 polymorphism) of Waf-1
is also involved in this process and that there is an interaction
between Waf-1 and p53 polymorphisms. To do this, Waf-1 and p53 genotypes
were determined for women enrolled in a breast cancer case-control study
(Caucasians, African-Americans and Latinas; 487 Waf-1 and 504 p53
genotypes were obtained). Multivariate logistic regression was used to
evaluate possible associations between Waf-1 and p53 polymorphisms,
race, and menopause. The primary aim was to determine whether an
interaction between Waf-1 and p53(1-2-1) existed. Whereas multivariate
analysis suggested associations between breast cancer and inheritance of
Waf-1(ser31) in African-Americans (OR, 2.32; 95% CI = 0.66-5.60; n = 37
cases and 65 controls) and Latinas (OR, 2.22; 95% CI = 0.71-6.89; n = 30
cases and 75 controls), and inheritance of p53(1-2-1) in Caucasians (OR,
3.15; 95% CI = 1.14-8.89; n = 93 cases and 187 controls), we did not see
an interaction between Waf-1(ser31) and p53(1-2-1). Consistent with the
finding that p53(1-2-1) is a risk factor for Caucasian women was the
observation of a strong interaction between race and p53 (P < 0.01).
24
UI - 11815404
AU - Peterson EA; Milliron KJ; Lewis KE; Goold SD; Merajver SD
TI -
Health insurance and discrimination concerns and BRCA1/2 testing in a
clinic population.
SO - Cancer Epidemiol Biomarkers Prev 2002 Jan;11(1):79-87
AD - Department of Internal Medicine, Comprehensive Cancer Center, University
of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI
48109, USA.
The discovery of the breast cancer genes BRCA1 and BRCA2 has afforded
those who seek breast and ovarian cancer risk counseling the option of
genetic testing. Concerns about cost, confidentiality, and the potential
for discrimination, however, may prevent some women from pursuing
genetic testing. To determine the impact of these concerns on BRCA
testing, we studied a cohort of 384 patients presenting de novo to a
Breast and Ovarian Cancer Risk Evaluation Program, between January 6,
1997 and March 13, 2000. Of the 184 individuals who were themselves
primary candidates for testing, 106 (58%) underwent BRCA1/2 sequencing.
Of the 78 eligible patients who declined testing, 48 cited concerns
about cost and insurance discrimination as their reason. On the basis of
the number of positive results ascertained in the tested group, we
estimate that approximately half of patients declining testing because
of insurance coverage concerns would be positive for a BRCA mutation. We
were unable to document any experiences of test result-based
discrimination, although there were other negative insurance-related
experiences. We conclude that in a high prior-risk clinic population,
approximately one-quarter of patients eligible for BRCA testing may
decline because of concerns about cost, confidentiality, and
discrimination. Our research provides evidence that these fears may be
discrepant with the actual experiences of patients in high-risk clinics.
25
UI - 11815405
AU - Bottorff JL; Ratner PA; Balneaves LG; Richardson CG; McCullum M; Hack T;
TI -
Chalmers K; Buxton J
Women's interest in genetic testing for breast cancer risk: the
influence of sociodemographics and knowledge.
SO - Cancer Epidemiol Biomarkers Prev 2002 Jan;11(1):89-95
AD - School of Nursing, Department of Health Care and Epidemiology,
University of British Columbia, T201-2211 Wesbrook Mall, Vancouver,
British Columbia, V6T 2B5 Canada. bottorff@nursing.ubc.ca
The objective of this study was to assess women's interest in genetic
testing for breast cancer risk. Randomly selected samples of 761 women
without breast cancer from the general population of British Columbia,
Canada, and 260 women with breast cancer from the provincial cancer
registry participated in a telephone survey that assessed interest in
genetic testing for breast cancer risk, knowledge of hereditary breast
cancer and genetic testing, and sociodemographics. Women with breast
cancer did not possess superior knowledge of breast cancer genetics
compared with women from the general population. Of the women with
breast cancer, 30.8% reported interest in testing or had been tested,
compared with 28.5% of women without breast cancer. Controlling for
differences in age, education, personal history of breast cancer, and
knowledge of genetics, women with at least one relative with breast
cancer were 2.3 times more likely to express interest in genetic testing
for breast cancer risk than those with no family history. There were
significant interactions between breast cancer status and education and
between age and knowledge of breast cancer genetics. Women without
breast cancer and with a positive family history, who were between 20
and 40 years of age, were most likely to be interested in testing. The
women with breast cancer who were interested in testing tended to be
approximately 50 years of age, had a positive family history, and had
more years of education. Women with a family history of breast cancer,
well-educated women with breast cancer, and younger women, particularly
those with knowledge of genetic testing, are important target audiences
for community-based education on genetic testing for breast cancer risk.
26
UI - 11815406
AU - Bonadona V; Saltel P; Desseigne F; Mignotte H; Saurin JC; Wang Q;
TI -
Sinilnikova O; Giraud S; Freyer G; Plauchu H; Puisieux A; Lasset C
Cancer patients who experienced diagnostic genetic testing for cancer
susceptibility: reactions and behavior after the disclosure of a
positive test result.
SO - Cancer Epidemiol Biomarkers Prev 2002 Jan;11(1):97-104
AD - Unit of Prevention and Genetic Epidemiology, Comprehensive Cancer Center
Leon Berard, 28 rue Laennec, 69008 Lyon, France.
The aim of this prospective study was to evaluate the consequences of
the disclosure of a positive genetic test result to patients affected
with cancer. Personal repercussions and patients' behavior with the
transmission of their results to relatives were considered. We conducted
semistructured interviews with 23 cancer patients identified as carriers
of a cancer-predisposing mutation for hereditary breast ovarian or
nonpolyposis colorectal cancers, 1 month after the disclosure of the
test result. Eight patients spontaneously expressed distressed reactions
("you no longer feel cured"), and 14 patients reported at least one
negative feeling (dissatisfied, discouraged, unhappy, or worried),
despite expecting to be a carrier. Sixteen patients expressed concerns
about the risk of developing another cancer, and 18 were concerned for
their children's future, in that they may carry the mutation and develop
a cancer. Although 8 patients found that disadvantages of knowing their
genetic status outweighed the advantages, all but 1 did not regret
having undergone genetic testing. All of the patients transmitted their
results to at least one close relative. Although 6 of them expressed
difficulties in being the only person who could transmit the information
and 9 said it was a heavy responsibility, all except 1 did not want
someone else to have to inform their families. Our results illustrate
the potential negative impact of diagnostic genetic testing in patients
with cancer. This includes distressed reactions and difficulties in
transmitting their results to relatives. Future large-scale studies are
warranted to confirm our findings.
27
UI - 11830600
AU - Finkel E
TI -
Consortium piecing together role of ATM gene in breast cancer.
SO - J Natl Cancer Inst 2002 Feb 6;94(3):158-9
28
UI - 11830610
AU - Chenevix-Trench G; Spurdle AB; Gatei M; Kelly H; Marsh A; Chen X; Donn
TI -
K; Cummings M; Nyholt D; Jenkins MA; Scott C; Pupo GM; Dork T; Bendix R;
Kirk J; Tucker K; McCredie MR; Hopper JL; Sambrook J; Mann GJ; Khanna KK
Dominant negative ATM mutations in breast cancer families.
SO - J Natl Cancer Inst 2002 Feb 6;94(3):205-15
AD - Queensland Institute of Medical Research, Brisbane, Australia.
georgiaT@qimr.edu.au
BACKGROUND: The ATM gene encoding a putative protein kinase is mutated
in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a
predisposition for cancer. Studies of A-T families suggest that female
heterozygotes have an increased risk of breast cancer compared with
noncarriers. However, neither linkage analyses nor mutation studies have
provided supporting evidence for a role of ATM in breast cancer
predisposition. Nevertheless, two recurrent ATM mutations, T7271G and
IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined
these two ATM mutations in a population-based, case-control series of
breast cancer families and multiple-case breast cancer families.
METHODS: Five hundred twenty-five or 262 case patients with breast
cancer and 381 or 68 control subjects, respectively, were genotyped for
the T7271G and IVS10-6T-->G ATM mutations, as were index patients from
76 non-BRCA1/2 multiple-case breast cancer families. Linkage and
penetrance were analyzed. ATM protein expression and kinase activity
were analyzed in lymphoblastoid cell lines from mutation carriers. All
statistical tests were two-sided. RESULTS: In case and control subjects
unselected for family history of breast cancer, one case patient had the
T7271G mutation, and none had the IVS10-6T-->G mutation. In three
multiple-case families, one of these two mutations segregated with
breast cancer. The estimated average penetrance of the mutations was 60%
(95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent
to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk
compared with that of the general population. Expression and activity
analyses of ATM in heterozygous cell lines indicated that both mutations
are dominant negative. CONCLUSION: At least two ATM mutations are
associated with a sufficiently high risk of breast cancer to be found in
multiple-case breast cancer families. Full mutation analysis of the ATM
gene in such families could help clarify the role of ATM in breast
cancer susceptibility.
29
UI - 11849780
AU - Iannuzzi CM; Atencio DP; Green S; Stock RG; Rosenstein BS
TI -
ATM mutations in female breast cancer patients predict for an increase
in radiation-induced late effects.
SO - Int J Radiat Oncol Biol Phys 2002 Mar 1;52(3):606-13
AD - Department of Radiation Oncology, Mount Sinai School of Medicine, New
York, NY 10029, USA. christopher.iannuzzi@mountsinai.org
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