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Breast cancer genetics Unsolved questions and open perspectives in an expanding clinical practice.

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American Journal of Medical Genetics Part C (Semin. Med. Genet.) 129C:56 –64 (2004)
Breast Cancer Genetics:
Unsolved Questions and Open Perspectives
in an Expanding Clinical Practice
Breast cancer is the most common cause of cancer death in the United Kingdom, with a lifetime risk of one in nine
in women. Only 5–10% of all cancers is thought to be due to strongly penetrant inherited predisposing genes,
such as BRCA1 and BRCA2. However, other less penetrant genes, including some autosomal recessive genes, are
likely to be of etiological importance in other families. This review addresses the current knowledge of breast
cancer susceptibility genes and explores the possibilities for future developments. Features of tumor pathology,
prognosis, and the scope for targeted treatments in mutation carriers are discussed, and the management of
known carriers and those at increased risk for developing breast cancer are evaluated. Genetic testing for cancer
susceptibility may become widely available in the future, and has important ethical and management
implications. ß 2004 Wiley-Liss, Inc.
KEY WORDS: BRCA1; BRCA2; breast cancer
Breast cancer is the most common
cause of cancer death in the United
Kingdom (lifetime risk one in nine in
women) [National Statistics Cancer
Registrations in England, 2000]
(, with increasing
prevalence. A recognized risk factor for
breast cancer is a birth date later than
1930. Population studies of immigrants
find that they acquire the level of cancer
risk of the host countries. Hormonal
influences associated with estrogen
exposure (e.g., age at menarche, contraceptive pill usage, pregnancies) are
important in determining breast cancer
risk [Colditz, 1998], and dietary (e.g.,
saturated fat intake) and other environmental factors may also play a part
[Bingham et al., 2003]. Their identification should be a priority to develop
strategies for disease prevention. Familial
clustering of breast cancer has been well
documented, with relative risks increasing as the age at diagnosis is younger or
the family history more extensive. Overall, however, only 5–10% of all breast
cancers are thought to be due to strongly
penetrant inherited predisposing mutations in genes such as BRCA1 and
BRCA2 [Claus et al., 1991; Pharoah
Professor Shirley Hodgson is Professor of Cancer Genetics at St. George’s Hospital, London.
She has been working in the field of cancer genetics since 1988, and has helped to develop cancer
genetics clinical services in several UK clinics (notably Guy’s and St. Mark’s Hospitals in London).
She has also been involved in translational research into the inherited aspects of cancer,
particularly colorectal and breast cancer. She was instrumental in initiating the British Familial
Cancer Record, a database for follow-up of familial cancer families in several cancer genetics clinic
in the UK; these have now become the clinical cancer genetics network of Cancer-Research-UK
funded clinics. She is the co-author of several books on inherited cancer.
Professor Patrick Morrison is a consultant clinical geneticist with a special interest in cancer
genetics, in the Northern Ireland Regional Genetics Service, Belfast. He has published over 120 peerreviewed articles on all aspects of genetics, particularly late onset diseases, familial cancers, and
insurance issues. He is currently co-writing a genetics textbook for surgeons and has co-authored
(with Prof. Neva Haites and Prof. Shirley Hodgson) a book on familial breast and ovarian cancer.
Dr. Melita Irving is a specialist registrar in clinical genetics, currently training at St. George’s
Hospital, London.
*Correspondence to: Shirley V. Hodgson, Professor of Cancer Genetics, Department of Clinical
Development Sciences, St. George’s Hospital Medical School, Cranmer Terrace, London, UK
SW19 0RE. E-mail:
DOI 10.1002/ajmg.c.30019
ß 2004 Wiley-Liss, Inc.
et al., 2002; Antoniou et al., 2003]. The
majority of multicase families with both
breast and ovarian cancers are due to
inherited BRCA1 mutations, whereas
those in families that include male breast
cancer cases are more often due to
BRCA2 mutations. However, in many
families with four or five cases of breast
cancer, without the above features, the
cancers are not due to mutations in these
genes. A hypothetical ‘‘BRCA3’’ gene
has been invoked as a cause for these
cancers. Multiple, lower-penetrance,
Multiple, lower-penetrance,
higher-frequency genes
(including some autosomal
recessive genes), are likely
to make a significant
contribution to this
unexplained familial risk.
higher-frequency genes (including some
autosomal recessive genes), are likely to
make a significant contribution to this
unexplained familial risk [Dong and
Hemminki, 2001; Chenevix-Trench
et al., 2002].
BRCA1 is located on chromosome
17q [Miki et al., 1994] and has 22 exons,
encoding 1,863 amino acids; BRCA2
[Wooster et al., 1995], lies on chromosome 13q and codes for a protein of
3,418 amino acids. Deleterious mutations are found throughout both genes
and tend to be truncating. Polymorphisms of unclear significance are also
found; improved methods of determining their pathogenicity include the use
of RT-PCR and analysis of gene transcripts [Couch and Weber, 1996;
Dunning et al., 1997; Claes et al.,
2003]. Three common founder mutations are present in some populations,
notably the Ashkenazi Jewish (ancestral)
mutations in BRCA1 [Shattuck-Eidens
et al., 1997] and BRCA2 [Abeliovich
et al., 1997], which overall occur in up to
2% of the Ashkenazi population, and the
Icelandic common mutation in BRCA2
[Thorlacius et al., 1996]. In these
populations, specific assays are used to
detect these mutations. A common
BRCA1 mutation, 2800delAA, is found
mainly in Northern Ireland and the West
of Scotland, showing the similar origins
of populations from these areas, whereas
the BRCA2 6503delTT mutation is
found on the East coast of Scotland,
suggesting that this may have been
introduced by Viking raiders or Scandinavian fisherman [Scottish/Northern
Irish BRCA1/BRCA2 Consortium,
2003]. Larger genomic deletions/duplications occur more often in BRCA1
than in BRCA2, and some are founder
mutations; these require specific detection methods, since they would not
normally be detected by sequencing.
Mutations in BRCA1 and BRCA2 have
a prevalence of 0.11% in the general UK
population and account for approximately 60% of cases of familial breast
cancer [Peto et al., 1999].
Both genes encode proteins
involved in double-strand DNA repair,
specifically in homologous recombination, a highly specific method of errorfree DNA repair. BRCA1 is also
involved in apoptosis and cell-cycle
control, and the effects of its deficiency
are cell-cycle dependent [Welcsh et al.,
2000]. BRCA1 has a RING-finger
domain that is likely to be involved in
protein interactions that could target
proteins for degradation. Both BRCA1
and BRCA2 contain BRCT repeats and
both interact with RAD51—this interaction being along most of the BRCA2
protein, but along only 5% of BRCA1
[Pellegrini et al., 2002; Shamoo, 2003].
Binding to RAD51 allows BRCA2 to
reach sites of DNA breaks.
BRCA1 is phosphorylated in
response to DNA damage in an ATMdependent manner, and relocates to
chromosomal regions of DNA replication. In cells with deficient BRCA1 and
BRCA2 proteins, DNA repair proceeds
by the more error-prone alternative
repair pathways of nonhomologous
end-joining. Transcriptional regulation
may also be a function of BRCA1/2 by
interaction with RNA Pol II and RNA
helicase A [Welcsh et al., 2000]. Both
proteins are normally nuclear and their
mRNAs are preferentially expressed during late G1–early S phase of the cellcycle. Punctate foci of BRCA1, BRCA2,
and RAD51 may be detected in the
nucleus in S phase, and in meiotic cells
they associate with unsynapsed regions
of synaptonemal complexes. BRCA1
may regulate the G2-M checkpoint by
controlling mitotic spindle assembly and
thus chromosome segregation. Mice
with homozygously deleted exon 11 of
BRCA1 demonstrate chromosomal
instability with aneuploidy and chromosome rearrangements. BRCA2 mutants
are also deficient in spindle assembly
checkpoints [Tutt and Ashworth, 2002;
Venkitaraman, 2002; Anand et al., 2003].
None of the functions of BRCA1/2
appear to be specific to the breast tissue.
The reason for the tissue specificity in
cancer susceptibility is unclear, although
the obvious involvement of estrogen
target organs makes it likely that the
secondary effects of gene mutation are
enhanced by a tissue environment
responsive to estrogens.
The search for a third high-penetrance gene, ‘‘BRCA3,’’ has been disap-
pointing to date. Researchers have
utilized a variety of approaches, including linkage analysis, sib-pair analysis, and
a combination of linkage and tumor
expression profiling, to identify families
with the same genetic phenotype
[Lathrop et al., 1984; Hedenfalk et al.,
2003]. Linkage data indicated a susceptibility locus on 13q21, but this was
discounted by further studies in other
populations [Kainu et al., 2000;
Thompson et al., 2002], and a similar
fate was met by other promising regions,
e.g., 8p and 6q [Seitz et al., 1997]. These
results tended to rule out single genes
with large effects playing a major role as
‘‘BRCA3.’’ Recent segregation analysis
in familial breast and ovarian cancer to
find the best-fitting model showed that
the majority of familial cases could be
accounted for by BRCA1 or BRCA2
mutations, with a polygenic cause for
the remaining cases. No evidence for a
putative high-risk susceptibility gene,
‘‘BRCA3,’’ was found, although there
was a case to be made for a possible
contribution from recessive alleles
[Antoniou et al., 2002]. Epidemiological
analysis suggests that if BRCA1 and
BRCA2 mutation carriers are excluded,
approximately 12% of women have a
roughly 10% risk of developing breast
cancer by the age of 70, accounting for
50% of all cases of breast cancer, whereas
about 50% of cases develop in women
who have a much smaller risk of breast
cancer (&3%) [Pharoah et al., 2002].
Peto [Peto and Mack, 2000; Peto, 2002]
has argued that since women who have
developed breast cancer have a constant
annual risk of 1.7% of developing a
second breast cancer, it can be postulated
that all women with breast cancer have
an inherited susceptibility to the disease,
likely to be due to several genes of
moderate effect.
The challenge is to identify such lower
penetrance genes. CHEK2 represents an
example of a moderate effect gene. A
common CHEK2 mutation (1100delC)
occurs in approximately 1% of the
general population [Meijers-Heijboer
et al., 2002], and in 3–6% of women
with breast cancer. This mutation was
detected in 12% of unselected bilateral
breast cancer cases and 13.5% of families
with a male breast cancer case, and may
therefore confer a 2- and 10-fold increased risk of breast cancer in females
and males, respectively. Other variations
in CHEK2 do not seem to make a major
contribution to breast cancer susceptibility [Schutte et al., 2003].
Epidemiological studies have previously shown an increased risk of breast
cancer in close relatives of ataxia telangiectasia (AT) patients, and there is some
evidence that certain missense mutations
in ATM, the AT gene, occur with
increased frequency in breast cancer
families. Examples of such ATM mutations are: L1420F, whose frequency was
found to be 4.8% in 13 familial breast
cancer families versus 0% in controls; and
IVS10-6T > G and 7271G > T, which
may segregate with the disease
[Stankovic et al., 1998; ChenevixTrench et al., 2002; Thorstenson et al.,
2003]. Such mutations are thought to
exert a dominant-negative effect
[Bishop and Hopper, 1997; Gatti et al.,
1999; Angele et al., 2000]. It is unclear
whether other ATM mutations confer
any increase in risk [Izatt et al., 1999].
Intriguingly, both ATM and CHEK2
interact in the BRCA1/2 DNA repair
pathway. ATM is involved in phosphorylation of BRCA1 in response to
radiation-induced DNA damage, and
the FANC-D LL protein causes ubiquitination of BRCA1 on DNA damage by
cross-linking agents. One of the genes
that causes the autosomal recessive
condition Fanconi anemia, FANC-D2,
has now been shown to be BRCA2
[D’Andrea and Grompe, 2003; Venkitaraman, 2003]. A germline Polish
founder mutation in the NBS1 gene
(657del15), which causes the Nijmegen
breakage syndrome, an AT-like condition, has been shown to occur with
increased frequency in breast cancer
cases, particularly in familial cases
[Gorski et al., 2003].
Clearly, many other lower penetrance genes are also likely to be
involved, and will be difficult to identify,
because they are unlikely to segregate
with breast cancer in conventional
linkage studies.
There are distinct features of
breast cancer tumor pathology
in BRCA1 mutation carriers
that are characteristic: notably,
a high mitotic count,
continuous pushing margins,
and lymphocytic infiltrates.
Three genetic conditions conferring
a high risk of breast cancer are well
described. Mutations in TP53, which
encodes a cell cycle regulatory protein,
cause Li-Fraumeni syndrome, characterized by early onset breast cancer in association with other childhood cancers, in
particular sarcomas and brain tumors [Li,
1990; Vogelstein and Kinzler, 1992]. LiFraumeni p53 mutations are highly
penetrant for early onset breast cancer but
are a rare cause overall. Inherited mutations in PTEN cause Cowden syndrome
[Li et al., 1997; Marsh et al., 1999], which
is associated with an increased susceptibility to breast cancer. However, so far,
this gene has not been involved in
nonsyndromic breast cancer [Freihoff
et al., 1999; Shugart et al., 1999].
Peutz-Jeghers syndrome, which is due
to LKB1 mutations, is another rare cause
of breast cancer in the general population
[Boardman et al., 1998].
Common polymorphisms such as
V1508M in the COMT gene, the
CYP1A1 1462V variant, the short
repeat sequence of the androgen receptor gene, and the transforming growth
factor b1 gene (TGFb) (C-509T) are
among those that have been calculated
from large case–control studies to confer
small, altered, relative risks of breast
cancer [Rebbeck et al., 1999; Kuschel
et al., 2002], but confirmation requires
further studies in large cohorts of cases
and controls. Variants in ATM, CHEK2,
and RAD51, hormone receptors, cellcycle regulators, genes regulating nonhomologous end-joining, carcinogen
metabolizing genes, and other factors,
are also potential modifiers of breast
cancer risk, although the evidence for
such effects is still being accumulated.
Polymorphisms in the second BRCA
allele may play a part [Fu et al., 2003], and
there is also good evidence for the
influence of modifier gene variants on
BRCA1/2 gene penetrance [Easton et al.,
1995; Struewing et al., 1997; Fodor et al.,
1998; Narod, 2002; Hartge, 2003].
There are distinct features of breast
cancer tumor pathology in BRCA1
mutation carriers that are characteristic:
notably, a high mitotic count, continuous pushing margins, and lymphocytic
infiltrates. In addition, most BRCA1associated tumors are hormone receptor
(ER and PgR) negative. In contrast,
BRCA2-associated tumors resemble
sporadic cancers in steroid receptor expression, but the histology tends to show
poor tubule formation and continuous
pushing margins without the other
features of BRCA1 tumors. BRCA2
tumors show a higher frequency of p53
mutations and expression than sporadic
cancers [Lakhani et al., 2002].
A basaloid ductal carcinoma phenotype may be more common in
BRCA1 carrier tumors, with increased
expression of basal cell keratins [Sorlie
et al., 2001]; these cancers may be
derived from stem cells that are CK5/
6-positive and confer a poor prognosis
[Foulkes et al., 2003].
Intriguingly, studies of gene expression profiles and comparative genomic
hybridization (CGH) using cDNA
microarrays in breast cancers from familial cases without germline BRCA1 or
BRCA2 mutations show a multiplicity
of different profiles, rather than a single
‘‘BRCA3’’ profile, further supporting
the probability that the remainder of
cases of familial breast cancer are due
to several lower penetrance genes
rather than a single ‘‘BRCA3’’ gene
[Wessels et al., 2002; Hedenfalk et al.,
2003]. BRCA1 and BRCA2 mutationassociated cancers, on the other hand,
have very distinct and characteristic
profiles. CGH on cDNA arrays and
metaphase spreads in tumors from familial breast cancer cases may indicate the
location of new breast cancer tumor
suppressor genes [Hedenfalk et al., 2003;
Ramus et al., 2003] and also show
characteristic patterns of loss of heterozygosity in BRCA1 and BRCA2 carriers
that can identify carriers with a very high
accuracy (96%). Such arrays, and the use
of gene expression profiles, may also be
able to detect the ‘‘signatures’’ of goodand poor-prognosis breast cancers [Ma
et al., 2003].
Genetic Counseling
and Risk Estimation
A number of models have been derived for the evaluation of risk. The Gail
risk evaluation model [Benichou et al.,
1996] uses a number of factors, such as
age at menarche, family history, and
parity. The Claus model based on the
Cancer and Steroid Hormone study
derives risk [Claus et al., 1991] using a
model of highly penetrant susceptibility
genes. Pedigree factors that indicate the
Pedigree factors that indicate
the presence of a mutation in a
susceptibility gene include
multiple early onset (age <50
years) breast cancers in the
family, breast and ovarian
cancer in one relative, male
breast cancer, and Ashkenazi
Jewish ancestry.
presence of a mutation in a susceptibility
gene include multiple early onset (age
<50 years) breast cancers in the family,
breast and ovarian cancer in one relative,
male breast cancer, and Ashkenazi
Jewish ancestry [Lange et al., 1988;
de la Hoya et al., 2003]. A molecular
diagnosis makes predictive testing available to at-risk relatives.
The estimated lifetime risk of breast
cancer in BRCA1 and BRCA2 mutation carriers is similar for breast cancer
(approximately 65%–80%), although
the average age at diagnosis is slightly
higher in BRCA2 carriers, and ovarian
cancer risk is higher in BRCA1 (39%)
than in BRCA2 (11%) mutation carriers.
Estimates vary depending upon the
mode of ascertainment [Antoniou et al.,
2003]. The original Linkage Consortium data were obtained from multicase
families, which may be enriched for high
penetrance mutations [Ford et al., 1994],
whereas population-based studies tend
to give lower penetrance estimates.
Different mutations in BRCA1 and
BRCA2 are associated with different
degrees of risk of ovarian cancer, and
there are increased relative risks of other
cancers, particularly prostate, pancreatic,
and colorectal in BRCA2 carriers
[Easton et al., 1995; Struewing et al.,
1997; Fodor et al., 1998; Ford et al.,
1998; Gayther et al., 2000; Risch et al.,
2001; Gruber and Petersen, 2002;
Thompson and Easton, 2002].
Surveillance in women at moderate
risk must be evaluated on a long-term
basis. From 30–50% of women on
surveillance diagnose their own cancers,
and many are missed by mammography.
However, there is evidence that cancers
detected by mammography are detected
earlier and have a better prognosis than
those detected symptomatically. Recent
trials of magnetic resonance imaging
(MRI) suggest it is much more sensitive
(100% for MRI vs. 44% for mammography) and more specific in detecting
breast cancer, particularly in young
women, because of their denser breast
tissue [Kuhl et al., 2000; Lee et al., 2003].
MRI is clearly preferable in BRCA
carriers, but expensive, and its usefulness
in those at moderate risk is as yet not
established. Nipple aspiration and ductal
ultrasound methods are undergoing
trials in high-risk women, but may not
be acceptable for screening for breast
cancer in those at moderate risk. The use
of proteomic pattern analysis in ductal
lavage washings or nipple fluid aspirates,
or in serum, is a new and promising
diagnostic technique for identifying
breast cancer early [Petricoin et al.,
The question as to whether noncancerous cells of BRCA1 and BRCA2
carriers are more susceptible to Xirradiation and cross-linking agents is
still unresolved, but has importance in
terms of treatment for cancer in heterozygotes and screening by frequent
mammography. The evidence so far is
that radiosensitivity in BRCA1/2 mutation carriers is not clinically different
from noncarriers, although an increased
cellular sensitivity to radiation has been
documented in lymphocytes and fibroblasts heterozygous for a BRCA1/2
mutation [Foray et al., 1999; Pierce
et al., 2000; Savelyeva et al., 2001;
Buchholz et al., 2002].
Since BRCA1/2-deficient cells
repair DNA by error-prone mechanisms
such as nonhomologous end-joining,
there is an opportunity to explore
therapeutic measures using inhibitors
of DNA end-joining [Venkitaraman,
2003]. Breast cancers in mutation carriers (especially BRCA2) may be more
sensitive to DNA cross-linking drugs
such as mitomycin C. Better understanding of tumor protein expression
provides the opportunity to target drug
therapy. Herceptin is a monoclonal
antibody, directed against the HER-2
receptor, a tyrosine kinase member of
the epidermal growth factor receptor
family of tyrosine kinases. HER-2 is
overexpressed in 20–30% of high-grade
invasive breast cancers. The evidence for
characteristic HER-2 expression in
BRCA1 and BRCA2-associated tumors
is conflicting. Lakhani et al. [2002]
showed that expression in BRCA1associated tumors is significantly lower
than in controls (3% vs. 15%). HER-2
expression in BRCA2 associated tumors
was also 3% [Johannsson et al., 1997].
However, other studies have not confirmed this finding [Robson et al., 1998;
Armes et al., 1999].
Preventative Measures
Tamoxifen and newer anti-estrogens,
e.g., raloxifene, are being evaluated for
prevention of breast cancer in women at
increased risk. Initial results with tamoxifen were disappointing; it did halve
the risk of breast cancer, but also
increased the risk of adverse cardiovascular events and endometrial cancer
[Narod et al., 2000; Cuzick et al.,
2003], and the overall mortality was
not reduced in the tamoxifen arm.
Further studies are proceeding to address
this, and to evaluate newer prophylactic
drugs, such as the aromatase inhibitors,
which reduce estrogen levels, e.g.,
There is good evidence that
oophorectomy halves the risk of
breast cancer, both in the general
population and in BRCA1/2
mutation carriers.
There is good evidence that
oophorectomy halves the risk of breast
cancer, both in the general population
and in BRCA1/2 mutation carriers
[Kauff et al., 2002; Rebbeck, 2002;
Meijers-Heijboer et al., 2003], and is a
prophylactic option. Prophylactic mastectomy reduces the risk of breast cancer
by over 90% [Eisen and Weber, 2001;
Narod, 2001; Offit et al., 2001; Rebbeck
et al., 2002; Meijers-Heijboer et al.,
2003; Taucher et al., 2003];
however, there is likely to be variable
amounts of residual breast tissue left
in situ. There are also psychological
issues to be addressed regarding surgery
[Sakorafas, 2003], and uptake of prophylactic mastectomy varies with cultural and religious background [Evans
et al., 1999].
Management of Mutation Carriers
The five-year and 10-year risk of
contralateral breast cancer after a first
primary tumor, in BRCA1 and BRCA2
mutation carriers, is 16.9% and 29.9%,
respectively; oophorectomy reduces
these risks (Hazard Ratio (HR) 0.44)
[Narod et al., 2000]. After lumpectomy,
the risk of ipsilateral recurrence must
also be considered. BRCA2 mutation
carriers have a slightly lower risk (HR
0.73), and tamoxifen reduces the recurrence risk (HR 0.59). Prophylactic contralateral mastectomy at surgery for a first
primary breast cancer should therefore
be considered. In a significant proportion of prophylactic mastectomies in
BRCA1/2 carriers reported, early
malignant change has been found in
the breast specimen [Scott et al., 2003].
Breast cancer prognosis in BRCA1/
2 mutation carriers appears to be worse
than in sporadic cases, although there is
conflicting evidence [Foulkes et al.,
2000; Lakhani et al., 2000; StoppaLyonnet et al., 2000; Moller et al.,
2002; Goffin et al., 2003].
Service delivery involves the
recognition of familial breast
cancer families at the primary
care level, and triage of referrals
into low, moderate, or high risk
categories, possibly by trained
nurses and counselors in family
history clinics. High risk
families should be referred to
genetics clinics.
program. Audit of screening outcomes is
essential, especially for those at moderate
risk, who will be more numerous and
diffusely sited than those at high risk.
There is a need to provide education about cancer genetics to nongenetics health professionals, to enhance
their participation in service delivery,
since many express uncertainty about
issues surrounding genetic management.
The establishment of clear national
guidelines is needed [Freedman et al.,
Experience with genetic testing for
breast cancer susceptibility over the last
decade has allowed ethical principles to
be formulated, including the concepts of
genetic solidarity and altruism, and
respect for persons. Most testing centers
will now have proper consenting procedures in place, with counseling and full
information. Insurance and employment discrimination is less of a problem
than previously, with better education
of health and insurance professionals.
Government policies around the world
are slowly changing to avoid discrimination. The UK (where health service is
generally free, and not insurer-based, as
in the US) has introduced a moratorium
on genetic testing and insurance that
allows up to £500,000 worth of insurance coverage to be obtained for
purpose of mortgage (house insurance
coverage) and £300,000 in cases of
health insurance. This applies to approved tests, so far only testing for Huntington disease, although BRCA1 and
BRCA2 testing is under consideration
by the genetics and insurance committee
(GAIC) [Morrison, 2001].
Service delivery involves the recognition
of familial breast cancer families at the
primary care level, and triage of referrals
into low, moderate, or high risk categories, possibly by trained nurses and
counselors in family history clinics. High
risk families should be referred to
genetics clinics. Low risk individuals
can be reassured and released from
follow-up, and those at moderate risk
may be enrolled into an agreed screening
The rapid development of proteomic
and cDNA microarray techniques has
opened up a new dimension of diagnostic potential. CGH, proteomic, and
gene expression studies on breast and
other cancers in affected women, taken
in the context of histopathological data,
will help identify their genetic background, and will in turn help identify
lower-penetrance genes that cause
inherited susceptibility. Such techniques
may also be performed on fine-needle
aspiration biopsy and needle biopsy
specimens of breast tumors [Symmans
et al., 2003].
More efficient, cheaper, and faster
mutation detection techniques will
enlarge the proportion of families for
which genetic tests will be available, and
speed up the process. Better methods of
determining the pathogenicity of novel
variants will be vital, particularly if
screening for variants in a number of
candidate genes is to be performed in the
future as a ‘‘risk estimation’’ package
[Comings et al., 2003]. However, if
consideration is to be given to the
development of such a ‘‘multigene test’’
for breast cancer susceptibility, there are
many very serious issues that would need
to be considered prior to its implementation, including counseling, pre- and
post-test system administration, and
avoidance of testing of nonconsenting
individuals. There seems to be little
point in offering such tests unless
effective prophylactic measures can be
offered to individuals at increased risk.
Undue anxiety may otherwise be
induced. Careful audit of management
is also clearly needed. Insurance and
employment issues need to be carefully
evaluated and funding needs to be in
place for testing, counseling, and for any
resultant surveillance programs, with
appropriate audit. Over-the-counter
genetic tests may be developed in the
future, similar to pregnancy or cholesterol tests, and in the UK, recent guidelines have been issued for such ‘‘high
utility’’ tests, stipulating that a qualified
professional must be involved in consenting and giving results to patients.
Tests for highly penetrant genes
should not be sold over the counter
[Human Genetics Commission, 2004]
( Clearly, these are
extremely important issues and it is
essential that the accuracy of risk interpretation from the test results is assessed
before test implementation, with continued long-term evaluation.
We thank Teresa Mielniczek and
Adrienne Knight for their secretarial
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