Genes other than BRCA1 and BRCA2 involved in breast
M M de Jong, I M Nolte, G J te Meerman, W T A van der Graaf, J C Oosterwijk,
J H Kleibeuker, M Schaapveld, E G E de Vries
J Med Genet 2002;39:225–242
This review focuses on genes other than the high
penetrance genes BRCA1 and BRCA2 that are involved
in breast cancer susceptibility. The goal of this review is
the discovery of polymorphisms that are either
associated with breast cancer or that are in strong
linkage disequilibrium with breast cancer causing
variants. An association with breast cancer at a 5%
significance level was found for 13 polymorphisms in
10 genes described in more than one breast cancer
study. Our data will help focus on the further analysis of
genetic polymorphisms in populations of appropriate
size, and especially on the combinations of such
polymorphisms. This will facilitate determination of
population attributable risks, understanding of
gene-gene interactions, and improving estimates of
genetic cancer risks.
factors play a role with family history being the
most important factor for determining breast
cancer risk. This risk is a function of the number
of relatives affected with breast and ovarian can-
cer, the degree of relationship to these relatives,
and their age at diagnosis of the disease.2 3
Hereditary breast cancer accounts for 5-9% of
all breast cancers.4It was estimated that the com-
bination of BRCA1 and BRCA2 gene mutations
was responsible for approximately 80% of the
families with hereditary breast cancer.5 6These
estimates, however, may be too high owing to the
way patients are selected, namely on the basis of
a pronounced family history of the disease. More
recent estimates put this risk at about 30%.7
Mutations of the BRCA1 and BRCA2 genes do not
explain the occurrence of breast cancer in every
breast cancer prone family.8At least one other
major breast cancer susceptibility gene is pro-
posed to exist.9 10In addition, a number of rare
genetic syndromes are associated with high
breast cancer risk. Together, these rare syndromes
account for less than 1% of all hereditary breast
Apart from these well defined,high penetrance
genes,there may be other genes that also increase
the susceptibility to breast cancer. Candidates are
proto-oncogenes and genes involved in metabolic,
oestrogen, and immunomodulatory pathways.12
Each of these genes probably confers only a small
reast cancer is the most common cancer in
women in the western world.1In breast can-
cer development,genetic and environmental
(odds ratio (OR) 1-1.5) to moderate (OR 1.5-2)
increase in the lifetime breast cancer risk.
Because mutations in these so-called low pen-
etrance genes are expected to be present in a large
(PAR) for breast cancer explained by these genes
(in combination with environmental exposures)
may be substantial13and (potentially) consider-
ably higher than the PAR caused by rare
mutations of high penetrance genes such as
BRCA1 and BRCA2.14 15The published polymor-
phisms (a locus where two or more alleles are
each present at a frequency >1% in the popula-
tion) were, in general, studied because of their
biological plausibility.16–21Some polymorphisms
may partly account for the difference in the sen-
sitivity of women to environmental factors, such
as the use of replacement oestrogens.20In subjects
mental factors might especially affect the risk of
developing breast cancer. One subject may be
10-200 times more sensitive than another22and
may therefore develop cancer, while others at the
same level of exposure will not. With the identifi-
cation of important low penetrance gene muta-
tions along with their interaction with environ-
mental factors, specific prevention may become
possible. Research on low penetrance genes
involved in breast cancer is still in its infancy.
Whole genome screens for determining low pen-
etrance genes are currently not yet financially
This review focuses on genes other than BRCA1
and BRCA2 that may be involved in breast cancer
susceptibility. Although mutations or polymor-
phisms in many of the genes described can also
play a role in other types of common cancer, such
as colorectal, ovarian, or prostate cancer, this
review addresses only breast cancer. The aim of
the pooled analysis was to find polymorphisms
that may either have a causative relation to breast
cancer or that are in strong linkage disequilib-
rium (LD) with breast cancer causing variants
(for example, situations where certain haplotype
combinations of alleles at different loci occur
more frequently than would be expected from
random association).We studied only the relation
of the polymorphisms to breast cancer risk, since
we assumed that environmental factors will play
Abbreviations: OR, odds ratio; CI, confidence interval;
PAR, population attributable risk; LD linkage
disequilibrium; LOH, loss of heterozygosity; RR, relative
See end of article for
Dr E G E de Vries,
Department of Medical
Hanzeplein 1, PO Box
30.001 RB, Groningen,
an equal role in all studies. The external variables taken into
account were,where possible,menopausal state and ethnicity.
Pooled analyses were performed on all polymorphisms. In
addition, the sample size required to detect an association
with breast cancer susceptibility with sufficient power was
Search of published studies
Published studies were identified using the PubMed databases
from 1980 to 2000, using the search terms “breast”, “cancer”,
“risk”, and “polymorphism(s)”. For each specific candidate
gene,a separate search was performed.For example,the terms
“HRAS1”, “breast”, “cancer”, and “risk” were used for HRAS1.
In addition, the references of studies identified by the
pooled analysis were those that compared genotype or allele
frequencies of candidate genes in breast cancer cases with
non-breast cancer controls using genomic DNA. The polymor-
phisms reported in breast cancer patients and controls in more
than one study are described separately. When more than one
polymorphism in one gene (for example,CYP1A1) or polymor-
phisms in different genes in the same region (for example,the
HLA region) were examined in only one single study, they are
also included.The different genes along with their localisation
and presumed function are presented in table 1.
Lay out per gene
For the known genetic syndromes associated with increased
breast cancer susceptibility, the possible germline mutations
followed by somatic mutations, loss of heterozygosity (LOH,
the loss of one of the two alleles at a given locus in a tumour),
and hypermethylation. According to Knudson’s “two hit
theory”,23the two hits required for tumour development are
generally thought of as an intragenic mutation (germline or
somatic) and LOH. Recently, it has been shown that
hypermethylation of the promoter region of a gene can also be
one of the hits required in cancer development24 25because this
can silence the gene.26
For a better insight into the possible effects of the various
genes on breast cancer susceptibility, a pooled analysis for
each polymorphism was performed. The results of this analy-
sis are shown in table 2. The raw numbers of cases and
controls from comparable studies were analysed together. The
genotype specific ORs and the 95% confidence intervals (CIs)
were calculated for all studies combined, without adjustment
for external variables.This can result in values that differ from
those in the original article. Whenever possible, a distinction
was made between women heterozygous and homozygous for
the variant allele. Where metabolic polymorphisms are
assumed to be associated with a specific phenotype, a distinc-
tion was made between phenotype and genotype based stud-
ies (for example,CYP2D6,NAT2).For the genotype studies,the
genotypes were combined according to phenotypic classes.
Also,where possible,separate analyses were performed for the
three major ethnic subgroups, white, African-American, and
The ORs and the 95% CIs of the studies used in the pooled
analysis of polymorphisms in three genes are shown in figs 1
(the HRAS1 polymorphism), 2 (the PROGINS polymorphism
of the PR gene), and 3 (the polymorphisms in the vitamin D
receptor (VDR) gene).
Breast cancer susceptibility genes with their localisation and presumed function
Gene Location and function
17q21, DNA RP*, guardian of genome integrity292 293
13q12-13, DNA RP, guardian of genome integrity294 295
17p13.1, DNA RP, protection against replication of damaged DNA296–298
11q22-23, DNA RP, sensor in cellular response to DNA double strand breaks299 300
10q23.3, TSG†, suppresses cell cycle progression and induction of apoptosis301
19p13.3, serine/threonine kinase, otherwise unknown function
11p15, proto-oncogene, control of cell growth and differentiation302
8p22, MP‡, detoxification of arylamines17 139 303 304
8p22, MP, detoxification of arylamines17 139 303 304
1p13.3, MP, detoxification of a wide range of xenobiotics, including environmental carcinogens, chemotherapeutic
agents, and reactive oxygen species305–307
11q13, MP, detoxification of numerous chemicals including chemotherapy agents and catechol oestrogens170 179 308
11q, MP, detoxification of a wide range of xenobiotics, including environmental carcinogens, chemotherapeutic agents,
and reactive oxygen species17 305 307
15q, MP, EP§, metabolism of oestrogens and PAHs17 185 309
2p21, MP, metabolism of PAHs194 310
22q11-ter, MP, metabolism of many commonly prescribed drugs, including debrisoquine and codeine17 311
10q24.3, EP, balance of oestrogens, progesterones, and androgens114 212
11q21.1, EP, catalysing the conversion of androgens into oestrogens, determines the local oestrogen level312–314
6q25.1, EP, binding and transfer of oestrogens to the nuclei, ER modulates transcription of a number of growth factors
22q11.2, EP, conjugation and inactivation of catechol oestrogens319–322
2q37, MP, EP, phase II drugs metabolism and maintain intracellular steady state levels of oestrogen323–325
6p21, IP¶, central mediator in the inflammatory response and immunological activities to tumour cells265–267
6p21, molecular chaperones, regulation of structure, subcellular localisation, and turnover of cell proteins271 326
12q, cell differentiation328–330
5q22, inhibits the progression of cells from G1 to S phase, apoptosis, cell-cell interactions331
19q13.2, lipid metabolism332
10q24.3-ter, MP, metabolism of acetone, ethyl glycol, and ethanol17 333
17q12-21, EP, catalyses the reaction between oestrone and oestradiol334 335
17q21, proto-oncogene, control of cell growth and proliferation336 337
9q33-34, cell growth338
*DNA RP: DNA repair pathway. †TSG: tumour suppressor gene. ‡MP: metabolic pathway. §EP: oestrogen pathway. ¶IP: immuno pathway. **IMP: iron
226 De Jong, Nolte, te Meerman, et al
genotypes with their ORs and 95% confidence intervals, PAR, and sample size required to detect an association
Genetic polymorphisms and their allele frequencies, total number of cases and controls published, risk
frequencyCases* Controls*Risk G†OR 95% CIPARSample size‡
Intron 30.17 6671981W§/V¶
Exon 40.36552 22192200
Intron 60.17733 2160 1500
0.24 646 7965% 9100
1 410 000
0.491324 1076 117 000
0.151371 1241 W/V
m2 0.11 7911468 8000
5 940 000
Codon 1190.14 339 361W/V
Codon 432 0.66745747 2700
Codon 4530.14223 223 31 000
CYP170.40 27252531 82 000
TCT intron 4
Intron 60.48 223 1643300
Codon 2640.30 160 1254600
PvuII0.54704 53 W/V
XbaI 0.29191 204 1200
Codon 325 0.21646 32427 000
PR 0.14 1106965 2400
COMT 0.441166116718 000
UGT1A1 0.34 655808 110 000
TNF-alpha 0.2140 106 W/V
HSP70-2 0.45 40 10685%11
0.2340 106 23%84
0.47135 110 W/V
BmsI 0.35 23146712%1900
FokI0.41 278410 3%41 000
TaqI0.571197 867 61 000
Poly-A0.27 143 300 42%310
260332 2 800 000
*Cases and controls: all studies combined. †Risk G: risk genotype. ‡Sample size: the number of patients and controls required to detect an association, with power of 90% and a significance level of
0.0026 (correction for mutiple testing). §W: wild type. ¶V: variant allele.
Other genes in breast cancer 227
The pooled analysis also shows the PAR and sample size
required to detect the association with breast cancer for each
polymorphism,with a power of 90% and a significance level of
0.0026 corrected for multiple testing (also shown in table 2).
A description of the sample size calculation is given in Appen-
The unknown “BRCA3” gene
Based on several studies, a region on chromosome 8p11-21 is
considered to be involved in hereditary and sporadic breast
cancer.Linkage analysis in eight French breast cancer families
showed a multipoint lod of 2.51 (a lod score >3.0 is the
accepted statistical significance level for linkage of a genetic
locus with a disease) with two markers on chromosome 8p.27
Linkage analysis in two large German breast cancer families,
with negative lod scores for the BRCA1 and BRCA2 locus,
showed a multipoint lod score of 3.30 at two other markers,
localised between the two markers in the French study, on
chromosome 8p.28In studies focusing on chromosome 8p,LOH
the pooled analysis comprising 2029 cases and 3252 controls.
The HRAS1 polymorphism and breast cancer risk. The results of 12 studies (OR and 95% CI) are depicted as well as the result of
OR and 95% CI
14 Rare allele carriers, Total
13 Rare allele carriers131
12 Rare allele carriers130
11 Rare allele carriers129
10 Rare allele carriers128
9 Rare allele carriers127
8 Rare allele carriers126
7 Rare allele carriers125
6 Rare allele carriers124
5 Rare allele carriers123
4 Rare allele carriers122
3 Rare allele carriers121
2 Rare allele carriers120
Rare allele carriers119
studies (OR and 95% CI) are depicted and the results for
heterozygosity or homozygosity of the variant allele are given
separately and in a pooled analysis, comprising 1106 cases and
The PR gene and breast cancer risk. The results of four
aW: wild type.
bV: variant allele.
OR and 95% CI
101 0.01 0.1
11 V carrier, Total
10 V/V, Total
9 W/V, Total
results of five studies (OR and 95% CI) are depicted in the graph
and the data for five polymorphisms are given separately, with the
distinction between heterozygosity and homozygosity for the variant
allele. For BsmI the total is 231 cases and 467 controls, for FokI 278
cases and 410 controls, and for TaqI 1197 cases and 867 controls.
aW: wild type.
The vitamin D receptor gene and breast cancer risk. The
bV: variant allele.
OR and 95% CI
24 Poly-A, V/V282
23 Poly-A, W/V282
22 TaqI, V/V Total
21 TaqI, W/V Total
20 TaqI, V/V279
19 TaqI, W/V279
18 TaqI, V/V247
17 TaqI, W/V247
16 TaqI, V/V280
15 TaqI, W/V280
14 FokI, V/V Total
13 FokI, W/V Total
12 FokI, V/V282
11 FokI, W/V282
10 FokI, V/V280
8BsmI, V/V Total
7 BsmI, W/V Total
6 BsmI, V/V282
4 BsmI, V/V281
3 BsmI, W/V281
2 ApaI, V/V280
Polymorphism and risk
228De Jong, Nolte, te Meerman, et al
was observed in 46-74% of unselected human breast
tumours in women with a specific BRCA2 mutations (that is,
the 999del5 mutation),36and in 83% of male breast tumours.37
In ductal breast carcinoma in situ,LOH on 8p was observed in
0-37% of cases,30 38 39suggesting LOH on 8p is associated with
invasive behaviour of the tumour.Based on these LOH studies,
there are at least two different regions of minimal overlap of
LOH on chromosome 8p. The region on 8p discussed
earlier27 28is localised in one of these regions.Mapped genes in
this region include hEXT1L,34WRN,40and LHRH.41 42No somatic
or germline mutations have, as yet, been detected in these
genes in breast cancer cases.
29–36in 86% of the familial tumours,32in 78% of
Rare genetic syndromes with increased breast cancer
The Tp53 gene and Li-Fraumeni syndrome
Inactivating mutations in the Tp53 gene have been found in
many tumour types43 44including breast cancer.45Li-Fraumeni
syndrome is an autosomal dominant disorder, caused by
germline mutations in the Tp53 gene. This syndrome is char-
acterised by an increased risk of soft tissue and osteosarco-
mas, leukaemias, brain tumours, adrenocortical carcinomas,
and breast cancers.46The risk of developing breast cancer
before the age of 45 is 18-fold higher for affected females as
compared to the general population.46The excess is greatest
below the age of 20 and declines with increasing age (relative
risk (RR) for breast cancer after the age of 45 = 1.8).46Germ-
line mutations in the Tp53 gene have been estimated to
account for less than 1% of breast cancer cases.47–51However,
somatic mutations in the Tp53 gene are reported in 19-57% of
human breast cancers52–57and LOH is found in 30-42%.52 54
There is no association between somatic Tp53 mutations and
LOH at the Tp53 locus,52–55suggesting that one inactivated
allele may be sufficient for breast cancer development.54
Hypermethylation of the promoter region of the Tp53 gene
does not play a role in breast cancers.58
Three different Tp53 polymorphisms (in intron 3, exon 4,
and intron 6) have been studied in breast cancer patients. All
three polymorphisms exhibit strong linkage disequilibrium
with each other.59In five studies examining the intron 3 poly-
morphism, none found an association with increased breast
cancer risk.60–64Surprisingly, the breast cancer risk for
homozygous carriers of the variant allele was decreased.
When all studies were combined, the OR for heterozygous
carriers of the variant allele was 0.97 (95% CI 0.79-1.18) and
was 0.46 (95% CI 0.25-0.84) for homozygous carriers. The
exon 461–65and the intron 661–64 66 67polymorphisms showed
similar results. Thus, a decreased breast cancer risk for homo-
zygous variant allele carriers was found for all three polymor-
phisms in the Tp53 gene.These homozygous variant allele car-
riers comprise 3% (intron 3), 13% (exon 4), and 3% (intron 6)
of all the women and, thus, up to 13% of women have
decreased breast cancer risks.
Four studies61–64examined all three polymorphisms in the
Tp53 gene in relation to breast cancer risk. In one of the two
studies examining haplotypes, an association was observed
between the haplotype composed of the three variant alleles
and the risk of breast cancer among white populations
(OR=2.18,95% CI 1.17-4.07).62This association was not found
in Hispanic (OR=0.24,95% CI 0.05-1.11) or African-American
patients (OR=1.13, 95% CI 0.46-2.81)62nor in patients from
Pakistan (OR=0.77, 95% CI 0.38-1.56).64The two other
studies61 63did not construct haplotypes, but compared
genotype combinations. The first study found a marginally
significant association between breast cancer and the geno-
type combination that is heterozygous for all three polymor-
phisms (OR=1.68, 95% CI 0.99-2.86).63This genotype combi-
nation did not exclude the haplotype composed of three
variant alleles from being at risk. The second study found
associations between breast cancer and two genotype
(OR=2.94, 95% CI 1.37-6.27), heterozygous for the intron 3
and 6 polymorphisms and homozygous for the exon 4 variant
allele, the haplotype of three variant alleles is still supported.
With the second genotype combination (OR=1.61, 95% CI
1.13-2.30), homozygous for the intron 3 and 6 wild type allele
and heterozygous for the exon 4 polymorphism, the variant
allele haplotype is not possible. The fact that the four studies
used different methods to examine the polymorphisms ham-
pers the comparison of results. However, the analysis showed
that the haplotype composed of the three variant alleles is
associated with an increased breast cancer risk,particularly in
white breast cancer patients.
The ATM gene and ataxia telangiectasia
Most A-T patients do not survive to an age at which breast
cancer generally occurs.68A-T carriers (heterozygous for ATM
mutations) are sensitive to late onset apoptosis after x ray
irradiation owing to accumulation of cell cycle checkpoint
abnormalities.69In several studies, A-T carriers appear to have
an increased breast cancer risk (OR 3.3-870–76and PAR
3.8-8.5%68 73–75).However,in all studies the OR was determined
One study found no increased breast cancer risk among A-T
carriers.77The risk of A-T carriers to develop breast cancer is
estimated to be 11% by the age of 50 and 30% by the age of
Germline mutations in the ATM gene are rare in breast can-
cer families without features of A-T.79 80In sporadic breast
cancers, germline and somatic mutations in the ATM gene are
also rare,81 82even in young patients83 84and patients with
bilateral breast cancer.85In 88 breast cancer patients with a
family history of breast cancer and leukaemia or lymphoma,
three germline mutations in the ATM gene have been found.79
Chen et al80examined these three mutations and none
appeared to be causal. In 82 Dutch breast cancer patients
(diagnosed before the age of 45, >5 years survival) including
33 bilateral cases, seven germline mutations were found, one
out of frame splice site mutation (detected three times), three
truncating mutations, and one in frame deletion.86It was
hypothesised that the existence of two distinct classes of A-T
mutations (truncating and missense) might explain some of
the seemingly contradictory data on cancer risk associated
with the ATM gene.87 88The truncating mutations act as null
mutations because they produce low cellular levels of an
unstable ATM protein. Because truncating mutation carriers
have 50% of wild type ATM activity, they will have an almost
normal phenotype. Some missense mutations encode stable,
but functionally abnormal proteins that are present at normal
intracellular levels. These proteins could compete in complex
formation with the normal ATM protein, resulting in a domi-
nant negative cellular phenotype. The functional loss in ATM
missense mutation carriers might be more severe than in ATM
truncating mutation carriers and, thus, only ATM missense
mutations might be associated with an increased cancer
risk.88In most studies, A-T carrier detection in breast cancer
cases was based on the protein truncation test and could only
detect truncating mutations. Support for the existence of two
functionally distinct classes of mutations can be derived from
a study describing an increased breast cancer risk in two A-T
families with a specific ATM missense mutation (T7271G) in
both homozygotes and heterozygotes, with an age specific
incidence rate based OR of 12.7 (95% CI=3.53-45.9).89This
mutation results in an aberrant full length ATM protein level
comparable with unaffected subjects.89Another explanation
for the seemingly contradictory data on breast cancer risk is
that the carrier frequency of A-T mutations could be much
lower than the described 1% of the general population causing
a low PAR. If this is the case, the OR for breast cancer in A-T
Other genes in breast cancer 229
carriers can be high (as found in the A-T families), while
mutations in the ATM gene are rarely detected in sporadic
breast cancer patients.
A recent study of 138 Austrian hereditary breast and ovar-
ian cancer (HBOC) patients without BRCA1 and BRCA2
mutations90showed functionally significant ATM germline
mutations in at least 8.7% of the HBOC patients. The
penetrance for one of the mutations (L1420F) was estimated
to be 85% at age 60.
In conclusion, although the exact association remains
unclear, a role for the ATM gene in breast cancer susceptibility
The PTEN gene and Cowden syndrome
Cowden syndrome is an autosomal dominant disorder,
characterised by the development of hamartomas and benign
tumours. Mutations in the PTEN gene are present in 80% of
Cowden syndrome families.91 92Truncating PTEN mutations in
Cowden syndrome families are associated with cancer93and
cause a 25-50% lifetime breast cancer risk in women.92 94 95No
mutations in the PTEN gene have been detected in breast can-
cer families and families with breast and brain cancer without
features of Cowden syndrome.96–99In sporadic breast cancer
patients, germline and somatic mutations in the PTEN gene
are rare100–104even in young patients.96 105LOH at the PTEN locus
is found in 11-41% of sporadic breast cancers,102–104 106but no
somatic mutations have been observed in the remaining
allele.103 104 106It is, however, still possible that an epigenetic
phenomenon such as hypermethylation of the promoter
region inactivates the remaining allele.107In one study (in 177
breast cancer patients with a positive family history for breast
cancer and without BRCA1 and BRCA2 mutations), an associ-
ation was found between a polymorphism in intron 4 of the
PTEN gene and a lower age of diagnosis of breast cancer (42.7
versus 48.1 years).98No comparison, however, was made with
healthy controls. In conclusion, the PTEN gene is not likely to
play a role in classical hereditary breast cancer. In sporadic
breast cancers,LOH at the PTEN locus is detected,but since no
alterations have been found in the remaining allele, it is not
currently known whether PTEN plays a role in sporadic breast
The LKB1 gene and Peutz-Jeghers syndrome
Peutz-Jeghers syndrome is an autosomal dominant disorder
characterised by hamartomatous polyps in the small bowel
and pigmented macules of the buccal mucosa, lips, fingers,
and toes.108This syndrome is caused by truncating germline
mutations in the LKB1 gene.109 110Patients with Peutz-Jeghers
syndrome have an increased breast cancer risk.108 111No germ-
line mutations were detected in 22 patients from 14 breast
cancer families with LOH on chromosome 19p.112In 62
primary breast cancers in women without Peutz-Jeghers syn-
drome, no somatic mutations were found in the LKB1 gene
and LOH was observed in only 8%.113In conclusion, the LKB1
gene seems to play a role in breast cancer susceptibility, but
only in patients with Peutz-Jeghers syndrome.
Low penetrant breast cancer susceptibility genes
There are several classes of potential low penetrance breast
cancer susceptibility genes, such as proto-oncogenes, meta-
bolic pathway genes, oestrogen pathway genes, and immu-
nomodulatory pathway genes.
Proto-oncogenes are involved in the regulation of normal cell
growth and differentiation. Mutations in proto-oncogenes
lead to disturbances in the cell cycle and can result in abnor-
mal growth or proliferation.114Well known proto-oncogenes
are the RAS genes, the HER2 gene, and the myc genes.
The HRAS1 gene encompasses four exons flanked by a variable
tandem region repeat at the 3′ end.115 116This minisatellite
locus is composed of four common alleles (94% of the white
population117) and dozens of variants,the so-called intermedi-
ate and rare alleles. Each variant allele is derived from the
common allele nearest in size to it.118The HRAS1 polymor-
phism was examined in 13 studies.119–131Positive ORs were
detected in all studies (fig 1), five of which reached
significance119 124 128 129 131with ORs of 2-7. Combining the stud-
ies showed an association between rare HRAS1 alleles and
breast cancer (OR=2.03, 95% CI 1.72-2.40), with a PAR of
14%. There are, however, several methodological problems in
performing this pooled analysis,since the choice of the cut off
point between rare, intermediate, and common alleles is diffi-
cult to make and the distribution of the alleles in subgroups of
the population varies between studies.132The choice of rare
alleles (frequency <4%) is not the same for all studies and
interpretation.132In most studies there are four common alle-
les and the rest of the alleles are listed as rare.With this as the
criterion, our pooled analysis indicated that the rare HRAS1
alleles are associated with a moderately increased risk of
Three studies focused on L-myc and breast cancer risk.133–135In
one study, no controls were examined.134Another study found
an association with breast cancer135for women heterozygous
(OR=2.25, 95% CI 1.12-4.51) and homozygous (OR=2.63,
95% CI 1.22-5.68) for the variant allele.When all three studies
were combined for our pooled analysis, no association with
breast cancer was found.
Metabolic pathway genes
Enzymes involved in metabolic pathways are of interest
because of their possible role in (de)toxification of chemical
compounds.136A number of metabolic pathway genes, includ-
ing the cytochrome p450 family, the GST family, and the NAT1
and NAT2 genes, are thought to have evolved as an adaptive
response to environmental exposure to toxins,including some
carcinogens. The prediction is therefore that any alteration in
the activity of these enzymes would result in an altered
susceptibility to potentially toxic (mutagenic) compounds.
This may determine the rate at which somatic mutations occur
in genes in response to environmental exposures, resulting in
an altered cancer susceptibility. The cytochrome p450 family
proteins are known as phase I enzymes. In general, these
enzymes metabolically activate carcinogens.137A genotype
associated with an increased phase I enzyme activity might
therefore increase breast cancer risk.138The NAT and GST fam-
ily proteins are known as phase II enzymes. These enzymes
metabolically inactivate carcinogens. The substrates for phase
II enzymes include carcinogenic compounds activated by the
phase I enzymes. A genotype associated with decreased phase
II activity might therefore increase breast cancer risk.138
N-acetyl transferase (NAT)
Both NAT1 and NAT2 are polymorphic with so-called fast and
slow phenotypes. Slow acetylators produce proteins that are
either poorly expressed,are unstable,or have partially reduced
catalytic activities.139In theory, having the slow acetylator
phenotype could mean that aromatic amines are metabolised
more slowly and that slow acetylators might, therefore, be at
increased breast cancer risk.114
The NAT1*10 allele is associated with the rapid acetylation
phenotype; all other alleles represent slow alleles.139–141This
allele is present in 30% of populations of European
230De Jong, Nolte, te Meerman, et al
ancestry.142Two studies found no association with breast can-
cer risk either separately or combined.143 144The NAT1 polymor-
phism does not appear to play a major role in breast cancer
susceptibility, although a small increase in breast cancer risk
cannot be excluded.
The acetylation capacity in NAT2*4 homozygotes in vivo is
higher than in NAT2*4 heterozygotes and all variant alleles
have lower acetylation capacities.145The population frequency
of the fast acetylator genotype of the NAT2 gene is
22-78%.145–147None of seven studies found an increased breast
cancer risk for the slow acetylator NAT2 phenotype,148–154while
two studies found a decreased breast cancer risk.148 153No
association with breast cancer risk was found when all studies
were combined. The results for the NAT2 genotype were simi-
lar. No effect on breast cancer risk was found when the stud-
ies were combined in our pooled analysis.143 155–159In conclu-
sion, the NAT2 polymorphism does not play a role in breast
Combination of NAT1 and NAT2
One study examined both polymorphisms.143No association
between these polymorphisms and breast cancer was ob-
served for either the NAT1 or NAT2 genes separately or
Glutathione S-transferase (GST) family
Deletion variants that are associated with a lack of enzyme
function exist at GSTM1 and GSTT1.160Homozygotes for null
deletions in the GSTM1 and/or GSTT1 genes may have an
impaired ability to eliminate carcinogens metabolically and
may therefore be at increased cancer risk.
GSTM1 is polymorphically expressed as GSTM1-0 or null
(homozygous deletion) and GSTM1a and GSTM1b.160Between
20 and 60% of the general population are homozygous null for
the GSTM1 gene.161–164The GSTM1 null variant has been well
examined in breast cancer studies with varying results.165–178
Our pooled analysis showed an association between this poly-
morphism and breast cancer risk, although this increase is
very small and only marginally significant (OR=1.13, 95% CI
1.00-1.26). The combined sample size is large enough to
exclude a moderate increase in breast cancer risk for GSTM1
null homozygous carriers.
In 31% (24/77) of the breast cancer cases,hypermethylation of
the GSTP1 promoter region was detected.179A polymorphism,
the isoleucine to valine substitution at codon 105, has been
associated with reduced conjugating activity of the gene.180
This polymorphism has
studies.170 176 181Our pooled analysis showed a moderately
increased breast cancer risk for women homozygous for the
the GSTP1 polymorphism appears to play a role in breast can-
cer susceptibility,although the total number of cases (n=301)
and controls (n=397) was small.
beenexamined in three
The GSTT1 gene has two functionally different genotypes,
GSTT1-0 or null (homozygous deletion) and GSTT1+ (one or
two undeleted alleles).160The GSTT1 null genotype has been
linked toincreased DNA
carcinogens.182In different populations, 9-64% are homo-
zygous null for the GSTT1 gene.164 182–184Six studies examining
this polymorphism showed no association with breast
cancer.169 170 172 175–177The results were similar for premenopausal
and postmenopausal women. Based on the combined sample
damage from experimental
size,a moderate increase in breast cancer risk can be excluded
for women homozygous null for the GSTT1 polymorphism.
Combination of GSTM1, GSTT1, and GSTP1 polymorphisms
Six studies169 170 172 175–177examined both GSTM1 and GSTT1 poly-
morphisms and breast cancer risk and four of them170 172 176 177
also analysed the GSTP1 polymorphism. In one study, no con-
trols were examined and it was therefore not included in our
Of the five studies that examined the combination of two of
the GST genes, one found an association between the two risk
genotype and breast cancer for all three combinations of GST
genes.170Another detected an association between the two risk
genotype for the GSTM1 and GSTT1 gene and breast cancer.177
Pooled analysis showed an increased breast cancer risk for the
one and the two risk genotype of all three gene combinations,
although only the two risk genotype of the GSTM1 and GSTP1
combination reached significance (OR=1.65, 95% CI 1.00-
For the two studies where all three polymorphisms were
examined, the results were similar.170 176The study that
observed associations with the two risk genotypes also
showed an association between the three high risk alleles and
breast cancer.170When both studies were combined, increased
breast cancer risks were observed for carriers of the one, two,
or three risk genotype, although only the two risk genotype
reached significance (OR=1.90, 95% CI 1.13-3.22).
Cytochrome p450 family
Certain substrates, including almost all carcinogens, are
metabolically activated by cytochrome p450 metabolism,
which results in the formation of mutagenic, chemically reac-
tive electrophiles.Most prescribed drugs are substrates for one
or more cytochrome p450 isoenzymes.17Individual cyto-
chrome p450 isoenzymes have a unique substrate specificity,
between the enzymesis
This gene codes for aryl hydrocarbon hydroxylase (AHH).114
AHH is strongly inducible; differences in xenobiotic metabolic
activity between subjects even within a family can be over
200-fold.185Changes in AHH activity, resulting in different
oestrogen levels, could affect breast cancer risk.16 114Four poly-
morphisms have been described in the CYP1A1 gene, namely
the m1 polymorphism, the m2 polymorphism (associated
with increased enzyme activity in vitro, both for homozygotes
and heterozygotes for the variant allele186 187),the m3 polymor-
phism (only present in African-Americans), and the m4 poly-
morphism. The m1 and m2 polymorphisms are in linkage
disequilibrium,17whereas the African-American specific poly-
morphism (m3) does not cosegregate.17Five studies examined
the m1 polymorphism with varying results.169 188–191Combining
all studies of white populations169 188 189 191showed an associ-
ation between heterozygous carriers of the variant allele and
an increased breast cancer risk (OR=1.33, 95% CI 1.06-1.66).
Two of the studies also examined African-Americans.169 191No
association with breast cancer was observed, but the total
number of cases (n=84) and controls (n=177) was small and
a (moderately) increased risk cannot be excluded. No overall
association was detected in a Chinese study.190An increased
breast cancer risk was found for postmenopausal women
homozygous for the m1 variant allele (OR=2.97, 95% CI 1.14-
7.76), but the number of subjects was small (78 cases and 81
controls). When all studies, regardless of ethnicity, were com-
bined, no association was found between breast cancer and
the m1 polymorphism.
No association with breast cancer risk was found in eight
studies examining the m2 polymorphism16 167 169 189–192regard-
less of whether they were analysed separately or were
Other genes in breast cancer 231
combined.However,by combining the two studies which ana-
lysed postmenopausal women only,167 190an association with
breast cancer was found for both heterozygous carriers of the
m2 variant allele (OR=1.59, 95% CI 1.07-2.37) and women
homozygous for the variant allele, although the latter associ-
ation is not significant (OR=2.53, 95% CI 0.92-6.96). This is
probably because of lack of power. The African-American spe-
cific m3 variant allele does not seem to play a role in breast
cancer susceptibility.169 191No association with breast cancer
was observed in the one study169that examined the m4 poly-
In conclusion, a small increased breast cancer risk was
found in the white population for the m1 polymorphism and
a moderately increased breast cancer risk in postmenopausal
women was detected for the m2 polymorphism. A moderate
increase in breast cancer risk for variant allele carriers cannot
be excluded for all four polymorphisms owing to lack of
power. Additional data are required to define the precise
association between this gene and breast cancer, particularly
in the white population and in postmenopausal women.
The CYP1B1 enzyme exceeds other p450 enzymes in both oes-
trogen hydroxylation activity and expression in breast
tissue.193Four polymorphisms have been described in this gene
and all variants have higher hydroxylation activity.193These
variant alleles may be associated with changes in oestrogen
metabolism and therefore breast cancer risk. Three of these
polymorphisms were examined in breast cancer patients and
controls.The codon 432 polymorphism was examined in three
studies.194–196Large differences in variant allele frequencies
were found between different populations with the variant
allele frequency ranging from 0.15 to 0.68, with even large
differences between two Asian studies.195 196When all studies
were combined, our pooled analysis found no association
between the codon 432 polymorphism and breast cancer. The
study examining the codon 119 polymorphism detected an
association with an increased breast cancer risk in women
heterozygous for the variant allele (OR=1.62, 95% CI 1.15-
2.29).195However,in women homozygous for the variant allele,
a non-significant decrease in risk was found (OR=0.6,95% CI
0.11-3.31).No association with breast cancer was observed for
the codon 453 polymorphism.194
One study examined both the codon 119 and codon 432
polymorphisms.195The two polymorphisms were genetically
independent and no association with an increased breast can-
cer risk was found for any combination of them.
The CYP2D6 variant allele is the result of a deletion of a 17.5 kb
region including the entire CYP2D6 gene.197In white popula-
tions, 5% are homozygous for this polymorphism.17 198These
poor metabolisers are unable to metabolise agents such as
debrisoquine and codeine.17Seven studies, with varying
phenotypically136 199 200and four genotypically.197 201–203When the
phenotype studies were combined, a moderately increased
breast cancer risk was found for poor metabolisers (OR=2.22,
95% CI 1.39-3.55) with a PAR of 8%.When the genotype stud-
ies were combined, an association was detected for carriers
(homozygous and heterozygous combined) of the variant
allele (OR=1.49, 95% CI 1.26-1.77), with a PAR of 6%. In con-
clusion,this polymorphism may play a role in increased breast
Oestrogen pathway genes
Experimental, clinical, and epidemiological studies show that
oestrogen and progesterone play a major role in growth and
differentiation of normal breast tissue.114 204A prolonged or
increased exposure to oestrogen is associated with increased
breast cancer risk.205 206Endogenous and exogenous hormones
stimulate cell proliferation, and thus enhance the chance of
accumulating random genetic errors. The most widely
accepted risk factors for breast cancer such as age at
menarche, age at first pregnancy, number of pregnancies,
breast feeding, age at menopause, and obesity,1 12 207can be
considered measures of the cumulative dose of oestrogen that
breast epithelium is exposed to over time.205 208Several oestro-
gen metabolites can directly or indirectly cause oxidative DNA
damage.209 210In conclusion, genes involved in the metabolism
of sex hormones (that is, oestrogens) are interesting
candidates for breast cancer susceptibility genes.207 211
Cytochrome p450 family
A polymorphism in the CYP17 gene was detected in the 5′
untranslated region. The variant allele of this polymorphism
has an additional SpI type promoter site. Since it is thought
that the number of 5′ promoter elements correlates with pro-
moter activity,114women with this allele might have higher
oestradiol levels.212An association between the presence of at
least one variant allele and an increased serum oestrogen and
progesterone level at day 11 and day 22 of the menstrual cycle
is found in young, nulliparous women.213One male breast
cancer study (64 cases and 58 controls) observed an increased
risk for variant allele carriers (OR=2.10, 95% CI 1.04-4.27).214
Ten studies on female breast cancer examined this.18 214–221One
found an association (OR= 1.99, 1.15-3.45) between variant
allele carriers (homozygous and heterozygous) and breast
cancer in young women (<37 years of age),222but the number
of cases (n=109) and controls (n=117) were small. Six other
studies in premenopausal women214 216 218 219 221 223showed no
association between this polymorphism and breast cancer.
When all studies were combined in our pooled analysis, no
association with breast cancer was found.In conclusion,based
on the combined sample size, even a small increase in breast
cancer risk overall can be excluded. However, because the
studies did not further discriminate for age, an increased risk
for breast cancer in young women carrying the variant allele
cannot be excluded.
Several polymorphisms have been described in the CYP19
gene. A tetranucleotide repeat polymorphism, (TTTA)n, is
located in intron 4, about 80 nucleotides downstream from
exon 4.224Our pooled analysis of the five studies examining the
(TTTA)10 allele polymorphism225–229showed an OR of 1.59
(95% CI 1.01-2.48), with a PAR of 1%. There is, however, a
problem in performing a pooled analysis on this polymor-
phism,because the studies use different methods to detect the
alleles. Two studies found eight different alleles while the
three others found seven, six, and five respectively. Two other
polymorphisms in intron 4 and 6 described in one study were
in strong linkage disequilibrium with the tetranucleotide
polymorphism.229No association with breast cancer was
detected for either polymorphism. Another polymorphism
(codon 264) also showed no association with breast cancer.230
In conclusion, this gene might play a (minor) role in breast
Oestrogen receptor (ER) gene
ER is a critical determinant of cellular responsiveness to oes-
trogen and is thought to play an important role in breast can-
cer promotion.114Germline and somatic mutations in the ER
gene in breast cancer cases are rare.231Five somatic mutations
in the ER gene have been found in only four out of 300 human
breast tumours.232–234Methylation of the promoter region of the
ER gene was detected in 25% of ER negative breast cancers,
while no methylation was found in ER positive tumours and
normal breast specimens.235Several polymorphisms in the ER
232De Jong, Nolte, te Meerman, et al
gene have been described.The PvuII polymorphism in intron 1
wasexaminedinthreestudies,233 236 237oneofwhichdidnotuse
controls.233The two other studies found no association with
breast cancer, although the genotypes of cases (and not of
controls) were only given in one.237When the three studies
were combined, with control genotypes from one study,236no
association was found. The total number of controls (n=53),
however, is very small. The XbaI polymorphism237showed a
decreased breast cancer risk (OR=0.50, 95% CI 0.25-0.99) for
homozygous carriers of the variant allele (10.5 kb allele). In
this study, both the number of cases (n=191) and controls
(n=204) was small. A third polymorphism, in codon 325, is
located in the hormone binding domain and might therefore
be correlated with the ER function.234This was examined in
three studies,233 234 238including one study without controls.233
No association with breast cancer was found when the three
studies were combined.
Surprisingly, only five relatively small studies examined
polymorphisms in the ER gene. Owing to the small sample
sizes, an association with breast cancer risk can neither be
confirmed nor excluded.
Progesteron receptor (PR) gene
Methylation of the CpG islands in the 5′ region of the PR gene
was found in 40% of PR negative breast cancers cases (6/15)
and not found in 15 PR positive tumours or normal breast
specimens.235A polymorphism in intron 7 of the PR gene has
been described. The variant PROGINS allele consists of a 306
bp insertion of the Alu subfamily.239Four studies studied this
polymorphism in relation to breast cancer risk.240–243Although
the studies observed different ORs for heterozygous carriers,
the ORs for women homozygous for the PROGINS allele were
similar,ranging from 0.27-0.63 (fig 2).Pooled analysis of these
studies showed that the OR for women homozygous for the
variant allele was 0.32 (95% CI 0.16-0.65). Thus, instead of an
increased risk, four studies separately and combined found a
decreased breast cancer risk for homozygous carriers of the
Androgen receptor (AR) gene
A mutation in the AR gene was detected in three male breast
cancer patients with (partial) androgen resistance, two
brothers244and one sporadic patient.245An increased risk of
breast cancer was found in women with BRCA1 mutations
(165 women with breast cancer,139 without) if they inherited
at least one AR allele with >27 CAG repeats.246Two other stud-
ies in sporadic breast cancer patients found no association
between the number of CAG repeats and breast cancer risk (in
total, 876 cases and 810 controls).247 248This polymorphism
therefore does not appear to play a major role in breast cancer
A polymorphism was identified in the COMT gene at codon
158249;the normal allele was designated COMT-H and the vari-
ant allele COMT-L. The variant allele encodes a thermolabile
form of the enzyme with reduced activity. Four studies exam-
ined this polymorphism.19 219 250 251No increased breast cancer
risk (overall, for premenopausal or for postmenopausal
women) was found when all studies were combined.
Uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) gene
A TA repeat polymorphism has been reported in the promoter
region of the UGT1A1 gene. Increasing the number of repeats
in this polymorphism leads to a decrease in enzyme
activity.252 253The wild type allele (UGT1A1*1) contains six TA
repeats and the most common variant allele (UGT1A1*28)
seven. Two other variant alleles (UGT1A1*33, five repeats and
UGT1A1*34,eight repeats) have been found almost exclusively
in the African-American population.252 254Among premeno-
pausal women, an association was found in an African-
American population.253An increased breast cancer risk
(OR=1.8, 95% CI 1.0-3.1) was detected for heterozygous and
homozygous carriers of the variant alleles with a decreased
enzyme activity (UGT1A1*28 and UGT1A1*34). In a white
population in another study, no association was found.254No
association between breast cancer risk and the UGT1A1*28
allele was detected when the studies were combined.
The principal function of the highly polymorphic HLA
antigens is to bind peptide fragments, so that they can be
optimally presented to cytotoxic T lymphocytes and natural
killer cells.255The HLA antigens play a major role in immunity,
self-recognition, and cell and tissue differentiation. Several
studies observed no association with breast cancer.256–259Other
studies have indicated that different HLA antigens may either
be risk factors for or protective against breast cancer.260–263No
strong associations with specific alleles were found and (some
of) the results were contradictory. In one study, a family was
examined in which more than 40% of the members of two
generations had cancer (mostly breast, endometrial, and
gastrointestinal).264Positive lod scores to markers within or
near the HLA region were found. None of the lod scores, how-
ever, reached significance.264In conclusion, several reports
have indicated that different HLA alleles may be risk factors
for or protective factors against cancer. No clear associations
with specific alleles have been detected.
Tumour necrosis factor ? (TNF?) gene
The TNFα gene is a central mediator in the inflammatory
response and immunological activities towards tumour
cells.265–267One polymorphism in the TNFα gene occurs in a
series of repeating conserved motifs and is not randomly dis-
tributed. It therefore most likely has some functional and
selective effect.268The rare TNF2 allele of this polymorphism
lies on the extended haplotype A1-B8-DR3-DQ2,266which is
production.269 270A comparison of the data268suggests that
there may be a small effect of the −308 polymorphism, with
the TNF2 allele being associated with slightly higher levels of
TNFα production. An association between TNF2 allele carriers
(heterozygous and homozygous) and breast cancer risk was
shown in one study which included 40 breast cancer patients
and 106 controls (OR=3.53, 95% CI 1.65-7.54).267
Heat shock protein 70 (HSP70) gene
In the HLA region, three intronless genes encoding members
of HSP70 are located centromerically to the TNF genes. The
genes have been identified as HSP70-1, HSP70-2, and HSP70-
hom.271HSP70 is a determining factor in immunological
mechanisms against tumour cells267and HSPs can serve as a
target for anti-tumour immune recognition by antibodies and
T cells.272 273Conversely, HSP70 expression on tumour cells is
can protect tumour cells against host immunological
reactions.267Whether HSP70 acts as an anti-tumour immune
response enhancer or as a tumour promoter may depend on
HSP70 genotypes.267One study showed that the variant allele
carriership of the HSP70-hom gene was associated with breast
cancer (OR=3.56, 95% CI 1.26-10.01), whereas carriership of
the HSP70-2 gene was not (OR=2.36, 95% CI 0.75-7.33).267
Experimental, clinical, and epidemiological investigations
have shown that iron can influence carcinogenesis.274In-
creased body iron stores have been associated with cancer risk.
A number of genes are involved in iron metabolism, including
the haemochromatosis gene (HFE) and the transferrin recep-
tor (TFR) gene.
Other genes in breast cancer233
The HFE gene and hereditary haemochromatosis (HH)
So far, two point mutations (Cys282Tyr and His63Asp) have
been detected in the HFE gene of HH patients. Over 80% of
Cys282Tyr mutation.275Heterozygous carriers, comprising 15%
of the American population, have, on average, increased iron
stores as compared to non-carriers.276 277In a study of 1950 HH
heterozygotes and 1656 controls, no increased breast cancer
risk was detected (OR=0.98, 95% CI 0.81-1.19).277In another
study with 165 cases and 294 controls, no association was
found between breast cancer and the HFE and TFR genotypes
when the genotypes were tested both separately and
together.278In conclusion, the HFE and TFR genes do not play
a major role in breast cancer susceptibility.
Vitamin D receptor (VDR) gene
Five polymorphisms of the VDR gene have been studied in
breast cancer patients and controls. Four of these, the TaqI,
ApaI,BsmI,and the poly-A polymorphism,are located in the 3′
region of the gene and are in linkage disequilibrium with each
other. One polymorphism, FokI, is located in the 5′ region of
the gene and is not in linkage disequilibrium with the other
polymorphisms. The TaqI polymorphism, associated with
increased serum vitamin D3 levels,279was examined in three
studies.247 279 280No association with breast cancer was found in
our pooled analysis (fig 3). The BsmI polymorphism was
investigated in two studies and, when they were combined,
again no association with breast cancer was found (fig
3).281 282The two other polymorphisms in the 3′ region of the
gene, the ApaI and the poly-A polymorphism, were each
addressed in one small study. For both polymorphisms, an
increased breast cancer risk was found for carriers (hetero-
zygous and homozygous) of the variant allele (ApaI,OR=1.56,
95% CI 1.09-2.24280; poly-A, OR=1.73, 95% CI 1.16-2.59282; fig
3). Pooled analysis of the two studies on the FokI
polymorphism280 282detected no association with breast cancer
(fig 3). In one study, haplotypes of the ApaI (variant allele a)
and the TaqI (variant allele T) polymorphisms were tested.
Women with the genotype aaTT (homozygous for the
haplotype of both variant alleles) had an increased breast
cancer risk (OR=2.5,95% CI 1.02-6.5) as compared to women
with the genotype Aatt.280The results of the different
polymorphisms in this gene are contradictory, and it remains
unclear whether the VDR gene plays a role in breast cancer
The APC gene
Breast tumours (n=227) were screened for truncating muta-
tions in exon 15 of the APC gene (77% of the coding sequence)
and only one somatic mutation was found.283Somatic
mutations in the APC gene were detected in 13 of 70 breast
cancer cases in another study.284Most of these mutations were
outside the mutation cluster region that has been noted for
colorectal cancer.284One of the polymorphisms in the APC
gene,the I1307K polymorphism,is specific to Ashkenazi Jews.
In Ashkenazi Jewish women with breast cancer without a
BRCA1 or BRCA2 mutation, no association between breast
cancer and the I1307K polymorphism was detected.285 286In
another study, the presence of the I1307K allele among
BRCA1/2 carriers was not associated with a further increase of
cancer risk.287This polymorphism probably does not play a role
in breast cancer susceptibility.
Combinations of polymorphisms in different genes
One study examined the four polymorphisms in the CYP1A1
gene and the GSTM1 and GSTT1 polymorphisms.169None of
these polymorphisms, either separately or combined, was
associated with increased breast cancer risks. Others analysed
a combination of the m2 polymorphism in the CYP1A1 gene
and the GSTM1 polymorphism and again no associations were
found.167One study219examined the m1 polymorphisms in the
CYP1A1 gene and the polymorphisms in the CYP17 and COMT
genes. The presence of at least two putative high risk
genotypes was associated with an increased risk of breast
cancer (OR=3.47, 95% CI 1.21-9.99).
In conclusion, in a few studies with small sample sizes,
combinations of polymorphisms were examined.
This review, which examined 34 polymorphisms in 18 differ-
ent genes, described in more than one breast cancer study,
whenever possible with pooled analysis, showed an associ-
ation with breast cancer for 13 polymorphisms in 10 genes.
Increased breast cancer risks were found for the polymor-
phisms in HRAS1, GSTM1, GSTP1, CYP1B1 (codon 119),
from 1-41%. Interestingly, decreased breast cancer risks were
found for women homozygous for the variant allele for the
the XbaI polymorphism in the ER gene, and the PROGINS
polymorphism in the PR gene. Women with these genotypes
may represent a subpopulation where prevention strategies
can be less intensive than in the general population. The
pooled analysis was performed on large (>2000 cases) sample
sizes for the HRAS1, GSTM1, and CYP19 polymorphisms. There
is, therefore, strong evidence for increased breast cancer risks
associated with these polymorphisms, although the increase
in breast cancer risk for the GSTM1 polymorphism is very
small. More research on these three genes will probably only
narrow the confidence intervals and not change either the
ORs or the allele frequencies. The sample sizes studied for
other polymorphisms, such as Tp53 (intron 3, exon 4, and
intron 6), GSTP1, CYP1B1 (codon 119), ER (XbaI), and VDR
(ApaI and poly-A),were quite small (<1000 cases).Because of
this, the association with increased breast cancer risk is not
confirmed.The sample sizes for the polymorphisms of CYP2D6
and PR wereintermediate(between1000and2000cases).Our
pooled analysis indicated that there is an association with
breast cancer, although more research (larger sample size)
could slightly change both the ORs and the allele frequencies.
The pooled analysis for 12 other polymorphisms in nine genes,
namely L-myc, NAT1, NAT2, GSTT1, CYP1A1, CYP17, AR, COMT,
and UGT1A1, showed no association with breast cancer. For
NAT2, GSTT1, and CYP17, the polymorphisms with large sam-
ple sizes, an association with breast cancer can be excluded.
For polymorphisms with small (L-myc, NAT1, CYP1A1 (m2, m3
and m4),AR,and UGT1A1) or intermediate (CYP1A1 (m1) and
COMT) sample sizes, an association with breast cancer cannot
Somewhat different rules are applicable for polymorphisms
described in only one study.To conclude from a negative result
that the original effect is likely to be an artefact, a sample size
of roughly four times the initial study is needed when
replicating these studies (see Appendix 1). Eight polymor-
EDH17B2,289HER2,290TBR-1,291and TFR278) are each described in
only one study, all of which have (very) small sample sizes. A
(TNF-α, HSP70-2, HSP70-hom, EDH17B2, and HER2). Replica-
tion of this is needed either to confirm or reject the tentative
Strikingly little research has been performed on combina-
tions of polymorphisms which are addressed in only a few
studies in breast cancer patients. An association with
increased breast cancer risk was found for combinations of
polymorphisms in the different GST genes, although the total
number of cases (n=238) and controls (n=240) was small
and the association was only marginally significant. No
234De Jong, Nolte, te Meerman, et al
evidence was observed for other associations with breast can-
cer for certain combinations, but this was mainly because of
small sample sizes. For polymorphisms not associated with
breast cancer when studied separately, an association is still
possible in combination with other polymorphisms. Since the
products of several genes interact (almost half of the reviewed
genes play a role in oestrogen metabolism), interactions
between the genes are likely.
When the variant itself is non-functional, but in linkage
disequilibrium with some other functional variant, the overall
risks may not be applicable to all populations, as linkage dis-
Finally,it is not unlikely that other genes exist that give rise
to variation in breast cancer susceptibility, but have not yet
been identified and/or tested. A whole genome screen would
be the ideal method to detect new breast cancer susceptibility
genes.This method,however,is still too expensive to carry out
in large study populations. Until this is (economically)
feasible, it would be useful to collect data on an appropriately
sized, well described study population. Analysis of several (or
all) of the polymorphisms already known to be associated
with breast cancer in the same population will increase our
understanding of the aetiology of breast cancer. More specific
risk assessments willbecome
often differ between
This work was supported by grant RUG-98-1665 of the Dutch Cancer
Society and by the Comprehensive Cancer Centre Northern
M M de Jong, W T A van der Graaf, E G E de Vries, Department of
Medical Oncology, University Hospital, Groningen, The Netherlands
M M de Jong, I M Nolte, G J te Meerman, J C Oosterwijk,
Department of Medical Genetics, University Hospital, Groningen, The
M M de Jong, J H Kleibeuker, Department of Gastroenterology,
University Hospital, Groningen, The Netherlands
M Schaapveld, Comprehensive Cancer Centre Northern Netherlands,
Groningen, The Netherlands
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Appendix 1 Sample size calculation
More than one study. The statistical power for actual inves-
tigations into disease genes can be tackled by postulating
a simple biallelic genetic model and assuming that the dis-
ease gene itself (or a 100% linked and associated marker)
is observed. Relative risks of the disease can then be speci-
fied for homozygotes for the wild type allele (aa), heterozy-
gotes (aA), and homozygotes for the variant allele (AA).
This allows for variations in penetrance and dominant,
additive, or recessive models. Other input parameters that
the model needs are the disease frequency, the frequency
of the variant allele, the required power, and the
significance level. The basis of the calculation is the deter-
mination of the a posteriori genotype distribution of the fre-
quencies of alleles transmitted from unaffected parents to
their affected child. The genotypes constructed by the alle-
les that are not transmitted serve then as (pseudo) controls
as in the transmission/disequilibrium test. Power calcula-
tions for the difference in the frequencies of binomial
entities are performed using a normal approximation. Sam-
ple sizes required are then calculated for detecting
differences between cases and controls in allele frequen-
cies, in variant allele carriers and in homozygotes for the
Although the assumption of 100% linked and associated
markers is not entirely realistic, it does indicate an order of
magnitude for the power of an actual investigation. This will
probably be lower as a function of genetic distance and
allelic frequency match between marker and disease
alleles. The actual calculations are done on a Microsoft
ExcelT spreadsheet, available from the first author on
Only one study. When only one association study is
available on a polymorphism, it is likely to be a positive
one. It is therefore unlikely that a reliable disease model can
be obtained from it. Because of this, the sample size cannot
be computed with the formula presented in the previous
section. A second study will need a sample size at least four
times as large as the original one in order either to replicate
or refute the association. The reason for the factor 4 is as
follows. Assume that the power for the first study to find a
significant difference between cases and controls is equal
to 0.50. For example, for a disease model with a variant
allele frequency of 0.20, a disease frequency of 10%, and
genotypic relative risks for aA and AA both equal to 1.5,
the power to detect a difference between cases and
controls at a significance level of 5% is 0.502 in a study
with 164 trios. To detect the same difference with a power
of 0.95, 656 trios are required, which is exactly a factor of
4 larger. Even for a weak genetic disease model with a
variant allele frequency of 0.50, a disease frequency of
10% and genotypic relative risks both equal to 1.1, this
factor is 3.9996 (5001 trios in first study versus 20 002 in
the replication study). In order to replicate the first study
with a power of 90% (instead of 95%), the required
increase in sample size is a factor of 3.165.
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Another risk factor for MI?
comprise the receptor complex, each specified by a single gene; the GPIbα subunit has the binding site
for von Willebrand factor.Douglas et al speculated that the GPIbα-5T/C sequence Kozak polymorphism—
affecting GPIb/IX/V expression—and GPIbα variable number tandem repeats (VNTRs)—affecting its
structure and lengthening the receptor—might alter the risk of MI. GPIbα Kozak polymorphism is a
thymine (T) or cytosine (C) at position −5 around the ATG initiator codon;GPIbα VNTR has four variants
(A-D) in descending molecular size.
Douglas et al analysed how common these genotypes were in patients aged 33–80 years (180 white, 76
Indian Asian),recruited at cardiac catheterisation,for those with confirmed MI (one group) and without
(another group) but otherwise matched for known risk factors.
GPIbα Kozak homozygous TT genotype was strongly linked with MI (infarct group TT 85.2%,TC 12.5%,
GPIbα VNTR genotypes showed no link, except marginally, between CC and all other genotypes. Neither
polymorphism was linked with severity of arterial disease.
TT Kozak genotype may be important in MI, the authors conclude, but confirmation awaits a larger
m Heart 2002;87:70–74.
latelet receptor gene Ibα-5T/C Kozak polymorphism may influence the risk of MI, concludes a pre-
liminary UK study. In the prelude to MI platelets attach, through a glycoprotein complex GPIb/IX/V,
to von Willebrand factor on plaques in the arterial walls. Four subunits (GPIbα, GPIbβ, GPIX, GPV)
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242 De Jong, Nolte, te Meerman, et al