Breast Cancer Genetics
1,2Rodney J. Scott 1Discipline of Medical Genetics, School of Biomedical Sciences, Faculty of Health,University of Newcastle and The Hunter Medical Research Institute, NSW, Australia.
2Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia.
Key words: BRCA1, BRCA2, genetics, function, pathology and intervention
AbstrAct
In the intervening period between now and the identification of major susceptibility genes for breast cancer considerable advances have been made in our understanding of not only the molecular mechanisms of disease but also how best to intervene to reduce the risk of overt disease.
Understanding the role of genes associated with breast cancer will have important implications with respect to classifying patients who harbour an inherited predisposition to disease and sporadic cases that are a result of epigenetic or somatic changes into specific groups that will benefit from targeted therapies.
Prophylactic options for women at increased genetic risk need to be studied such that maximum benefits from this knowledge can be applied to reduce the burden of disease.
IntroductIon
despite the advances that have been made in the identification of persons at risk of disease, breast cancer still remains the most frequently diagnosed female malignancy and accounted globally for more than 1,151,000 cases in 2002.1 up to 30% of women diagnosed
with breast cancer report one or more first- or second-degree relatives with the disease suggesting a significant proportion of patients harbour common low penetrant risk alleles for this malignancy.2 somewhere between
5% and 10% of all breast cancer cases can be identified as belonging to families where there is an inherited predisposition to disease characterized by multiple early onset cases presenting as an autosomal dominant trait.3
Genetic susceptibilities to breast cancer have been considered ever since the publication of Paul broca in 1866 where he described familial associations of the disease.4 In 1990 the first breast cancer susceptibility
gene (TP53) was identified in patients from families that belonged to the Li-Fraumeni syndrome.5 the TP53 gene
integrity.6 In the same year as TP53 was identified a
second genetic locus was identified by linkage analysis located on the long arm of chromosome 17.7 Within 3
years this initial report had been confirmed by other groups8, 9 and further, at this time it was also recognised
that ovarian cancer was one of the other major diseases associated with the BRCA1 locus.10 Within three years
the BRCA1 gene had been identified by skolnick’s group in utah11 and subsequently confirmed as the first major
breast cancer susceptibility gene.12 during the course of
searching for the BRCA1 gene it became apparent that at least one other breast cancer susceptibility locus existed and in 1994 the BRCA2 locus was identified and within one year the BRCA2 gene was identified.13 More recently
several new candidate genetic susceptibility genes have been identified that include ATM, CHEK2, PALB2 and
BRIP1.14-17 Little can be said at the time of writing about
PALB2 and BRIP1 as there is insufficient information
available to define their penetrance, frequency in the population and pathogenicity. More information is known about the relationship between ATM mutations and breast cancer risk. since swift reported an association with breast cancer in female relatives of ataxia telangiectasia patients18, 19 numerous reports have
substantiated these findings with mutation data20, 21 but
the imparted risk does appear to question the notion of AtM mutations being associated with a simple causal relationship to disease.21 the association of cHEK2 to
hereditary breast cancer has recently been assessed in a large multi-centre study which indicates that the main risk of disease is linked with the 1100delc mutation is breast cancer in women but insufficient information was available to determine cancer risk in males.15 Further
studies are required to precisely define the role of this gene in relation to breast cancer risk as well as determining the role it may have in male cancer risk.
With the introduction of new high-throughput methods for the identification of somatic mutations it is to be expected that new cancer susceptibility genes may be identified.22 these high-throughput approaches
will not however, be capable of identifying differences in methylation patterns associated with disease development. one study examining ductal lavage from healthy brcA1 or brcA2 patients has revealed the presence of hypermethylation in a series of 4 genes known to be involved in breast cancer development.23
It is now over 10 years since the discovery of the 2 major autosomal dominantly inherited predispositions to breast cancer has been made. At the time of the identification of BRCA1, and BRCA2 a year later, little was known
about these genes nor could much be gleamed from genetic databases at that time as the two genes showed little similarity to any other known genes or predicted proteins.11, 13 In the intervening period much has been
learned about the functions of brcA1 and brcA2 as well as more specific information about the epidemiology of these two inherited breast cancer predispositions. the most notable result of all of the findings to date, however, has been the development of a much-improved understanding of what should be done, at a clinical level, to alleviate patients from the burden of their predisposition to disease. notwithstanding these significant advances there remain many hurdles to overcome before all predispositions to breast cancer are fully elucidated.
EPIdEMIoLoGy
Initial data concerning the frequency of inherited predispositions to breast cancer was based on the ascertainment of high-risk families. by examining family data from index cases estimates of the frequency of gene carriers could be determined. the first estimate of carrier frequency in the general population was determined to be somewhere between 1:2000 and 1:500.24 these
figures were based on multiple case families where there were more than 4 early onset breast and/or ovarian cancer cases which notably did not include smaller case families as they could not provide sufficient evidence for linkage to the brcA1 locus. since the identification of the genes (both brcA1 and brAc2) more precise estimates have been made as they no longer rely on linkage analysis but rather actual mutations such that the current carrier frequency estimate is close to 1:450,3
which also takes into account more accurate disease penetrance information.
the original penetrance estimates for breast cancer were of the order of 51% by 50 years of age and 85% by 70 years of age for BRCA1 with similar figures for
BRCA2.25 the identification of population specific
mutations allowed for a re-analysis of the penetrance data and somewhat more modest estimates were forthcoming from the Ashkenazi Jewish population26-29
re-analysis of population based data in Australia suggested an even lower disease penetrance, in the order of 40% by 70 years of age.31 the most likely explanations
for this difference being 1) genetic and or environmental factors which promote disease development in some families but not others and 2) the absence of mutation data on women who have died.
the current risk estimate is based on mutation data that results primarily on prematurely terminated proteins as these are considered to be almost always causative. Problematic are missense mutations that alter amino acids, which most often do not appear to affect protein function. some attempt has been made to assess the pathogenicity of missense mutations as a few have now been shown to be associated with an increased risk of disease.32
MoLEcuLAr bIoLoGy
sequence similarities of BRCA1 and BRCA2 were not available at the time of their discovery yet it now appears that there are vertebrate and plant orthologues of these genes.33, 34 Much as been learned about the
function of brcA1 and brcA2 as well as how they relate to cellular responses to stress. both gene products have distinct yet related functions and together they appear to be involved in the maintenance of genomic integrity. At present there is a consensus view that there are additional features of BRCA1 and BRCA2, which remain to be described.
the function of brcA1 is complex as it involves a series of proteins that have distinct binding sites on brcA1 and there appears to be specific functional activity localized to different regions of the protein. brcA1 functions as an E3 ubiquitin ligase that is important for a number of different aspects of genetic homeostasis.35 the majority of proteins that have been
identified that interact with brcA1 are also associated with some aspect of dnA repair or cell cycle checkpoint control.36 Initial studies suggest that brcA1 is involved
in at least two types of double strand break (dsb) repair, non homologous end joining nHEJ and homologous recombination repair (Hrr) as well as the control of transcription.37 A number of different facets to
dnA repair have been associated with brcA1 and these can be broadly categorized into those that are intimately involved in dnA damage sensing,38 dnA
damage recognition,39 a contribution to s and G2 phase
checkpoint control,40 transcriptional control41 and
X-chromosome inactivation.42
brcA1 is part of a large super protein complex known as bAsc. the bAsc includes a variety of genes associated with either dnA repair or cell cycle checkpoint control suggesting that it may act as a dnA damage sensor. brcA1 appears to have an increased affinity for branched structures compared to double-stranded dnA suggesting that this protein acts, at least in part, as a damage sensor.43 For example, double strand
dnA breaks occur after endogenous or exogenous environmental insult and are repaired by either nHEJ or Hrr.44 there are two pathways to homologous
recombination, one that involves gene conversion and the other that is associated with single-strand conversion. the preferred mechanism in wild type cells is that of gene conversion, which requires the homologous template that resides on the sister chromatid.45
once a dnA break has been recognised an initial event that can be visualised is the formation of foci around the dsb. Foci formation is mediated by rPA (replication protein A), which is a multifunctional molecule that not only functions in dsb repair but is also required for dnA replication.46 If cells are irradiated rPA and brcA1
can be observed co-locating together at the dnA break. In brcA1 deficient cells the number of damage induced rPA foci is much greater than that compared to their wild-type counterparts47 suggesting that brcA1
is involved in the modulation of this process. After ionizing radiation the brcA1 protein is phosphorylated and this process is dependent on the presence of the
ATM gene product. After dnA damage brcA1 is
rapidly phosphorylated in dividing cells suggesting that there is a functional relationship between dnA damage sensing and cell cycle checkpoint control.48-50 It appears
that the loss of brcA1 is associated with a bypass of the G2/M checkpoint of the cell cycle, which results in the accumulation of dnA damage.51
the high degree of similarity in the phenotype of
BRCA1 and BRCA2 mutation carriers is indicative that
the two respective proteins either function similarly or that they have a unique and different functional specificity within an overall process. Less is known about the function of brcA2 than brcA1 and what is known has been gained from studies on cell lines examining specific processes that can be observed as phenotypic differences compared to control cells.52 the brcA2
protein encompasses a cluster of eight brc repeat sequences that interact with a series of proteins.53 six
with rAd51, a protein that is essential for dnA recombination repair.45 brcA2 mutant cells display
significant defects in Hrr but interestingly, HnEJ does not appear to be affected suggesting that brcA2 protein specifically targets only one dsb repair process.54
one of the outcomes of a loss of fidelity of Hrr is an increased likelihood of chromosomal rearrangements brought about by the inadequacies of nHEJ.55 As a
consequence of impaired Hrr brcA2 mutant cells have reduced resistance to dnA-damaging agents, for example ionizing radiation results in an increased (1.5 – 2 fold) rate of cell killing compared to control cells.56
GEnEtIcs
Many mutations have been identified in both
BRCA1 and BRCA2 that segregate with familial breast
and/or ovarian cancer and from this information it has been revealed that there are some genotype/ phenotype correlations. two of the earliest observations demonstrated that mutations towards the 5’ end of
BRCA1 are more likely to be associated with ovarian
cancer development57 whereas in BRCA2 there is an
ovarian cancer cluster regions bounded by nucleotides 3035 and 6629.58 Virtually all of the unequivocally
causative mutations result in a prematurely truncated protein (see http://research.nhgri.nih.gov/bic/ for a comprehensive list of mutations in BRCA1 & 2) that predicts a loss of function. one truncating mutation in
BRCA2, however, appears to be an exception (K3326X)
since it is considered to be a polymorphism as it occurrs at similar rates in both breast cancer and control groups.59 Missense variants remain difficult to classify
since functional assays remain elusive. some inroads into assessing the pathogenicity of missense changes in
BRCA1 and BRCA2 have been made that indicate some
are causative whereas others are either neutral or remain unclassified.60 the recognition that some truncating
mutations may not be as penetrant as others suggests that there are differences in the pathogenicity of these alterations and indeed the K3326X mutation may well represent a low penetrant mutation for breast cancer yet be more significant with respect to the susceptibility to pancreatic cancer.61
notwithstanding there are several population specific mutations that have been identified by virtue of their over-representation in particular patient groups. there are two mutations in BRCA1 (del185AG and 5382insc) and one in brcA2 (6174delt) that were first identified in the Ashkenazi Jewish population62 suggesting
that they are specific to that group. Intriguingly, the 5382insc mutation is also significantly over-represented in the Polish population63 suggesting that it may have
either originated in the Polish population or is a result of admixing between the two. nevertheless, all three mutations have been present for many generations, a finding supported by the relative sparsity of de novo mutations.64, 65
since the introduction of a new technique, known as multiplex ligation probe amplification (MLPA), the presence of exonic gains or losses can be readily assessed. recent evidence suggests that a small but significant fraction of mutations are a result of this type of mutation but there do appear to be regional differences in the frequency of such changes.66-68 the disease
characteristics of women harbouring such changes are similar to that of women with obvious pathogenic alterations.69-71
Pathology and Gene Expression Profiling
the first report of differences in the pathology of breast cancers that are associated with mutations in
BRCA1 or BRCA2 compared to those that were not,
appeared in 1997. In that report tumours derived from women harbouring BRCA1 mutations appeared to have histological characteristics that were different to those from women harbouring BRCA2 mutations and breast cancers from women who did not have a family history of disease.72 the analysis revealed that cancers
associated with BRCA1 mutations had higher mitotic counts, more continuous pushing margins, and were more likely to have a lymphocytic infiltrate compared to cancers derived from women who did not have a family history of disease. the tumours also tend to be hormone receptor negative and are not often Her-2 positive but they do tend to express myoepithelial markers such as cytokeratin 5/6 and/or P-cadherin.73 cancers associated
with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules), a higher percentage of the tumor perimeter with a continuous pushing margin and a lower mitotic count than sporadic disease.74
BRCA2 associated tumours deviate from BRCA1
tumours in that there is no tendency for them to be hormone receptor negative but they are more often Her-2 negative.73, 75
that did not arise on a background of BRCA1 or
BRCA2 mutation. BRCA1 mutation carriers with
ovarian cancer were more likely to have invasive serous adenocarcinomas and less likely to present with borderline or mucinous tumors. the tumors also tend to be of higher grade, have a higher percentage solid component and are TP53 positive. the pathological features of ovarian tumours from BRCA2 carriers, intriguingly, was similar to that of tumours from BRCA1 carriers.76
Gene expression profiling of breast tumours has begun to provide new insights into the molecular events underlying this disease. current published evidence suggests that this new methodology may prove to be valuable in assessing tumour specific characteristics that can be used to accurately categorize individual patients. Much emphasis has been placed on predicting the metastatic potential of primary malignant tumours and as such several publications have been forthcoming which suggest that gene expression profiling may yield results that can be used to predict outcome. both supervised and unsupervised clustering methodologies have been used to identify “gene sets” which potentially can predict outcome.77,78 unfortunately, there is little
overlap between the gene sets identified by one group compared to another,79 which suggests that there are
either commonplace reasons for such differences or there are bioinformatic shortcomings in the way gene expression data is analyzed. nevertheless there appears to be concordance between various groups with respect to identifying gene sets that may be useful in predicting disease outcome.80 none of them, however, appear at this
stage to be significantly better for prognostic purposes compared to conventional histological markers.
With respect to inherited predispositions to breast cancer gene expression array analysis has revealed that the molecular pathways associated with germline brcA1 or brcA2 mutations are specific but also appear in sporadic breast tumours suggesting that epigenetic modification of either brcA1, brcA2 or their downstream partners may be a relatively frequent event.81 the results of this study were challenged
however, as the “sporadic” breast cancer population may well have contained brcA1 or brcA2 mutation carriers.82
Genomic rearrangements in breast cancer have recently begun to be examined to identify genomic features that may be associated with the pathophysiology of the disease. three recent reports indicate that
there are common regions of change that are linked to outcomes which may make them useful for clinical decision making.83-85
rIsK AssEssMEnt
As discussed above the risk of breast or ovarian cancer in BRCA1 or BRCA2 carriers is substantial and any women found to harbour a germline mutation in either of these two genes should be made aware of the risks of these two malignancies. In addition to breast and ovarian cancer other malignancies are over-represented in mutation carriers, which appear to be specific for each gene.
BRCA1 mutation carriers have an increased risk of a
number of other malignancies and these include cancers of the uterine body and cervix, pancreatic cancer and to a lesser extent prostate cancer. cancers at other sites are more likely to occur in women than men. With respect to prostate cancer, disease is more likely to occur in men under the age of 65 years. overall, however, there was no increase in cancer risk in males harbouring germline mutations in BRCA1 but there is a small but significant risk of disease at other sites than the breast and ovary in women.86
BRCA2 mutation carriers have an increased risk of
developing a variety of other malignancies than breast and ovarian cancers and these include, pancreatic cancer, gall bladder and bile duct cancer, stomach cancer, malignant melanoma and prostate cancer.87
roLE oF ModIFIEr GEnEs
the notion that disease expression in BRCA1 or
BRCA2 mutation carriers may be influenced by genetic
variation in a series of other genes seems to be an attractive mechanism by which to explain differences within and between populations at risk. A significant effort has been undertaken to identify genetic disease risk modifiers and the results to date are encouraging but suffer from poor reproducibility. notwithstanding, evidence is accumulating to suggest that there are a number of modifier genes that influence disease expression in women harbouring BRCA1 or BRCA2 mutations. these include genes such as AlB1,88 HRAS,89
the progesterone receptor,90 Prohibitin,91 RAD51,92 and
MTHFR,93 which have been relatively consistently
have also been studied but the results have been equivocal and have not lead to any firm conclusions with respect to their value in disease prediction modeling.
ProPHyLAXIs
the primary aim of identifying women at risk of breast and/or ovarian cancer is to reduce their risk of disease. since the introduction of mutation screening for BRCA1 and BRCA2 significant advances in our understanding of the advantages of intervention strategies to reduce disease risk have been made in several key areas, which will be discussed below. notably, compliance to screening procedures has been observed as an immediate outcome from BRCA1 or BRCA2 mutation testing.94 In addition
to measures that prevent disease those that have the potential to enhance risk have been investigated and these include hormone replacement and radiation exposure.
surgical Intervention
breast and ovarian cancer risk can be significantly reduced by prophylactic mastectomy or bilateral oophorectomy, respectively. In women diagnosed with a germline mutation in BRCA1 or BRCA2 the lifetime risk of developing breast cancer is approximately 80% by 75 years of age compared to a population risk of 9% by this age. several studies have shown that prophylactic mastectomy considerably reduces the risk of breast cancer95-97 to an estimated level of 4% at 75
years of age.98 nevertheless, this preventative strategy
remains a very radical intervention, and extensive long-term data on satisfaction of this procedure in reducing risk remain to be collected. In one follow-up study patients’ satisfaction with this approach and its impact on sexual relationships has been assessed. the majority of patients were satisfied with their outcome but a significant proportion of patients experienced surgical complications and reported a perceived lack of information about the procedure.99
several studies have demonstrated that oophorectomy is associated with an approximate 50% reduced risk of breast cancer in women who had undergone this procedure,100,101 this effect was consistently observed
in both BRCA1 and BRCA2 mutation carriers over a period of 15 years,100 suggesting that this is a long-lasting
strategy that can reduce breast cancer risk in women with inherited deleterious mutations in BRCA1 or brcA2. In summary there is an increasing body of evidence to
suggest that surgical risk reduction strategies are very effective in minimizing breast cancer occurrence in this high-risk population.
oophorectomy and ovarian cancer risk
ovarian cancer remains the second most frequently diagnosed malignancy in both BRCA1 and BRCA2 mutation carriers. the evidence that prophylactic salpingo-oophorectomy reduces the likelihood of ovarian cancer development is compelling as it reduced ovarian cancer risk by about 90%102 but there remains a
substantial residual risk for peritoneal cancer in BRCA1 and BRCA2 mutation carriers following surgery.103 At
present, however, there remain questions about the value of this approach especially in relation to overall mortality compared to cancer-specific mortality. recent findings suggest that bilateral salpingo oophorectomy is associated with an overall survival and cancer-specific survival advantage in women with BRCA mutations, which further enhances the value of this surgical intervention.104 nevertheless, this approach does have
several drawbacks as the patients may experience an impaired quality of life that includes menopausal symptoms, osteopenia and cardiovascular disease risk. recent evidence suggests, however, that short-term hormone replacement therapy in premenopausal women may not necessarily negate the benefits from oophorectomy but it should be offered in consultation with the requirements of each patient.102
chemoprevention
there have been several studies demonstrating the benefits of tamoxifen on contralateral breast cancer105
and more recently the risk reduction benefits in women who harbour BRCA1 or BRCA2 mutations.106
Mechanistically the role of anti-estrogens in mediating risk reduction remains unclear but recent evidence suggests that estrogen stimulated proliferation can be inhibited by anti-estrogens and that this is not mediated by progesterone receptor activity. currently, it is not obvious how brcA1 or brcA2 is involved in progesterone expression, nevertheless anti-estrogens are associated with a decreased risk of malignancy in
BRCA1 or BRCA2 mutation carriers.106
tamoxifen use is beneficial in women who were either premenopausal or had undergone natural menopause but did not provide additional benefit to women who had opted for oophorectomy.107 A caveat to this
finding, however, was that the group of women who had undergone this procedure was small and there remains the possibility that benefit exists.107
With the introduction of more specific aromatase inhibitors improved risk reduction is expected but as yet insufficient evidence has been gathered to determine the efficacy of new measure.
dnA damaging Agents
both brcA1 and brcA2 have been implicated in dnA damage recognition of dnA recombination repair.8, 108, 109 A major effect of ionizing radiation is
the generation of dnA double strand breaks that are repaired by dnA recombination repair. Any alteration in the fidelity of this process is predicted to result in an accelerated accumulation of mutations. Exposure to ionizing radiation may alter the risk of disease development in women harboring germline mutations in either BRCA1 or BRCA2, however, it remains unclear how great the magnitude of the affect is on risk.110, 111
some evidence to suggest that ionizing radiation alters disease risk has been forthcoming which suggests that any exposure is associated with an increased likelihood of malignancy but particularly in women who were exposed to radiation under the age of 20 years.112 of
particular importance is the risk of breast cancer in women who opt for regular mammography since this surveillance measure could potentially increase the risk of malignancy. In a large study of 1600 BRCA1 and
BRCA2 mutation carriers overall no association with
mammography and disease was observed but there was a slightly greater risk of disease in women aged between 31 and 40 years of age.113 In summary, it remains
unclear what, if any, relationship exists between ionizing radiation exposure and disease expression in BRCA1 or
BRCA2 mutation carriers.
oral contraceptives
reproductive factors have consistently been shown to be associated with breast cancer risk but the effect is complex and not simply related to age of first birth and number of subsequent births114, 115 For women
harbouring germline mutations in BRCA1 or BRCA2
decisions have to be made in relation to the benefits of oral contraception on ovarian cancer risk116 and the
ease of this method of birth control and the overall risk of breast cancer. currently there is little information available for women with germline mutations in BRCA1 and BRCA2 with respect to the affects of parity and age of first birth. some information has been published examining oral contraceptives and risk but the findings are not consistent as some studies suggested an increase in risk117 whereas others showed no relationship for
BRCA2 mutation carriers but a modest increase in BRCA1 mutation carriers. In a more recent study it
was reported that for BRCA1 mutation carriers there was essentially no change in disease risk with oral contraceptives but for BRCA2 mutation carriers disease risk was not changed if they were used for up to one year but if women had been using them for five or more years there was an increase in disease risk.118
dietary Intervention
dietary intervention to reduce disease risk in BRCA1 or BRCA2 mutation carriers remains an attractive approach but evidence has thus far been lacking. notwithstanding, there are several candidate agents (for review see119), which have been examined in the
context of sporadic disease that could prove to be useful in reducing the risk of malignancy in women predisposed to develop breast and/or ovarian cancer. currently, no randomized control trial has been completed or undertaken to prove the efficacy of such an intuitive approach.
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