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High-risk breast cancer predisposition genes.

Introduction

Breast cancer is an important health issue. Worldwide, more than a million women are diagnosed with breast cancer every year. In the UK, breast cancer is the most commonly occurring cancer in women. Between 1 in 9 and 1 in 12 women in the UK will develop breast cancer during their lifetime (up to the age of 80 years) [1]. The French surgeon Broca hypothesised over 140 years ago that a proportion of breast cancer cases may be due to genetic susceptibility, this suggestion initially arose because of clustering of breast cancer cases in his wife's family [2]. Since then, a family history of breast cancer has been identified as an important risk factor for the development of the condition.

Epidemiological evidence that women with a family history of breast cancer are at an increased risk of developing the disease has been accumulating for many years. The Cancer and Steroid Hormone (CASH) case-control study was one of the first large studies to investigate familial breast cancer risk [3]. The study revealed that the relative risk of breast cancer was 2.1 in female first-degree relatives of women with breast cancer. Furthermore, it was predicted that the underlying genetic susceptibility was due to one or more, rare, highly penetrant autosomal dominant genes with a population frequency of around 0.0033, or 1 in 300. Carriers of the theoretical mutation were considered to be at a 92% lifetime risk. The CASH study provided epidemiological evidence that: (1) breast cancer in familial clusters develops at a relatively early age compared to non-familial breast cancer; (2) bilateral breast cancer occurs more commonly in familial clusters; and (3) familial cases of breast cancer are often associated with cases of ovarian cancer in relatives [3]. There is also evidence that the occurrence of male breast cancer and prostate cancer suggests a strong familial risk. Female relatives of males affected with breast cancer have a 2-3-fold increased risk compared with that of the general population [4].

The increased risk of breast cancer in relatives of probands affected by the disease could potentially be attributed to shared environmental and/or genetic factors. However, twin studies indicate that most of the excess familial risk is due to an inherited predisposition. One study estimated the lifetime risk of breast cancer to be 33% for individuals with a monozygotic twin who had been diagnosed with the disease [5]. More recently the simplistic epidemiological model of a single or a few high-risk genes accounting for the familial element has been set aside with the identification of multiple common genetic variants that slightly increase the risk of breast cancer [6-8]. The likelihood is that every woman who develops breast cancer will have at least one genetic variant associated with breast cancer risk. This new 'polygenic' model of genetic predisposition does not negate the importance of the now identified high-risk genes, particularly for those women whose breast cancer risk is almost entirely driven by a single genetic fault.

In this review we will provide a brief overview of the high-risk genes, so far identified, that predispose to the development of breast cancer.

High-risk breast cancer susceptibility genes

The evidence of a familial predisposition to breast cancer led to an extensive search for genes that underlie this susceptibility. Three classes of breast cancer susceptibility genes have emerged so far. They can be classified according to the level of breast cancer risk they confer and the prevalence of disease-causing variants in the population. For the purpose of this review, high-risk genes are defined as those that clearly cause a lifetime risk of breast cancer of >40% and as such are relatively rare with population frequencies in most outbred populations of below 1 in 200.

High-penetrance breast cancer susceptibility genes

The identification of BRCA1 and BRCA2 in the last decade of the twentieth century was a major advance in the understanding of breast cancer susceptibility. As predicted by previous epidemiological data, mutations in these genes are rare. The associated phenotype is inherited in an autosomal dominant manner. Mutation carriers have a 10-20-fold increased risk of breast cancer and an increased risk of ovarian and other cancers [9,10]. Pathogenic mutations in BRCA1 and BRCA2 account for approximately 16% of familial breast cancer (breast cancer in those who also have a positive family history) [9,11].

BRCA1 and BRCA2

Attention, thus far, has been mostly focused on two high-risk predisposing genes: BRCA1 on the long arm of chromosome 17 [12] and BRCA2 [13] on the long arm of chromosome 13. They are thought to account for over 80% of highly penetrant inherited breast cancer, and for about 2-3% of all breast cancer in outbred non-'founder' populations (in populations with so-called founder effects, mutations that are usually >400 years old are carried by a large proportion of the breast cancer population). BRCA1 and BRCA2 have a combined population frequency of approximately 0.2% (Table 1) [14]. It appears that mutations in BRCA1 and BRCA2 are present in the majority of families with an inherited link to both breast and ovarian cancer. In families with breast/ovarian cancer, approximately 60-80% of cases are caused by BRCA1, and approximately 20-40% are related to mutations in BRCA2 [14,15]. If there are two or more cases of epithelial ovarian cancer in a family, that is strong evidence in itself that BRCA1 is likely to be involved [15]. There is also now increasing evidence that families with BRCA1 and BRCA2 involvement have differing risks of susceptibility to ovarian cancers. The overall cumulative lifetime risk across all linked families is 85% for breast and 40-60% for ovarian cancer for BRCA1 [14,16,17] and 85% and 10-30%, respectively, for BRCA2 [16,18].

Risks may also vary by the position of the mutation within each gene, with higher risks in the ovarian cluster regions in the central portion of each gene [18]. However, the positional variation may not be sufficient to alter risk estimation [15]. Controversy still exists over the true lifetime breast cancer risk associated with mutations in BRCA1/2 with some population studies apparently showing risks as low as 40% [19]. The method of ascertainment of a family clearly affects the risk for individuals within the families, as those with earlier onset cases are likely to harbour other factors that predispose to breast cancer. Attempts to adjust for ascertainment bias has resulted in lower overall risks being estimated for BRCA1 and BRCA2 [20], especially when these studies include population-based series [21]. However, part of the ascertainment bias may be the presence of other lower risk susceptibility genes that also increase breast cancer risk even in the context of a BRCA1/2 mutation [8]. Risks quoted to women should also take into account the higher risks in the present day rather than risks derived from historical series [15]. It is vital that the risk quoted takes into account the context of breast cancer in the family and that until reliable tests are generated from the presence of other genetic variants women are quoted a range of risk (as in Table 1) and steered towards the upper, middle or lower end of that range depending on their family history [15]. For example, a Jewish woman with no family history of breast cancer who tests positive on mutation screening is likely to be at the lowest end of the range (given that testing in the Jewish population occurs even without a family history), but a woman (whether Jewish or not) with three close relatives with breast cancer diagnosed <40 years of age would be at the upper end. Indeed risk-assessment programmes that incorporate mutation information already do this [22]. In some populations with founder effects, BRCA1/2 mutations are far more frequent and account for a greater proportion of familial aggregation and breast cancer overall. Three common mutations carried by around 2.5% of the Ashkenazi Jewish population cause 95% of BRCA1/2 inherited breast cancer.

TP53

Mutations in the TP53 gene on 17p are also known to predispose to early breast cancer [23] and account for over 70% of cases of Li-Fraumeni syndrome [24]. The risk of very early onset breast cancer (<30 years) is higher than for BRCA1, and those carrying hereditary TP53 mutations also have a very substantially increased risk of sarcomas, brain malignancy and other tumours [24]. The overall impact of Li-Fraumeni syndrome on breast cancer incidence is very small (Table 1), but lifetime risk of breast cancer in women is extremely high and individuals with these mutations are at risk of multiple primary tumours especially after radiotherapy [25]. In one series of breast cancers in women <31 years of age, 4% had constitutional TP53 mutations [26], but the frequency is much lower in those diagnosed with breast cancer at older ages. Certainly in women presenting below 30-35 years of age, the possibility of a TP53 mutation should be considered. A family history of early onset sarcoma, glioma or other childhood tumours should be sought and if the breast cancer is a comedo ductal carcinoma in situ (DCIS), or has occurred within an area of comedo DCIS, TP53 testing with genetic counselling should be offered. Women with a TP53 mutation should be told of the radiation risks and that mastectomy may be their best surgical option.

Other genes possibly associated with high risk

Carriers of the ataxia telangiectasia (ATM) gene were thought to be at a five-fold increased risk of breast cancer [27], but the disease is now known to be caused by a single gene on llq [28]. Although initial studies produced conflicting results as to whether ATM was a major gene in breast cancer predisposition [29], careful large-scale association studies have indicated a relative risk of approximately two-fold for pathogenic mutations [30].

The gene for Cowden disease has been identified as PTEN on chromosome 10 [31]. Inactivating mutations in this gene result in a syndrome of macrocephaly, skin and thyroid tumours and breast cancer, but these mutations account for very few high-risk breast cancer families.

Additionally, after a substantial lull in identification of susceptibility genes, further moderate-risk but relatively rare genes (population frequency 0.1-2%) are now being identified (Table 1) [31-35]. These genes and single nucleotide polymorphisms are likely to account for the fact that women with strong family histories who test negative for a BRCA1/2 mutation in their family still appear to be at increased risk [36,37]. The location of further genes is being sought by genome-wide association studies and the likelihood is that many more low-risk genes still remain to be identified. However, it is probably unlikely that any other significant high-risk breast cancer genes will be identified.

At present, for the vast majority of women, an estimate of lifetime risk of breast cancer can be made based on their family history and other risk factors [38]. Only high-risk genes are currently used clinically, although some companies are now marketing tests for the lower-risk variants. Ultimately, accurate risk assessment is likely to involve tests utilising 40-80 genes as well as lifestyle and reproductive factors.

Genetic testing programme

The population that could benefit from presymptomatic genetic testing is difficult to define. Potentially any person could undergo mutation testing for BRCA1 or BRCA2, or both. However, there would be little benefit to anyone unless there was at least some chance that they were at risk of such a gene fault in the first place. Individuals without a family history of breast or ovarian cancer would, therefore, have no alteration to their lifetime risk of these cancers from a negative screening result. There would also be no benefit to the health service system as these women would not be in screening programmes outside the National Screening programmes. Even those with one or two relatives may not benefit that much in terms of reassurance. The National Institute for Health and Clinical Excellence guidance in the UK has set a threshold of at least a 20% likelihood of a mutation in the affected individual family member [1]. This likelihood, and other thresholds such as 10% used in much of Europe, can now be assessed using a simple scoring system (Table 2) [39]. This is as accurate as more involved computer programs (such as BRCAPRO and BOADICEA) at predicting the likelihood of a mutation [40-42]. Testing may eventually be widened to allow for analysis of much smaller aggregations of breast cancer, particularly if targeted therapies for the affected individual [e.g. poly (ADP-ribose) polymerase (PARP) inhibitors] are licensed for use. Currently around only 1 in 1000 people come from families suitable for testing, and a maximum of only 3% of breast cancer cases could be prevented by testing in this way for BRCA1/2. However, there could be possible cost saving from withdrawing from existing screening those women who test negative.

Molecular techniques such as gene sequencing combined with an analysis for large gene rearrangements such as multiple ligation-dependent probe amplification will detect 90-95% of BRCA1/2 mutations. Commercial laboratories in the USA (e.g. Myriad) currently charge around $3000 for a complete screen of BRCA1/2. In populations with founder effects, such as the Ashkenazi Jewish population, testing is far cheaper as it can be targeted to a few mutations. A case could be made in these populations for far more extensive screening on a population basis. In an unaffected Jewish woman with no available affected relative for testing, a negative test has good negative predictive value, particularly in a family with both breast and ovarian cancer [43].

Conclusions

There have been huge advances in our knowledge of hereditary breast cancer over the last 10-15 years. Although it is now possible to offer definitive testing in a few high-risk families, much is still to be learnt about the remaining genes that confer low to moderate elevations in risk. In the meantime, the efficacy of screening and preventative options should be evaluated. Guidelines regarding the appropriate management have recently been published for the UK [1] and similar approaches are being used in other parts of Europe and in North America.

References

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[9.] Anglian Breast Cancer Study Group. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer, 2000, 83, 1301-1308.

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[14.] Ford D, Easton M, Stratton S et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet, 1998, 62, 676-689.

[15.] Evans DGR, Young K, Bulman M et al. Mutation testing for BRCA1/2 in ovarian cancer families: use of histology to predict status. Clin Genet, 2008, 73, 338-345.

[16.] Easton DF, Ford D and Bishop DT. Breast and ovarian cancer incidence in BRCA1 mutation carriers. Am J Hum Genet, 1994, 56, 265-271.

[17.] Evans DG, Shenton A, Woodward E et al. Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a clinical cancer genetics service setting. BMC Cancer, 2008, 8, 155.

[18.] Gayther SA, Mangion J and Russell P. Variations of risks of breast and ovarian cancer associated with different gerrnline mutations of the BRCA2 gene. Nat Genet, 1997, 15, 103-105.

[19.] Struewing J, Hartge P, Wacholder S et al. The risk of breast cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med, 1997, 336, 1401-1407.

[20.] Chen S, Iversen ES, Friebel T et al. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol, 2006, 24, 863-871.

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[27.] Swift ML, Reitnauer PJ, Morrell D and Chase CL. Breast and other cancers in families with ataxia telangiectasia. N Engl J Med, 1987, 316, 1289-1294.

[28.] Savitsky K, Bar-Shira A, Gilad S et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science, 1995, 268, 1749-1753.

[29.] Chenevix-Trench G, Spurdle AB, Gatei M et al. Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst, 2002, 94, 205-215.

[30.] Renwick A, Thompson D, Seal S et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet, 2006, 38, 873-875.

[31.] Liaw D, Marsh DJ, Li J et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet, 1997, 16, 64-67.

[32.] Meijers-Heijboer H, Wijnen J, Vasen H et al. The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet, 2003, 72, 1308-1314.

[33.] Seal S, Thompson D, Renwick A et al. Truncating mutations in the Fanconi anemia J gene, BRIP1, are low penetrance breast cancer susceptibility alleles. Nat Genet, 2006, 38, 1239-1241.

[34.] Stacey SN, Sulem P, Johannsson OT et al. The BARD1 Cys557Ser variant and breast cancer risk in Iceland. PLOS Med, 2006, 3, e217.

[35.] Rahman N, Seal S, Thompson D et al. PALB2 which encodes a BRCA2-interacting protein is a breast cancer susceptibility gene. Nat Genet, 2007, 39, 165-167.

[36.] Amir E, Evans DG, Shenton A et al. Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme. J Med Genet, 2003, 40, 807-814.

[37.] Pharoah PD, Antoniou AC, Bobrow B et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet, 2002, 31, 33-36.

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[40.] Antoniou AC, Durocher F, Smith P et al.; INHERIT BRCAs program members. BRCA1 and BRCA2 mutation predictions using the BOADICEA and BRCAPRO models and penetrance estimation in high-risk French-Canadian families. Breast Cancer Res, 2006, 8, R3.

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D Gareth R Evans (1,2) and Anthony Howell (2)

(1) University Department of Medical Genetics and Regional Genetic Service, St Mary's Hospital, Central Manchester Foundation Trust, Manchester, UK

(2) Genesis Prevention Centre, University Hospital of South Manchester & Wythenshawe Hospital NHS Foundation Trust, Manchester, UK

Correspondence to: D Gareth R Evans, University Department of Medical Genetics and Regional Genetic Service, St Mary's Hospital, Central Manchester Foundation Trust, Hathersage Road, Manchester M13 0JH, UK (email: gareth.evans@cmft.nhs.uk)
Table 1: High- and moderate-risk genes predisposing to breast cancer

Gene             Other tumour         Population    Proportion
                 susceptibility       frequency     of breast
                                      (%)           cancers
                                                    (%)

BRCA1            Ovary/prostate       0.1           1.5
  (AD??)           colorectal
BRCA2            Ovary/prostate       0.1           1.5
  (AD)             pancreas
                   HoZ-Fanconi (AR)
TP53             Sarcoma, glioma      0.0025        0.02
  LFS (AD)         adrenal
PTEN             Thyroid              0.0005        0.004
  Cowden's         colorectal
  disease (AD)
CHEK2            Colorectal,          0.5           0.5
                   prostate
ATM              HoZ A ( R)           0.5           0.5
  (AD and AR)      lymphoma,
                   leukaemia
STK11            Colorectal           0.001         0.001
  (AD)
BRIP1            HoZ-Fanconi (AR)     0.1           0.1
PALB2            HoZ-Fanconi (AR)     0.1           0.1
E Cadherin       Familial diffuse     <0.0001       <0.001
                   gastric cancer
Totals                                              80 for any

Gene             Proportion           Proportion    Lifetime
                 of HPHBC             of familial   risk in
                 (%)                  breast        women
                                      cancer risk   (RR %)
                                      (%)

BRCA1            40                   5-10          60-85
  (AD??)
BRCA2            40                   5-10          50-85
  (AD)
TP53             2                    0.1           80-90
  LFS (AD)
PTEN             0.3                  0.02          25-50
  Cowden's
  disease (AD)
CHEK2            0                    2             18-20
                                                    (2.0)
ATM              0                    2             20
  (AD and AR)
STK11            0.6                  0.04          50
  (AD)
BRIP1            0                    0.4           20
                                                    (2.0)
PALB2            0                    0.4           20
                                                    (2.0)
E Cadherin       0                    ?             39-52
Totals           5                    83            27

AD, autosomal dominant; AR, autosomal r e cessive; HoZ, homozygous;
HPHBC, highly penetrant hereditary breast cancer (e.g. >3 affected
relatives); LFS, Li-Fraumeni syndrome; RR, relative risk.

Table 2: Manchester scoring system for
identification of a pathogenic BRCA1/2 mutation

                      BRCA1                 BRCA2

FBC <30               6                     5
FBC 30-39             4                     4
FBC 40-49             3                     3
FBC 50-59             2                     2
FBC >59               1                     1
MBC <60               5 (if BRCA2 tested)   8
MBC >59               5 (if BRCA2 tested)   5
Ovarian cancer <60    8                     5 (if BRCA1 tested)
Ovarian cancer >59    5                     5 (if BRCA1 tested)
Pancreatic cancer     0                     1
Prostate cancer <60   0                     2
Prostate cancer >59   0                     1

Scores for each cancer in a direct lineage are summated. A score
of 10 (single column) is equivalent to a 10% chance of
identifying a mutation in that particular gene. A combined score
(both columns) of 20 points would qualify for NHS testing at the
20% threshold. A combined score of 16 points is equivalent to a
10% combined frequency for BRCA1/2. FBC, female breast cancer;
MBC, male breast cancer.
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Title Annotation:Feature Article
Author:Gareth, D.; Evans, R.; Howell, Anthony
Publication:Advances in Breast Cancer
Article Type:Report
Geographic Code:4EUUK
Date:Mar 1, 2009
Words:4026
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