BASIC SCIENCE

The genetics of breast cancerAlexandra J Murray

D Mark Davies

AbstractBreast cancer is the commonest cancer affecting women. A family history

of breast cancer increases a woman’s lifetime risk of developing the

disease. Most of the genetic risk is due to low-risk and moderate-risk

susceptibility alleles rather than high-penetrance genes such as BRCA1

and BRCA2. Pathogenic variants in these two tumour suppressor genes

only account for about 2% of all breast cancers. Female carriers of the

BRCA gene pathogenic variants have a high lifetime risk of developing

breast and ovarian cancer and male carriers have an increased risk of

prostate and breast cancer.

Patients with a significant family history of breast cancer should be

referred to their local cancer genetics service for a formal cancer genetics

risk assessment, discussion of risk management options such as surveil-

lance and risk-reducing surgery and consideration of genetic testing. If

a BRCA pathogenic variant is identified in a family, predictive testing

can be offered to unaffected family members to clarify risks and help

with risk management decisions.

Patients with cancer are increasingly likely to have tailored treatment,

based on genetic information. Targeted therapies exploiting vulnerabil-

ities associated with deficient BRCA function are being developed.

Keywords Autosomal dominant; breast cancer; cancer genetics; genetic

testing; germline mutation; magnetic resonance imaging; mammography;

ovarian cancer; pathogenic variants; risk assessment; screening; somatic

mutation; tumour suppressor gene

Background

Breast cancer is the commonest cancer affecting women. A

woman in the developed world has a lifetime risk of developing

breast cancer of approximately 9e11%. In 2009, over 48,000

women in the UK were diagnosed with breast cancer. Each year,

about 350 men are also diagnosed with breast cancer.

The risk of developing breast cancer for women in the general

population increases with age. Other factors known to increase

the risk include the use of hormone replacement therapy (HRT),

especially combined oestrogen and progesterone preparations,

hormonal contraceptives, obesity and alcohol. High parity,

young age at first childbirth, breastfeeding, late menarche and

early menopause all decrease the risk.

Alexandra J Murray FRCP is a Consultant Clinical Geneticist at the

University Hospital of Wales, Cardiff and Singleton Hospital, Swansea,

UK. Conflicts of interest: none declared.

D Mark Davies MRCP PhD is a Clinical Lecturer in Cancer Genetics and

Medical Oncology at the University Hospital of Wales, Cardiff, UK.

Conflicts of interest: none declared.

SURGERY 31:1 1

The clustering of breast cancer in families is almost entirely

due to genetic variation rather than shared lifestyle or environ-

ment. The risk of developing breast cancer is twice as high in

women who have an affected first-degree relative (FDR) than

women in the general population. The majority of the genetic

risk is due to low-risk or moderate-risk susceptibility alleles, each

of which confers only a very small increased risk in isolation but

which in combination may have quite a significant effect.1

Currently these low-penetrance genes cannot be used clinically

in the management of individual patients but they may, in time,

be helpful in the context of population screening programmes for

disease prevention. Pathogenic variants in high-penetrance genes

such as BRCA1 and BRCA2 (Table 1) confer a high risk of breast

cancer, but these variants are rare and only account for a small

percentage of breast cancers.

BRCA1 and BRCA2

Pathogenic variants in the BRCA1 and BRCA2 genes account for

the majority of families with an apparently dominant-looking

predisposition to breast cancer. However, they are only respon-

sible for about 2% of all breast cancers.

The BRCA1 and BRCA2 genes are tumour suppressor genes

and their proteins are involved in fundamental cell processes,

including repair of DNA double-strand breaks and checkpoint

control of the cell cycle.

The role of tumour suppressor genes in cancer development

can be explained by the ‘two-hit hypothesis’ proposed by Alfred

Knudson. In the case of BRCA1 or BRCA2, a breast cancer

develops if both copies of the relevant gene in a single cell are

damaged. Although the DNA in our tissues acquires somatic

mutations over time, in most cases it is still likely to take many

years for both copies of a BRCA gene to become mutated in any

one cell. However, if a person inherits a germline pathogenic

variant in a BRCA gene from one parent, any cell subsequently

only requires a single somatic mutation to inactivate the second

copy of the gene. This explains why hereditary cancers often

develop at an earlier age than sporadic ones.

Variation in the sequence of the BRCA genes is common.

Some variation has no effect on protein function and therefore no

increase in cancer risk. Some variants interfere with protein

function and lead to an increased risk of cancer. Such a change is

often loosely referred to as a ‘mutation’. However, some biolo-

gists define a mutation as simply a change in DNA sequence,

while others consider a mutation to be a sequence change

occurring below a certain frequency in a population or

a sequence change associated with disease. To prevent this

confusion the term variant is preferred and variants are classified

as pathogenic, non-pathogenic or of unknown significance,

depending on their associated cancer risk.

The BRCA1 gene is a large gene of 24 exons, located on the

long arm of chromosome 17. Pathogenic variants can be found in

any part of the gene and most result in truncation or total loss of

the BRCA1 protein. There is a wide spectrum of pathogenic

variants but there are a few common, ‘founder’ pathogenic

variants in certain populations such as Ashkenazi Jews. The

commonest of these, 185delAG, is responsible for about one in

five cases of early onset breast cancer in Ashkenazi Jewish

women. The BRCA2 gene has 27 exons and is found on the long

� 2013 Elsevier Ltd. All rights reserved.

Syndromes which predispose to breast cancer

Syndrome Causative

gene

Main associated cancers

Hereditary breast

and ovarian

cancer

BRCA1 Breast, ovarian

BRCA2 Breast, ovarian, prostate, melanoma,

sarcoma, pancreatic

LieFraumeni TP53 Breast, soft tissue sarcoma,

osteosarcoma, brain, leukaemia,

adrenocortical carcinoma

Cowden PTEN Breast, endometrial, thyroid

Peutz Jeghers LKB1 Breast, pancreatic, gastrointestinal,

lung

Table 1

BASIC SCIENCE

arm of chromosome 13. As with BRCA1, pathogenic variants can

occur throughout the gene and there are founder pathogenic

variants in some populations including the 6174delT mutation in

Ashkenazi Jews.

Cancer risks

Pathogenic variants in these genes show incomplete penetrance

(i.e. some people who carry a pathogenic variant will not develop

cancer). Pathogenic variants in the BRCA1 gene are particularly

associated with an increased risk of early onset breast cancer,

ovarian cancer and fallopian tube cancer. The lifetime risks of

developing breast and ovarian cancer for a woman with a BRCA1

pathogenic variant are usually quoted as about 85% and 40%

respectively. The risks for a woman with BRCA2 pathogenic

variants may be a little lower, particularly the ovarian cancer

risk, which is probably less than 20%. Pathogenic variants in

BRCA2 are also associated with pancreatic cancer, sarcoma and

malignant melanoma. Male carriers of BRCA pathogenic variants

have an increased risk of prostate cancer, and those with BRCA2

pathogenic variants also have a significantly increased lifetime

risk of developing breast cancer of about 6%.

The breast cancers associated with BRCA1 tend to be high-

grade, triple-negative (oestrogen receptor (ER)-, progesterone

receptor (PR)- and human epidermal growth factor receptor 2

(HER2)-negative) tumours. The pathological spectrum of BRCA2

breast cancers is broadly similar to those of non-carriers.

Management

The first step in managing a person who is concerned about her

risk of developing breast cancer is to take a family history.

Although it is important to ask about both the maternal and

paternal relatives, each side of the family should be considered

separately. Not everyone with a family history of breast cancer

will have an increased risk of developing the disease. Where

appropriate, referral can be made to their local regional genetics

service for risk assessment, counselling, advice about screening

programmes and sometimes genetic testing. Many regional

genetics services have local referral guidelines that help to

identify who should be referred. Although there may be some

regional variations, it is reasonable to consider making a referral

if a person has:

SURGERY 31:1 2

� one first-degree relative with breast cancer diagnosed

before age 40

� two first- or second-degree relatives with breast cancer

diagnosed before age 60

� three or more first- or second-degree relatives with breast

cancer at any age

� a close relative with bilateral breast cancer

� a close male relative with breast cancer

� a close relative affected by breast and ovarian cancer.

Most referral guidelines, such as those above, assume the person

being referred is not themselves affected by a relevant cancer. An

easy way to adapt such guidelines for a person who has been

affected by cancer is to imagine that person has a twin sister and

ask whether that twin sister warrants referral.

If the family history is complex and involves other types of

cancer such as ovarian cancer, prostate cancer, sarcoma, glioma

or adrenocortical carcinoma, it is best to refer to the local

guidelines or contact the regional genetics service directly.

Risk assessment

On receipt of a referral, the genetics team will gather detailed

information about the family history and draw up a family tree or

pedigree. In many cases this will involve confirming diagnoses

by reviewing medical records, pathology reports and cancer

registry records. The next step is a formal risk assessment, often

facilitated by the use of computer programmes that estimate

either the BRCA1/BRCA2 pathogenic variant carrier probabilities

or breast/ovarian cancer risks, such as BOADICEA.2

Patients will be assigned to one of three risk categories for

breast cancer:

� Women at or near population risk of developing breast

cancer (i.e. a 10-year risk of less than 3% for women aged

40e49 years and a lifetime risk of less than 17%) e these

women can be managed in primary care and do not require

any additional screening other than that offered to all

women i.e. 3-yearly mammograms from about the age of

50 through the NHS breast screening programme.

� Women at raised risk of developing breast cancer (i.e. a 10-

year risk of 3e8% for women aged 40e49 years or a life-

time risk of �17% but <30%) e these women may not be

seen in their local genetics clinic but will be offered

screening in secondary care or as part of a regional or

national screening programme for women with a family

history of breast cancer.

� Women at high risk of developing breast cancer (i.e. a 10-

year risk of >8% for women aged 40e49 years or a lifetime

risk of �30% or a �20% chance of a BRCA1, BRCA2 or

TP53 pathogenic variant in the family) e these women

should be seen in their local genetics clinic for discussion

about screening programmes and, where appropriate,

genetic testing and risk-reducing surgery.

Breast screening

Breast cancer screening for women with a family history should

be offered in accordance with the NICE guidelines on familial

breast cancer.3 Women in the raised risk group or higher should

be offered annual mammographic surveillance from age 40 years

and then 3-yearly screening from 50 years. Annual MRI

� 2013 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

surveillance should be offered to women aged 30e49 years who

are known to have a BRCA1 or BRCA2 pathogenic variant and

women aged 20 years or older who are TP53 pathogenic variant

carriers (i.e. LieFraumeni syndrome). MRI surveillance is also

indicated in certain other high-risk situations which are detailed

in the NICE guidance.

Genetic testing

When the family history is suggestive of a BRCA pathogenic

variant, genetic testing can be undertaken. Ideally, this is per-

formed on DNA extracted from a blood sample of a family

member affected by a BRCA related cancer. The clues in the

family history that are suggestive of a pathogenic variant include:

� multiple individuals on one side of the family with breast

or ovarian cancer

� a young average age of diagnosis

� male breast cancer

� associated cancers (e.g. prostrate cancer, sarcoma,

pancreatic cancer)

� individuals with more than one primary cancer, including

bilateral breast cancer

� Ashkenazi Jewish ancestry.

In most laboratories both genes will be sequenced to identify

point mutations or small deletions, and MLPA (Multiplex

Ligation-dependent Probe Amplification) will be performed to

look for deletions or duplications of one or more whole exons.

If a pathogenic variant is identified in either gene, unaffected, at-

risk familymembers canbe offered predictive testing to clarify their

risks. Predictive testing should only be undertaken in regional

genetics centreswith appropriate pre-test andpost-test counselling.

Risk-reducing surgery in unaffected BRCA pathogenic variant

carriers

Some women at high risk of breast or ovarian cancer want to be

more proactive in managing their risk and request risk-reducing

surgery as an alternative to regular surveillance. The two options

available to these women are mastectomy and bilateral salpingo-

oophorectomy (BSO).4 Risk-reducing mastectomy in BRCA path-

ogenic variant carriers reduces the risk of breast cancer by around

95%. Ideally, women considering risk-reducing mastectomy

should be seen and assessed by a multidisciplinary team who can

assist in the decision making process. They need appropriate

counselling and sufficient time to weigh up the advantages,

namely a reduced risk of breast cancer and the alleviation of

anxiety, and the disadvantages, which include the risk of surgical

complications and possible psychological problems.

BSO in BRCA pathogenic variant carriers reduces the risk of

ovarian cancer by approximately 90% and will reduce a wom-

an’s risk of developing breast cancer by up to 50%, depending on

her age at the time of the procedure. The effects of the surgically

induced menopause can be alleviated by the use of hormone

replacement therapy (HRT). The decision to use HRT will depend

on a woman’s personal circumstances. Although HRT is known

to be associated with an increased risk of breast cancer, it

SURGERY 31:1 3

appears that the use of HRT does not reverse the reduction in

breast cancer risk in these women. The effectiveness of screening

for ovarian cancer remains unproven.

Medical management of affected BRCA pathogenic variant

carriers

The BRCA status of women affected by cancer is increasingly

impacting on how they are treated.5 Female pathogenic variant

carriers who have had breast cancer, have a significantly higher

risk of developing a second breast cancer in the contralateral

breast (approximately 25% compared to 10% in non-carriers).

This raises the question whether a risk-reducing contralateral

mastectomy should be performed, possibly as part of the initial

surgical procedure. There is no evidence that BRCA pathogenic

variant carriers are more radiosensitive than the general pop-

ulation, in terms of response or toxicity. There is pre-clinical

evidence that BRCA associated tumours may be more sensitive

to certain chemotherapy drugs and this is currently being tested

in large scale clinical trials.

Advances in the understanding of the biological function of

BRCA 1/2 encoded proteins have led to the development of tar-

geted therapies, which are currently in clinical trials.6 The

BRCA1 and BRCA2 proteins are involved in DNA repair. The

poly(ADP-ribose) polymerase (PARP) proteins also have impor-

tant roles in DNA repair. Inhibiting PARP in the presence BRCA

deficiency leads to cell death but PARP inhibition in cells with

normal BRCA function is well tolerated. The concept that the

mutation or inhibition of two pathways can lead to cell death,

when mutation or inhibition of either alone would not, is termed

synthetic lethality. PARP inhibitors have been tested in clinical

trials in patients with BRCA-related cancers and have shown very

encouraging results in phase 1 and II trials. However, the results

of larger phase III studies have been mixed and considerable

work remains to define the role of PARP inhibitors. A

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