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Breast cancer (polygenic risk)
Also known as Breast cancer
Breast cancer is a complex condition affecting many individuals, primarily women, throughout their lifetime. Polygenic risk refers to the small contributions of multiple common genetic changes that, together, can increase an individual's susceptibility to developing breast cancer.
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Overview
Breast cancer is a condition where cells in the breast begin to grow abnormally and uncontrollably, forming a tumour. It is one of the most common cancers diagnosed in the UK. Many factors can influence an individual's risk of developing breast cancer, including age, family history, lifestyle choices, and genetics [PMID:33671239]. While some types of breast cancer are linked to specific, rare genetic changes that have a strong effect on risk, most cases are considered 'polygenic'. This means that many common genetic variations, each with a small effect, combine to influence an individual's overall risk.
Understanding polygenic risk can help in assessing an individual's likelihood of developing breast cancer. It differs from single-gene inheritance patterns where a fault in one specific gene dramatically increases risk. Instead, polygenic risk involves the interplay of numerous genetic markers across the genome, alongside non-genetic factors. This approach offers a more nuanced view of an individual's predisposition to the condition [PMID:36528731].
Symptoms & clinical features
The symptoms of breast cancer can vary, and individuals should be aware of any changes in their breasts and promptly seek medical advice. Common symptoms may include a new lump or area of thickened tissue in either breast or armpit that was not there before.
Other potential symptoms can include a change in the size or shape of one or both breasts, skin changes such as dimpling, puckering, or redness, and nipple changes, such as discharge, inversion or rash. Pain in the breast or armpit that is not related to the menstrual cycle may also be a symptom. If any of these symptoms appear, it is important to contact a GP for further investigation.
Video: Is cancer in your genes?
Affected organs
Breast cancer primarily affects the breast tissue. It can originate in the milk ducts (ductal carcinoma) or the milk-producing glands (lobular carcinoma). Should the cancer spread beyond the breast, it can affect other organs. This spread typically occurs through the lymphatic system or the bloodstream, leading to secondary tumours (metastases) in areas such as the lymph nodes in the armpit, lungs, liver, bones, or brain.
Risks & severity
The lifetime risk of developing breast cancer for women in the UK is approximately 1 in 8, or around 12%. However, this risk can vary significantly based on individual factors, including polygenic risk scores derived from genetic testing, family history, and lifestyle factors. While breast cancer can occur at any age, the risk generally increases with age.
Polygenic risk scores (PRS) combine information from many common genetic variations to estimate an individual's genetic susceptibility to conditions like breast cancer. A higher PRS indicates an increased genetic predisposition, but it does not mean that breast cancer will definitely develop. The severity and prognosis of breast cancer depend on various factors, including the type of cancer, its stage at diagnosis, and how it responds to treatment.
Genetic causes
Breast cancer risk is influenced by a complex combination of genetic and non-genetic factors. For most people, the genetic component of breast cancer risk is 'polygenic', meaning it involves contributions from many common genetic variations, each with a small individual effect. Genes such as FGFR2, LSP1, MAP3K1, and TOX3 are among those that contain common genetic variations known to be associated with breast cancer risk [PMID:24076352]. These genes encode proteins involved in various cellular processes crucial for cell growth, division, and communication.
For example, FGFR2 produces a protein involved in cell signalling pathways that regulate cell proliferation and differentiation. Common variations near this gene may alter its function, contributing to an increased risk of breast cancer. Similarly, LSP1 is involved in lymphocyte activity and cell scaffolding, while MAP3K1 plays a role in cell signalling pathways important for cell growth and survival. TOX3 is involved in gene regulation. Pathogenic variants in any of these genes, along with many others across the genome, can subtly modify cellular processes, collectively increasing an individual's susceptibility to developing breast cancer.
Inheritance pattern
Polygenic risk for breast cancer is inherited in a complex pattern, rather than a simple Mendelian fashion (like autosomal dominant or recessive inheritance). This means that a person inherits a combination of many common genetic variants from both parents. Each of these variants contributes a small amount to the overall risk of developing breast cancer.
Unlike conditions caused by a single gene, there isn't a simple 50% chance of passing on the risk. Instead, family members will share some, but not all, of the predisposing genetic variants. This explains why breast cancer can 'run in families' even when a specific high-risk single-gene mutation (like in BRCA1 or BRCA2) is not identified. An individual's overall genetic risk is a sum of these many small contributions, combined with environmental and lifestyle factors.
Diagnosis & testing
Diagnosing breast cancer typically begins with a clinical examination by a GP, who may refer an individual to a specialist breast clinic. Further investigations often include imaging techniques such as mammography (X-ray of the breast), ultrasound, or MRI scans. A biopsy, where a small sample of breast tissue is removed for microscopic examination, is usually required to confirm a diagnosis.
For individuals with a family history of breast cancer, or those seeking a more detailed risk assessment, genetic testing for polygenic risk may be considered. In the NHS Genomic Medicine Service, genetic testing involves specific R-codes for hereditary breast cancer, but polygenic risk scores are a newer tool for assessing risk. A clinical genetics service or genetic counsellor can discuss the relevance of such testing and interpret the results in the context of an individual's overall risk profile.
Management & lifestyle
Managing breast cancer involves a multidisciplinary approach tailored to the individual, considering the type and stage of cancer, as well as personal preferences and health status. Treatment options may include surgery (such as a lumpectomy or mastectomy), radiotherapy, chemotherapy, hormone therapy, targeted therapy, and immunotherapy. Surveillance following treatment is crucial, involving regular check-ups and imaging.
For individuals with an elevated polygenic risk, management focuses on personalised screening strategies and risk reduction. This may involve earlier and more frequent mammograms, adopting a healthy lifestyle (e.g., maintaining a healthy weight, regular physical activity, limiting alcohol intake), and potentially discussing risk-reducing medications with a healthcare professional. Individuals are encouraged to follow NHS screening guidelines and discuss any concerns with their GP or a specialist. Genetic counselling can also provide valuable support and information regarding risk management.
UK care pathway
In the UK, suspected breast cancer prompts referral via the NHS 'two-week wait' pathway to a specialist breast clinic. If a genetic component to breast cancer is suspected, particularly with a strong family history, referral to a clinical genetics service is typically undertaken. These services, often accessed through an R-code within the NHS Genomic Medicine Service, provide specialist genetic counselling and testing. Genetic counsellors can help individuals understand their risk, the implications for family members, and the available screening and risk-reduction strategies.
Frequently asked questions
What does 'polygenic risk' mean for breast cancer?
Polygenic risk means that your likelihood of developing breast cancer is influenced by many common genetic variations, each having a small effect. These variations combine, along with lifestyle and environmental factors, to create your overall breast cancer risk, rather than one single 'faulty' gene.
If I have a high polygenic risk score, will I definitely get breast cancer?
No, a high polygenic risk score (PRS) indicates an increased genetic predisposition, meaning you have a higher likelihood compared to someone with a lower PRS. However, it does not guarantee that you will develop breast cancer, as many other factors also play a role. It helps inform personalised screening and risk reduction strategies.
How is polygenic risk different from inheriting a BRCA1 or BRCA2 gene variant?
Polygenic risk involves many common genetic variants with small effects, contributing to a moderate increase in overall risk. Inheriting a BRCA1 or BRCA2 gene variant, on the other hand, means you have a specific, rare change in a single gene that dramatically increases your lifetime risk of developing breast and other cancers, and this risk is often passed down in a predictable pattern within families.
Can lifestyle changes reduce my breast cancer risk if I have a high polygenic risk?
Yes, even with an elevated polygenic risk, lifestyle choices can help to reduce your overall breast cancer risk. Maintaining a healthy weight, regular physical activity, limiting alcohol, and not smoking are all recommended. Discussing these and other potential risk-reducing strategies with your GP or a genetic counsellor is advisable.
Where can I get more information or support for breast cancer?
The NHS website, Breast Cancer Now, and Macmillan Cancer Support are excellent resources for information and support about breast cancer in the UK. Your GP can also provide guidance and refer you to specialist services, including clinical genetics, if appropriate.
References
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