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Lung cancer (polygenic risk)
This type of lung cancer risk is influenced by many genes, each contributing a small effect, alongside environmental factors. It affects individuals based on their unique genetic make-up and lifestyle choices, such as smoking history.
Overview
Lung cancer is a serious condition where abnormal cells grow uncontrollably in the lungs. When we talk about polygenic risk for lung cancer, it means that many different genes, rather than a single gene, work together to influence an individual's chance of developing the disease. Each of these genes contributes a small amount to the overall risk. This complex interaction between multiple genes and environmental factors, such as smoking, determines a person's overall susceptibility to lung cancer [PMID:33671764].
Symptoms & clinical features
The symptoms of lung cancer, regardless of its underlying genetic or environmental causes, often develop in later stages of the disease. Common symptoms may include a persistent cough that doesn't go away or gets worse, coughing up blood, breathlessness, persistent chest pain, unexplained weight loss, and fatigue. Some individuals may also experience recurrent chest infections. These symptoms can also be caused by other less serious conditions.
Video: Is cancer in your genes?
Affected organs
Lung cancer primarily affects the lungs, which are vital organs located in the chest that are responsible for breathing. As the cancer progresses, it can spread to other parts of the body through the bloodstream or lymphatic system, a process known as metastasis. This spread can impact various organs such as the lymph nodes, bones, brain, liver, and adrenal glands, leading to additional symptoms related to these areas.
Risks & severity
Lung cancer is a significant health concern, with an estimated lifetime risk of around 6% in the general population. The severity and prognosis of lung cancer vary widely depending on the type of cancer, its stage at diagnosis, and the individual's overall health. Polygenic risk means that while specific genetic variations might increase susceptibility, they do not guarantee that an individual will develop the disease. Environmental factors, particularly smoking, are major contributors to lung cancer risk and significantly interact with genetic predispositions [PMID:33671764]. Age of onset is typically later in life, commonly affecting individuals over 60, though it can occur earlier.
Genetic causes
Polygenic risk for lung cancer involves variations in several genes, each contributing a small increase to an individual's overall susceptibility. Key genes that have been associated with lung cancer risk include CHRNA5, TERT, and TP63 [PMID:22080352]. CHRNA5 provides instructions for making a component of nicotinic acetylcholine receptors, which are found in nerve cells and play a role in nicotine addiction and the body's response to nicotine from tobacco. Variations in CHRNA5 may influence how a person responds to smoking and their risk of lung cancer. TERT is involved in maintaining telomeres, structures at the ends of chromosomes that protect genetic information; abnormal TERT function can contribute to uncontrolled cell growth. TP63 is a gene that helps control cell growth and development, and variants in this gene may also affect cancer risk. The combined effects of variations in these and many other genes, alongside environmental exposures, determine an individual's overall polygenic risk.
Inheritance pattern
Polygenic or complex inheritance means that lung cancer risk is influenced by multiple genes working together, rather than a single gene following a simple dominant or recessive pattern. This also means that environmental factors play a significant role. If someone has a higher polygenic risk, it suggests they have inherited a combination of genetic variations that make them more susceptible to lung cancer. However, this does not mean their children will automatically have the same risk, as offspring inherit a different combination of genetic variants from both parents. Inheritance patterns for complex conditions do not follow the straightforward predictions seen in single-gene disorders, making it challenging to predict risk within families with certainty.
Diagnosis & testing
Diagnosing lung cancer typically involves a combination of clinical assessment, imaging scans such as X-rays, CT scans, and PET scans, and biopsies. A biopsy, where a small tissue sample is taken from the suspected tumour, is crucial for confirming the diagnosis and determining the specific type of lung cancer. While polygenic risk scores are emerging research tools, they are not currently used for routine clinical diagnosis of lung cancer within the NHS. Genetic counselling services can provide information about an individual's potential genetic risks and discuss the implications for family members. Referral to clinical genetics services, often via an NHS R-code, would typically be initiated by a specialist if there were concerns about a strong family history or other genetic predispositions, but polygenic risk for lung cancer is not currently part of routine genetic testing pathways.
Management & lifestyle
Management of lung cancer is highly individualised and depends on the type, stage, and location of the cancer, as well as the patient's overall health. Treatment options may include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. For individuals with an increased polygenic risk, management focuses on reducing environmental risk factors, most notably avoiding smoking and exposure to secondhand smoke. Regular check-ups and being aware of potential symptoms are also important. The NHS provides comprehensive cancer services, and individuals diagnosed with lung cancer will be managed by a multidisciplinary team of specialists. Genetic counselling can offer support and information for those concerned about their family's risk profile.
UK care pathway
Within the UK's NHS Genomic Medicine Service, individuals with suspected or diagnosed lung cancer will generally be managed through established oncology pathways. While polygenic risk scoring is a developing area, it is not currently a standard part of the diagnostic or management pathway for lung cancer within the NHS. Referral to clinical genetics services, guided by specific NHS R-codes, typically occurs for rare single-gene disorders or strong family histories that suggest a Mendelian inheritance pattern, rather than for polygenic risk. Genetic counsellors can provide valuable support and information regarding genetic conditions and family history of cancer.
Frequently asked questions
What does 'polygenic risk' mean for lung cancer?
Polygenic risk means that your chance of developing lung cancer is influenced by many different genes, each contributing a small effect, rather than just one gene. This combined genetic influence, alongside lifestyle and environmental factors, determines your overall susceptibility.
If I have a polygenic risk, will I definitely get lung cancer?
No, having a polygenic risk does not mean you will definitely develop lung cancer. It means you have a higher genetic susceptibility. Environmental factors, especially smoking, significantly interact with this genetic risk. Many people with a higher polygenic risk never develop the disease, especially if they avoid major risk factors.
Are there specific genes involved in polygenic lung cancer risk?
Yes, research has identified several genes that contribute to polygenic lung cancer risk, such as CHRNA5, TERT, and TP63. Variations in these genes can influence how your body responds to environmental factors like nicotine, or affect cell growth and repair mechanisms.
Can my family members inherit my polygenic risk for lung cancer?
Polygenic risk is complex. While your children will inherit some of your genetic variations, they will also inherit variations from the other parent. This means their specific combination of genes, and therefore their polygenic risk, will be unique. It doesn't follow the straightforward inheritance patterns seen in conditions caused by a single gene.
How can I reduce my risk if I have a higher polygenic susceptibility?
The most effective way to reduce your risk, even with a higher polygenic susceptibility, is to avoid or stop smoking and minimise exposure to secondhand smoke. Maintaining a healthy lifestyle, including a balanced diet and regular physical activity, may also contribute to overall health and potentially reduce cancer risk.
References
- Gorman BR, Ji SG, Francis M. Multi-ancestry GWAS meta-analyses of lung cancer reveal susceptibility loci and elucidate smoking-independent genetic risk. Nature communications. 2024. PMID: 39366959
- Lebrett MB, Smith MJ, Crosbie EJ. Validation of lung cancer polygenic risk scores in a high-risk case-control cohort. Genetics in medicine : official journal of the American College of Medical Genetics. 2023. PMID: 37154150
- Chang SL, Chuan PM, Lai CH. Greater lung cancer polygenic risk score in higher air pollution areas linked to greater rate of lung adenocarcinoma: a single-centre study in East Asia. BMJ open respiratory research. 2025. PMID: 41083276
- Ma Z, Zhu Z, Pang G. Development and validation of a lung cancer polygenic risk score incorporating susceptibility variants for risk factors. International journal of cancer. 2025. PMID: 39378120
- Wang X, Zhang Z, Ding Y. Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification. Genome medicine. 2024. PMID: 38317189
- Xie J, Zhu M, Ji M. Relationships between sleep traits and lung cancer risk: a prospective cohort study in UK Biobank. Sleep. 2021. PMID: 33823024