The presence of genetic risk factors significantly increases the probability of developing lung cancer in smokers, particularly heavy smokers. However, even with a high genetic risk for lung cancer, individuals who never smoke do not have a significantly increased risk of developing the condition, a prospective cohort study has found. 

Data were used from the UK Biobank study which recruited more than 500,000 individuals aged 40-69 between 2006 and 2009. As well as giving detailed lifestyle information these volunteers contributed blood samples for genotyping.

A total of 33 genetic variants associated with lung cancer were used to calculate a polygenic risk score. Individuals were classified as high, intermediate and low genetic risk.

Individuals with a diagnosis of lung cancer after their baseline assessment were identified from national cancer registries.

Multivariable Cox proportional hazard models were used to explore the association between genetic risk categories, smoking categories, and the combination of genetic risk and smoking categories. Interactions between polygenic risk scores and smoking status were tested.

A total of 345,794 individuals, mean age 56.3 (53.9% female) with complete data on genotype and phenotype, were followed up for a median of 7.2 years, and included in the analysis. There were 90,727 (26.2%) former smokers and 33,994 (9.8%) current smokers; 40,889 (11.8%) had intermediate smoking exposure (20-39.9 pack-years) and 19,027 (5.5%) heavy smoking exposure ( ≥ 40 pack-years).

Over the 2,454,915 person-years of follow-up there were 1,687 cases of incident lung cancer. As the genetic risk increased, the incidence rate and hazard ratio (HR) of lung cancer gradually increased.

As expected, increased numbers of pack-years were associated with more frequent incident lung cancer. After adjusting for the polygenic risk score, compared with never smoking:  Current smoking HR 14.54 (95% CI: 12.47-16.94)

Heavy smoking HR 17.80 (95% CI: 15.23-20.81).

For individuals who had never smoked the risk of lung cancer in the high genetic risk group was not significantly different from those in the low genetic risk group.

For smokers with a high genetic risk, risk of lung cancer was significantly increased, especially in heavy smokers.

Risk of incident lung cancer according to genetic risk and smoking status

• Low genetic risk and current smoking:

HR 11.31 (95% CI: 7.84-16.33)

• High genetic risk and current smoking:

HR 22.46 (95% CI: 15.99-31.53)

• High genetic risk and heavy smoking ( ≥ 40 pack years):

HR 27.02 (95% CI: 19.28-37.88)

This study reinforces evidence that smoking is demonstrably a causal factor for lung cancer and in smokers with a genetic risk the probability of developing lung cancer significantly increases further. However, even with a high genetic risk for lung cancer, individuals who never smoke do not have a significantly increased risk of developing the condition.

Dr Peter Saul

Zhang P, Chen P-L, Li Z-H et al. Association of smoking and polygenic risk with the incidence of lung cancer: a prospective cohort study. Br J Cancer 2022;126:1637-46