Genetic risk, health-associated lifestyle, and risk of early-onset total cancer and breast cancer

Abstract

Background: Early-onset cancer (diagnosed under age 50) generally manifests as an aggressive disease phenotype. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants remains unclear.

Methods: We analyzed a prospective cohort of 66 308 participants who were under age 50 and free of cancer at baseline in the UK Biobank. Using Cox regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer based on sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs).

Results: In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI = 1.83, 1.49 to 2.26) and males (2.03, 1.51 to 2.73) as well as early-onset breast cancer in females (3.06, 2.20 to 4.26). An unfavorable lifestyle (highest vs lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer and breast cancer was stronger in the highest genetic risk category than the lowest: HRs (95% CIs) were 1.55 (1.12 to 2.14) and 1.69 (1.11 to 2.57) in the highest genetic risk category and 1.03 (0.64 to 1.67) and 0.81 (0.36 to 1.85) in the lowest.

Conclusions: Genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.

Figure 1.

The associations between PRS and early-onset total and breast cancer risk. A) Multivariable-adjusted analysis of female-specific total cancer PRS and early-onset total cancer in females. B) Multivariable-adjusted analysis of male-specific total cancer PRS and early-onset total cancer in males. C) Multivariable-adjusted analysis of breast cancer PRS and early-onset breast cancer in females. Multivariable analyses of early-onset total cancer were stratified by sex and adjusted for the first 10 genetic principal components for ancestry, genotyping batch, average total household income, education, BMI (female only), and family history of cancer (family history of breast cancer was used in analyses of breast cancer), plus adjustment of HLS. Multivariable analyses of early-onset breast cancer were adjusted for above-mentioned covariates and were additionally adjusted for age at menarche, parity, age at first live birth, oral contraceptive use, menopausal status and hormone replacement therapy use, and history of mammograms. Reference group: individuals with low PRS. PRS = polygenic risk score; HLS = health-associated lifestyle score; SD = standard deviation; BMI = body mass index.

Figure 2.

The associations between HLS and early-onset total and breast cancer risk. A) Multivariable-adjusted analysis of female-specific HLS and early-onset total cancer in females. B) Multivariable-adjusted analysis of male-specific HLS and early-onset total cancer in males. C) Multivariable-adjusted analysis of female-specific HLS and early-onset breast cancer in females. Multivariable analyses of early-onset total cancer were stratified by sex and adjusted for the first 10 genetic principal components for ancestry, genotyping batch, average total household income, education, BMI (female only), and family history of cancer (family history of breast cancer was used in analyses of breast cancer), plus adjustment of PRS. Multivariable analyses of early-onset breast cancer were adjusted for above-mentioned covariates and were additionally adjusted for age at menarche, parity, age at first live birth, oral contraceptive use, menopausal status and hormone replacement therapy use, and history of mammograms. Reference group: individuals with healthy HLS. PRS = polygenic risk score; HLS = health-associated lifestyle score; BMI = body mass index.

Figure 3.

The associations between HLS and early-onset total and breast cancer risk, stratified by PRS category. A) Multivariable-adjusted analysis of female-specific HLS and early-onset total cancer in female patients, stratified by female-specific total cancer PRS. B) Multivariable-adjusted analysis of male-specific HLS and early-onset total cancer in male patients, stratified by male-specific total cancer PRS. C) Multivariable-adjusted analysis of female-specific HLS and early-onset breast cancer in female patients, stratified by breast cancer PRS. Multivariable analyses of early-onset total cancer were stratified by sex and adjusted for the first 10 genetic principal components for ancestry, genotyping batch, average total household income, education, BMI (female only), and family history of cancer (family history of breast cancer was used in analyses of breast cancer). Multivariable analyses of early-onset breast cancer were adjusted for above-mentioned covariates and were additionally adjusted for age at menarche, parity, age at first live birth, oral contraceptive use, menopausal status and hormone replacement therapy use, and history of mammograms. Reference group: individuals with healthy HLS within each PRS stratum. PRS = polygenic risk score; HLS = health-associated lifestyle score; BMI = body mass index.