Genetic Risk, Health-Associated Lifestyle, and Risk of Early-onset Total Cancer and Breast Cancer

Abstract

Importance: Early-onset cancer (diagnosed under 50 years of age) is associated with aggressive disease characteristics and its rising incidence is a global concern. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants is unknown.

Objective: To examine the associations between genetic risk, lifestyle, and risk of early-onset cancers.

Design setting and participants: We analyzed a prospective cohort of 66,308 white British participants who were under age 50 and free of cancer at baseline in the UK Biobank.

Exposures: Sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs, which summarize smoking status, body mass index [males only], physical activity, alcohol consumption, and diet).

Main outcomes and measures: Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer.

Results: A total of 1,247 incident invasive early-onset cancer cases (female: 820, male: 427, breast: 386) were documented. 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: 1.85, 1.50-2.29) and males (1.94, 1.45-2.59) as well as early-onset breast cancer in females (3.06, 2.20-4.25). 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 was stronger in the highest genetic risk category than the lowest: HRs in females and men were 1.85 (1.02, 3.36), 3.27 (0.78, 13.72) in the highest genetic risk category and 1.15 (0.44, 2.98), 1.16 (0.39, 3.40) in the lowest.

Conclusions and relevance: Both genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Compared to those with low genetic risk, individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.

Figure 1.

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. Multivariate analyses of early-onset total cancer were stratified by sex, and adjust for the first 10 genetic principal components for ancestry, genotyping batch, average total household income, education, BMI (females only), and family history of cancer (family history of breast cancer was used in analyses of breast cancer), plus adjustment of HLS. Multivariate 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. Abbreviations: PRS, polygenic risk score; HLS, health-associated lifestyle score; SD, standard deviation; BMI, body mass index.

Figure 2:

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. Multivariate analyses of early-onset total cancer were stratified by sex, and adjust for the first 10 genetic principal components for ancestry, genotyping batch, average total household income, education, BMI (females only), and family history of cancer (family history of breast cancer was used in analyses of breast cancer), plus adjustment of PRS. Multivariate 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. Abbreviations: PRS, polygenic risk score; HLS, health-associated lifestyle score; BMI, body mass index.

Figure 3:

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 females, stratified by female-specific total cancer PRS. B: Multivariable-adjusted analysis of male-specific HLS and early-onset total cancer in males, stratified by male-specific total cancer PRS. C: Multivariable-adjusted analysis of female-specific HLS and early-onset breast cancer in females, stratified by breast cancer PRS. Multivariate analyses of early-onset total cancer were stratified by sex, and adjust for the first 10 genetic principal components for ancestry, genotyping batch, average total household income, education, BMI (females only), and family history of cancer (family history of breast cancer was used in analyses of breast cancer). Multivariate 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. Abbreviations: PRS, polygenic risk score; HLS, health-associated lifestyle score; BMI, body mass index.

Figure 3:

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 females, stratified by female-specific total cancer PRS. B: Multivariable-adjusted analysis of male-specific HLS and early-onset total cancer in males, stratified by male-specific total cancer PRS. C: Multivariable-adjusted analysis of female-specific HLS and early-onset breast cancer in females, stratified by breast cancer PRS. Multivariate analyses of early-onset total cancer were stratified by sex, and adjust for the first 10 genetic principal components for ancestry, genotyping batch, average total household income, education, BMI (females only), and family history of cancer (family history of breast cancer was used in analyses of breast cancer). Multivariate 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. Abbreviations: PRS, polygenic risk score; HLS, health-associated lifestyle score; BMI, body mass index.

Figure 4.

Joint associations of PRS and HLS with early-onset total and breast cancer risk A: Multivariable-adjusted joint association analysis of female-specific total cancer PRS and female-specific HLS with early-onset total cancer in females. B: Multivariable-adjusted joint association analysis of male-specific total cancer PRS and male-specific HLS with early-onset total cancer in males. C: Multivariable-adjusted joint association analysis of breast cancer PRS and female-specific HLS with early-onset breast cancer in females. Multivariate analyses of early-onset total cancer were stratified by sex, and adjust for the first 10 genetic principal components for ancestry, genotyping batch, average total household income, education, BMI (females only), and family history of cancer (family history of breast cancer was used in analyses of breast cancer). Multivariate 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 both low PRS and healthy HLS. Abbreviations: PRS, polygenic risk score; HLS, health-associated lifestyle score; BMI, body mass index.

Figure 4.

Joint associations of PRS and HLS with early-onset total and breast cancer risk A: Multivariable-adjusted joint association analysis of female-specific total cancer PRS and female-specific HLS with early-onset total cancer in females. B: Multivariable-adjusted joint association analysis of male-specific total cancer PRS and male-specific HLS with early-onset total cancer in males. C: Multivariable-adjusted joint association analysis of breast cancer PRS and female-specific HLS with early-onset breast cancer in females. Multivariate analyses of early-onset total cancer were stratified by sex, and adjust for the first 10 genetic principal components for ancestry, genotyping batch, average total household income, education, BMI (females only), and family history of cancer (family history of breast cancer was used in analyses of breast cancer). Multivariate 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 both low PRS and healthy HLS. Abbreviations: PRS, polygenic risk score; HLS, health-associated lifestyle score; BMI, body mass index.