Body Mass Index, Genetic Predisposition, and Obesity-Related Second Cancer Risk in Cancer Survivors

Importance Excess body weight is an established risk factor for second primary cancers (SPCs) among cancer survivors. Whether genetic susceptibility to higher body mass index (BMI) is associated with the risk of obesity-related SPCs remains unclear. Objective To examine associations of genetic predisposition to higher BMI with the risk of obesity-related SPCs and its joint association with BMI. Design, Setting, and Participants This prospective cohort study used data from the Cancer Prevention Study II Nutrition Cohort, a large prospective study of adults residing in 21 states in the US who were cancer-free at the time of the 1992 survey and responded to biennial follow-up questionnaires starting in 1997. Response rates to the biennial questionnaires ranged from 78.1% to 92.1%. Participants for this analysis included cancer survivors who received a diagnosis of a first primary, nonmetastatic invasive cancer between 1992 and 2015, provided a biospecimen sample, and were followed up through 2017. Analyses were conducted between September 2025 and August 2026. Exposures A polygenic score for BMI (PGS-BMI) and BMI. Main Outcomes and Measures Cox proportional hazards models were used to evaluate associations between PGS-BMI and obesity-related SPC risk, as well as between BMI and obesity-related SPC risk stratified by PGS-BMI tertiles. Results This analysis included 14 309 cancer survivors. Their median (IQR) age at first cancer diagnosis was 72.9 (68.2-77.4) years. Approximately 58.6% (8378) of survivors were male, and 58.6% (8382) had a BMI in the overweight (25 to <30) or obese (≥30) range. During a median (IQR) follow-up of 9.1 (4.6-14.2) years, there were 722 (5.0%) obesity-related SPCs. Compared with survivors in the lowest PGS-BMI tertile, those in the highest tertile had greater risk of obesity-related SPCs (hazard ratio [HR], 1.26 [95% CI, 1.06-1.51]). Obesity was associated with increased risk across tertiles of the PGS-BMI without evidence of interaction ( P = .89 for interaction). Compared with survivors with low genetic predisposition and BMI lower than 25, those with low genetic predisposition and obesity had higher obesity-related SPC risk (HR, 1.59 [95% CI, 1.21-2.09]) and those with high genetic predisposition and obesity had the highest risk (HR, 1.82 [95% CI, 1.38-2.40]). The 10-year cumulative incidence ranged from 3.4% (95% CI, 2.9%-4.0%) to 5.1% (95% CI, 4.3%-5.9%) across joint exposure groups. Conclusions and Relevance In this cohort study of cancer survivors, genetic susceptibility to higher BMI was associated with a modestly increased risk of obesity-related SPCs, whereas obesity was associated with greater risk regardless of genetic predisposition. These findings underscore the importance of weight management for all cancer survivors and suggest that a meaningful proportion of obesity-related SPCs may be preventable.