Search

Background: Neuroblastoma is the most common pediatric solid tumor. MYCN‐amplification is an important negative prognostic indicator and inherited genetic contributions to risk are incompletely understood. Genetic determinants of stature increase risk of several adult and childhood cancers, but have not been studied in neuroblastoma despite elevated neuroblastoma incidence in children with congenital overgrowth syndromes. Methods: We investigated the association between genetic determinants of height and neuroblastoma risk in 1538 neuroblastoma cases, stratified by MYCN‐amplification status, and compared to 3390 European‐ancestry controls using polygenic scores for birth length (five variants), childhood height (six variants), and adult height (413 variants). We further examined the UK Biobank to evaluate the association of known neuroblastoma risk loci and stature. Results: An increase in the polygenic score for childhood stature, corresponding to a ~0.5 cm increase in pre‐pubertal height, was associated with greater risk of MYCN‐amplified neuroblastoma (OR = 1.14, P =.047). An increase in the polygenic score for adult stature, corresponding to a ~1.7 cm increase in adult height attainment, was associated with decreased risk of MYCN‐amplified neuroblastoma (OR = 0.87, P =.047). These associations persisted in case‐case analyses comparing MYCN‐amplified to MYCN‐unamplified neuroblastoma. No polygenic height scores were associated with MYCN‐unamplified neuroblastoma risk. Previously identified genome‐wide association study hits for neuroblastoma (N = 10) were significantly enriched for association with both childhood (P = 4.0 × 10−3) and adult height (P = 8.9 × 10−3) in >250 000 UK Biobank study participants. Conclusions: Genetic propensity to taller childhood height and shorter adult height were associated with MYCN‐amplified neuroblastoma risk, suggesting that biological pathways affecting growth trajectories and pubertal timing may contribute to MYCN‐amplified neuroblastoma etiology. [ABSTRACT FROM AUTHOR]

Cancer site-specific polygenic risk scores (PRS) effectively identify individuals at high risk of individual cancers, but the effectiveness of PRS on overall cancer risk assessment and the extent to which a high genetic risk of overall cancer can be offset by a healthy lifestyle remain unclear. Here, we constructed an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific PRSs. Lifestyle was determined according to smoking, alcohol consumption, physical activity, body mass index, and diet. Cox regression by sex was used to analyze associations of genetic and lifestyle factors with cancer incidence using UK Biobank data ( N = 442,501). Compared with participants at low genetic risk (bottom quintile of CPRS), those at intermediate (quintiles 2 to 4) or high (top quintile) genetic risk had HRs of 1.27 (95% confidence interval, 1.21-1.34) or 1.91 (1.81-2.02) for overall cancer, respectively, for men, and 1.21 (1.16-1.27) or 1.62 (1.54-1.71), respectively, for women. A joint effect of genetic and lifestyle factors on overall cancer risk was observed, with HRs reaching 2.99 (2.45-3.64) for men and 2.38 (2.05-2.76) for women with high genetic risk and unfavorable lifestyle compared with those with low genetic risk and favorable lifestyle. Among participants at high genetic risk, the standardized 5-year cancer incidence was significantly reduced from 7.23% to 5.51% for men and from 5.77% to 3.69% for women having a favorable lifestyle. In summary, individuals at high genetic risk of overall cancer can be identified by CPRS, and risk can be attenuated by adopting a healthy lifestyle. SIGNIFICANCE: A new indicator of cancer polygenic risk score measures genetic risk for overall cancer, which could identify individuals with high cancer risk to facilitate decision-making about lifestyle modifications for personalized prevention., (©2021 American Association for Cancer Research.)