Search

Background: In a 2018 descriptive study, cancer incidence in children (age 0–19) in diagnosis years 2003 to 2014 was reported as being highest in New Hampshire and in the Northeast region. Methods: Using the Cancer in North America (CiNA) analytic file, we tested the hypotheses that incidence rates in the Northeast were higher than those in other regions of the United States either overall or by race/ethnicity group, and that rates in New Hampshire were higher than the Northeast region as a whole. Results: In 2003 to 2014, pediatric cancer incidence was significantly higher in the Northeast than other regions of the United States overall and among non-Hispanic Whites and Blacks, but not among Hispanics and other racial minorities. However, there was no significant variability in incidence in the states within the Northeast overall or by race/ethnicity subgroup. Overall, statistically significantly higher incidence was seen in the Northeast for lymphomas [RR, 1.15; 99% confidence interval (CI), 1.10–1.19], central nervous system neoplasms (RR, 1.12; 99% CI, 1.07–1.16), and neuroblastoma (RR, 1.13; 99% CI, 1.05–1.21). Conclusions: Pediatric cancer incidence is statistically significantly higher in the Northeast than in the rest of the United States, but within the Northeast, states have comparable incidence. Differences in cancer subtypes by ethnicity merit further investigation. Impact: Our analyses clarify and extend previous reports by statistically confirming the hypothesis that the Northeast has the highest pediatric cancer rates in the country, by providing similar comparisons stratified by race/ethnicity, and by assessing variability within the Northeast.

Despite substantial observational and experimental evidence that aspirin use can provide protection against the development of colorectal neoplasia, our understanding of the molecular mechanisms involved is inadequate and limits our ability to use this drug effectively and safely for chemoprevention. We employed an untargeted plasma metabolomics approach using liquid chromatography with high-resolution mass spectroscopy to explore novel metabolites that may contribute to the chemopreventive effects of aspirin. Associations between levels of metabolic features in plasma and aspirin treatment were investigated among 523 participants in a randomized placebo-controlled clinical trial of two doses of aspirin (81 or 325 mg/day) and were linked to risk of colorectal adenoma occurrence over 3 years of follow-up. Metabolic pathways that were altered with aspirin treatment included linoleate and glycerophospholipid metabolism for the 81-mg dose and carnitine shuttle for both doses. Metabolites whose levels increased with 81 mg/day aspirin treatment and were also associated with decreased risk of adenomas during follow-up included certain forms of lysophosphatidylcholine and lysophosphatidylethanolamine as well as trihydroxyoctadecenoic acid, which is a derivative of linoleic acid and is upstream of cyclooxygenase inhibition by aspirin in the linoleate and arachidonic acid metabolism pathways. In conclusion, our findings regarding lysophospholipids and metabolites in the linoleate metabolism pathway may provide novel insights into the chemopreventive effects of aspirin in the colorectum, although they should be considered hypothesis-generating at this time. Prevention Relevance: This research used metabolomics, an innovative discovery-based approach, to identify molecular changes in human blood that may help to explain how aspirin use reduces the risk of colorectal neoplasia in some individuals. Ultimately, this work could have important implications for optimizing aspirin use in the prevention of colorectal cancer.

In a randomized trial of folic acid supplementation for the prevention of colorectal adenomas, we previously found indications of increased risk during later treatment and follow-up. This could have been due to the unmetabolized folic acid (UFA) or natural reduced and methylated folates (mF) to which it is metabolized. In post hoc analyses, we measured mF (the sum of 5-methyl-tetrahydrofolate and 4-alfa-hydroxy-5-methyl-THF) and UFA concentrations in the serum of 924 participants. Using binomial regression models with a log link, we assessed the associations between plasma mF or UFA and adenoma occurrence. We found no association between plasma mF or UFA and overall adenoma risk. However, during later follow-up, the prespecified, composite endpoint of high-risk findings (advanced or multiple adenomas) was positively associated with plasma mF (Plinear trend = 0.009), with a 58% increased risk for participants in the upper versus lowest quartile. An irregular association was seen with plasma UFA, with suggestions of an inverse trend (Plinear trend=0.049). A modest, significant inverse association was also seen between mF and risk of serrated lesions, with a 39% lower risk for upper versus lower quartile participants (Plinear trend = 0.03). In conclusion, during the later follow-up period in which folic acid supplementation was previously seen to increase the risk of advanced and multiple adenomas, higher serum mF was associated with a higher risk of multiple and/or advanced adenomas, but no clear indication that UFA played a direct role. There were indications that higher mF was associated with reduced risk of serrated polyps. Cancer Prev Res; 10(8); 451–8. ©2017 AACR.

Additional analyses of folate and adenoma outcomes.

Table S1 shows metabolic features with confirmed or putative identities.

Supplementary Table from Plasma Metabolomics Analysis of Aspirin Treatment and Risk of Colorectal Adenomas

Supplementary Figure from Plasma Metabolomics Analysis of Aspirin Treatment and Risk of Colorectal Adenomas

Figure S1 shows changes in aspirin catabolite intensities between baseline and year 3 blood plasma samples.

In a randomized trial of folic acid supplementation for the prevention of colorectal adenomas, we previously found indications of increased risk during later treatment and follow-up. This could have been due to the unmetabolized folic acid (UFA) or natural reduced and methylated folates (mF) to which it is metabolized. In post hoc analyses, we measured mF (the sum of 5-methyl-tetrahydrofolate and 4-alfa-hydroxy-5-methyl-THF) and UFA concentrations in the serum of 924 participants. Using binomial regression models with a log link, we assessed the associations between plasma mF or UFA and adenoma occurrence. We found no association between plasma mF or UFA and overall adenoma risk. However, during later follow-up, the prespecified, composite endpoint of high-risk findings (advanced or multiple adenomas) was positively associated with plasma mF (Plinear trend = 0.009), with a 58% increased risk for participants in the upper versus lowest quartile. An irregular association was seen with plasma UFA, with suggestions of an inverse trend (Plinear trend=0.049). A modest, significant inverse association was also seen between mF and risk of serrated lesions, with a 39% lower risk for upper versus lower quartile participants (Plinear trend = 0.03). In conclusion, during the later follow-up period in which folic acid supplementation was previously seen to increase the risk of advanced and multiple adenomas, higher serum mF was associated with a higher risk of multiple and/or advanced adenomas, but no clear indication that UFA played a direct role. There were indications that higher mF was associated with reduced risk of serrated polyps. Cancer Prev Res; 10(8); 451–8. ©2017 AACR.

Epidemiological studies indicate that vitamin D has antineoplastic effects in the colorectum and suggest that vitamin D supplementation may be a promising chemopreventative approach to reduce risk of colorectal cancer. Thus, it is important to consider how genetic factors may modify vitamin D status and response to vitamin D supplementation. We investigated this question among 2,259 participants randomized in the Vitamin D/Calcium Polyp Prevention Study, an on-going, double-blind, placebo-controlled clinical trial of supplementation with vitamin D3 (1000 IU/day) and/or calcium carbonate (1200 mg elemental calcium/day) for the prevention of colorectal adenomas. Candidate single nucleotide polymorphisms (SNPs) were genotyped in or near seven genes involved in vitamin D or calcium metabolism, transport or signaling. Excluding SNPs with MAF0.8, 23 SNPs were analyzed in vitamin D binding protein (GC), 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1), 1-hydroxylase (CYP27B1), 7-dehydrocholesterol reductase (DHCR7), vitamin D receptor (VDR), and calcium-sensing receptor (CaSR). These included 5 SNPs previously associated with circulating 25-hydroxyvitamin D levels in genome-wide association studies (GWAS): rs2282679, rs12785878, rs3829251, rs10741657 and rs6013897. Linear regression was used to estimate associations with baseline serum 25-hydroxyvitamin D levels and with levels of 25-hydroxyvitamin D achieved after approximately one year of vitamin D supplementation in the trial after adjusting for baseline levels. Analyses were restricted to non-Hispanic white participants (82%) to avoid population stratification and additive genetic models were used. Baseline 25-hydroxyvitamin D was statistically significantly associated with genotype at 3 GWAS hits in GC, DHCR7 and CYP2R1 and at 5 other SNPs in GC, CYP2R1 and CYP24A1. When response to supplementation was investigated, compliance with pill taking was taken into account by restricting analyses to optimally compliant subjects. Genotype at 3 SNPs in VDR, CYP2R1, and CYP24A1 statistically significantly modified the 25-hydroxyvitamin D level achieved with vitamin D supplementation. In conclusion, we have identified variation in or near key vitamin D and calcium pathway genes that modify serum 25-hydroxyvitamin D status and the response to supplementation with vitamin D. This research may identify individuals at risk for poor response to vitamin D supplementation. The public health significance of this work is substantial due to the prevalence of vitamin D insufficiency and the high incidence of colorectal cancer, osteoporosis, and other common diseases associated with poor vitamin D status. Citation Format: Elizabeth L. Barry, Leila A. Mott, Janet L. Peacock, Judith R. Rees, John A. Baron. Genetic correlates of serum 25-hydroxyvitamin D levels and response to vitamin D supplementation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2196. doi:10.1158/1538-7445.AM2013-2196