Search

Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly share this data, we created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing pediatric cancer survivorship data. More than 1,600 phenotypic variables and 400 million genetic variants from more than 7,700 childhood cancer survivors can be explored on this free, open-access portal. Summary statistics of variables are computed on-the-fly and visualized through interactive and customizable charts. Survivor cohorts can be customized and/or divided into groups for comparative analysis. Users can also seamlessly perform cumulative incidence and regression analyses on the stored survivorship data. Using the portal, we explored the ototoxic effects of platinum-based chemotherapy, uncovered a novel association between mental health, age, and limb amputation, and discovered a novel haplotype in MAGI3 strongly associated with cardiomyopathy specifically in survivors of African ancestry. Significance: The St. Jude Survivorship Portal is the first data portal designed to share and explore clinical and genetic data from childhood cancer survivors. The portal provides both open- and controlled-access features and will fulfill a wide range of data sharing needs of the survivorship research community and beyond. See co-corresponding author Xin Zhou discuss this research article, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932617204/7d99fa4958., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Hodgkin lymphoma (HL) survivors experience neurocognitive impairment despite receiving no central nervous system-directed therapy, though little is known about the underlying mechanisms., Experimental Design: HL survivors (n = 197) and age-, sex- and race/ethnicity frequency-matched community controls (n = 199) underwent standardized neurocognitive testing, and serum collection. Luminex multiplex or ELISA assays measured markers of inflammation and oxidative stress. Linear regression models compared biomarker concentrations between survivors and controls and with neurocognitive outcomes, adjusting for age, sex, race, body mass index, anti-inflammatory medication, and recent infections., Results: HL survivors [mean (SD) current age 36 (8) years, 22 (8) years after diagnosis] demonstrated higher concentrations of interleukin-6 (IL6), high-sensitivity c-reactive protein (hs-CRP), oxidized low-density lipoprotein, and glutathione peroxidase (GPx), compared with controls (P's < 0.001). Among survivors, higher concentrations of IL6 were associated with worse visuomotor processing speed (P = 0.046). hs-CRP ≥3 mg/L was associated with worse attention, processing speed, memory, and executive function (P's < 0.05). Higher concentrations of malondialdehyde were associated with worse focused attention and visual processing speed (P's < 0.05). Homocysteine was associated with worse short-term recall (P = 0.008). None of these associations were statistically significant among controls. Among survivors, hs-CRP partially mediated associations between cardiovascular or endocrine conditions and visual processing speed, whereas IL6 partially mediated associations between pulmonary conditions and visuomotor processing speed., Conclusions: Neurocognitive function in long-term survivors of HL appears to be associated with inflammation and oxidative stress, both representing potential targets for future intervention trials., (©2024 American Association for Cancer Research.)

Background: An increased risk of neurocognitive deficits, anxiety, and depression has been reported in childhood cancer survivors., Methods: We analyzed associations of neurocognitive deficits, as well as anxiety and depression, with common and rare genetic variants derived from whole-exome sequencing data of acute lymphoblastic leukemia (ALL) survivors from the PETALE cohort. In addition, significant associations were assessed using stratified and multivariable analyses. Next, top-ranking common associations were analyzed in an independent SJLIFE replication cohort of ALL survivors., Results: Significant associations were identified in the entire discovery cohort (N = 229) between the AK8 gene and changes in neurocognitive function, whereas PTPRZ1, MUC16, TNRC6C-AS1 were associated with anxiety. Following stratification according to sex, the ZNF382 gene was linked to a neurocognitive deficit in males, whereas APOL2 and C6orf165 were associated with anxiety and EXO5 with depression. Following stratification according to prognostic risk groups, the modulatory effect of rare variants on depression was additionally found in the CYP2W1 and PCMTD1 genes. In the replication SJLIFE cohort (N = 688), the male-specific association in the ZNF382 gene was not significant; however, a P value<0.05 was observed when the entire SJLIFE cohort was analyzed. ZNF382 was significant in males in the combined cohorts as shown by meta-analyses as well as the depression-associated gene EXO5., Conclusions: Further research is needed to confirm whether the current findings, along with other known risk factors, may be valuable in identifying patients at increased risk of these long-term complications., Impact: Our results suggest that specific genes may be related to increased neuropsychological consequences., (©2023 American Association for Cancer Research.)

Background: What are the major determinants of women's breast cancer risk? Rare mutations such as those in the BRCA1/2 genes, polygenic scores of common alleles identified by genome-wide association studies, or nongenetic factors?, Methods: The population-based Nordic Twin Study of Cancer, with 3,933 breast cancer cases among 21,054 monozygotic (MZ) and 30,939 dizygotic (DZ) female twin pairs, provides three key clues to this question: (i) the average lifetime risk, approximately 8%, does not differ by twin zygosity; (ii) the mean time interval between diagnoses when both twins develop disease (i.e., disease concordance) also does not differ by zygosity; but, (iii) conditioning on one twin having developed disease, the incidence rate in the co-twin is approximately 1% per year if the pair is MZ and 0.5% per year if DZ., Results: Assuming that nongenetic risk factors are shared similarly between twins regardless of zygosity, we can draw two conclusions from (i) to (iii)., Conclusions: First, (i) and (iii) imply that the chief determinant of risk is in the germline DNA, because the conditional incidence rate is several-fold higher than the average risk (8% lifetime) in MZ twins but only half as much in DZ twins. Second, the seeming inconsistency between the two-fold conditional incidence rate (iii) and the equality of the mean inter-twin disease intervals in disease concordance (ii) can be resolved if the risk factors in the germline DNA are rare variants, not common variants., Impact: This paper details simple deductive reasoning for these conclusions and draws a critical inference regarding breast cancer etiology. See related In the Spotlight, p. 1477., (©2023 American Association for Cancer Research.)

We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5 years. Deep sequencing over 39 CH-related genes reveals mutations in 15% of the survivors, significantly higher than the 8.5% in 324 community controls. CH in survivors is associated with exposures to alkylating agents, radiation, and bleomycin. Therapy-related CH shows significant enrichment in STAT3, characterized as a CH gene specific to survivors of Hodgkin lymphoma, and TP53. Single-cell profiling of peripheral blood samples revealed STAT3 mutations predominantly present in T cells and contributed by SBS25, a mutational signature associated with procarbazine exposure. Serial sample tracking reveals that larger clone size is a predictor for future expansion of age-related CH clones, whereas therapy-related CH remains stable decades after treatment. These data depict the distinct dynamics of these CH subtypes and support the need for longitudinal monitoring to determine the potential contribution to late effects., Significance: This first comprehensive CH analysis in long-term survivors of pediatric cancer presents the elevated prevalence and therapy exposures/diagnostic spectrum associated with CH. Due to the contrasting dynamics of clonal expansion for age-related versus therapy-related CH, longitudinal monitoring is recommended to ascertain the long-term effects of therapy-induced CH in pediatric cancer survivors. See related commentary by Collord and Behjati, p. 811. This article is highlighted in the In This Issue feature, p. 799., (©2023 The Authors; Published by the American Association for Cancer Research.)

Numerous common genetic variants have been linked to breast cancer risk, but they only partially explain the total breast cancer heritability. Inference from Nordic population-based twin data indicates rare high-risk loci as the chief determinant of breast cancer risk. Here, we use haplotypes, rather than single variants, to identify rare high-risk loci for breast cancer. With computationally phased genotypes from 181,034 white British women in the UK Biobank, a genome-wide haplotype-breast cancer association analysis was conducted using sliding windows of 5 to 500 consecutive array-genotyped variants. In the discovery stage, haplotype-breast cancer associations were evaluated retrospectively in the prestudy-enrollment data including 5,487 breast cancer cases. Breast cancer hazard ratios (HR) for additive haplotypic effects were estimated using Cox regression. The replication analysis included a prospective cohort of women free of breast cancer at enrollment, of whom 3,524 later developed breast cancer. This two-stage analysis detected 13 rare loci (frequency <1%), each associated with an appreciable breast cancer-risk increase (discovery: HRs = 2.84-6.10, P < 5 × 10-8; replication: HRs = 2.08-5.61, P < 0.01). In contrast, the variants that formed these rare haplotypes individually exhibited much smaller effects. Functional annotation revealed extensive cis-regulatory DNA elements in breast cancer-related cells underlying the replicated rare haplotypes. Using phased, imputed genotypes from 30,064 cases and 25,282 controls in the DRIVE OncoArray case-control study, 6 of the 13 rare-loci associations were found generalizable (odds ratio estimates: 1.48-7.67, P < 0.05). This study demonstrates the complementary advantage of utilizing rare haplotypes to capture novel risk loci and suggests the potential for the discovery of more genetic elements contributing to cancer heritability as large data sets of germline whole-genome sequencing become available., Significance: A genome-wide two-stage haplotype analysis identifies rare haplotypes associated with breast cancer risk and suggests that the rare risk haplotypes represent long-range interactions with regulatory consequences influencing cancer risk., (©2022 American Association for Cancer Research.)

Background: Gonadotoxic treatment-related infertility has a significant impact on quality of life in childhood cancer survivors. Genome-wide association analyses to delineate the risk of infertility in childhood cancer survivors have not been previously reported., Methods: Leveraging genotype data from a large survivor cohort, the Childhood Cancer Survivor Study (CCSS), we investigated the role of SNPs on future pregnancy or siring a pregnancy in survivors without pelvic, testicular, or brain radiation who had ever been married. We calculated sex-stratified hazard ratios, using Cox proportional hazards modeling, adjusting for birth cohort (before 1965 vs. 1965 or later) and doses of relevant chemotherapies; replication was attempted in the independent St. Jude Lifetime Cohort study (SJLIFE)., Results: In the CCSS cohort, nine SNPs were found to be suggestive (P &lt; 10-7) or statistically significantly (P &lt; 5 × 10-8) associated with pregnancy, however, none of the SNPs were replicated in SJLIFE. Cohorts differed based on the overall pregnancy rate, frequency of sterilizing procedures, and birth cohort., Conclusions: We were not able to replicate our findings of SNPs associated with pregnancy in childhood cancer survivors., Impact: Future attempts at replication should be considered in cohorts treated in a comparable era. In addition, understanding the role of genetics in fertility in childhood cancer survivors may be better approached using more advanced sequencing techniques., (©2022 American Association for Cancer Research.)

Therapy-related pulmonary complications are among the leading causes of morbidity among long-term survivors of childhood cancer. Restrictive ventilatory defects (RVD) are prevalent, with risks increasing after exposures to chest radiotherapy and radiomimetic chemotherapies. Using whole-genome sequencing data from 1,728 childhood cancer survivors in the St. Jude Lifetime Cohort Study, we developed and validated a composite RVD risk prediction model that integrates clinical profiles and polygenic risk scores (PRS), including both published lung phenotype PRSs and a novel survivor-specific pharmaco/radiogenomic PRS (surPRS) for RVD risk reflecting gene-by-treatment (GxT) interaction effects. Overall, this new therapy-specific polygenic risk prediction model showed multiple indicators for superior discriminatory accuracy in an independent data set. The surPRS was significantly associated with RVD risk in both training (OR = 1.60, P = 3.7 × 10-10) and validation (OR = 1.44, P = 8.5 × 10-4) data sets. The composite model featuring the surPRS showed the best discriminatory accuracy (AUC = 0.81; 95% CI, 0.76-0.87), a significant improvement (P = 9.0 × 10-3) over clinical risk scores only (AUC = 0.78; 95% CI: 0.72-0.83). The odds of RVD in survivors in the highest quintile of composite model-predicted risk was ∼20-fold higher than those with median predicted risk or less (OR = 20.01, P = 2.2 × 10-16), exceeding the comparable estimate considering nongenetic risk factors only (OR = 9.20, P = 7.4 × 10-11). Inclusion of genetic predictors also selectively improved risk stratification for pulmonary complications across at-risk primary cancer diagnoses (AUCclinical = 0.72; AUCcomposite = 0.80, P = 0.012). Overall, this PRS approach that leverages GxT interaction effects supports late effects risk prediction among childhood cancer survivors., Significance: This study develops a therapy-specific polygenic risk prediction model to more precisely identify childhood cancer survivors at high risk for pulmonary complications, which could help improve risk stratification for other late effects., (©2022 American Association for Cancer Research.)

Background: Survivors of childhood cancer are at risk for therapy-related subsequent malignant neoplasms (SMN), including thyroid SMN. Telomere length (TL) is associated with cancer risk, but the relationship between TL and SMN risk among survivors is less clear., Methods: We conducted a nested, matched case-control study of radiation-exposed 15-year+ adult survivors of childhood cancer with thyroid SMN (cases) and without SMN (controls). Forty-six cases were matched to 46 controls by primary diagnosis, chemotherapy (yes/no), radiation field, and follow-up duration. Lymphocyte TL (LTL) was measured by telomere flow-FISH cytometry using blood samples banked at a mean of 38.9 years (cases), 39.2 years (controls). Genetic variation in telomere genes was assessed by whole genome sequencing. Point estimates for LTL <10th percentile were determined for cases and controls., Results: Cases had shorter median LTL than controls in three out of four leukocyte subsets. Cases were more likely to have NK cell LTL <10th percentile ( P = 0.01), and 2.8-fold more likely to have naïve T-cell LTL <10th percentile than controls (CI, 1.07-8.78). Five out of 15 cases with a rare indel or missense variant had naïve T-cell LTL <10th percentile, compared with one out of eight controls., Conclusions: Long-term survivors have shorter than expected LTL, a finding that is more pronounced among survivors with thyroid SMN., Impact: The long-term impact of childhood cancer treatment on immune function is poorly understood. Our findings support immune function studies in larger survivor cohorts to assess long-term deficits in adaptive and innate immunity that may underlie SMN risk., (©2021 American Association for Cancer Research.)

Background: Prior studies have identified that survivors of childhood acute lymphoblastic leukemia (ALL) report poor health status. It is unknown how risk-stratified therapy impacts the health status of ALL survivors., Methods: We estimated and compared the prevalence of self-reported poor health status among adult (≥18 years) survivors of childhood ALL diagnosed at age <21 years from 1970 to 1999 and sibling controls, excluding proxy reports. Therapy combinations defined treatment groups representative of 1970s therapy ( 70s ), standard- and high-risk 1980s and 1990s therapy ( 80sSR , 80sHR , 90sSR , 90sHR ), and relapse/bone marrow transplant ( R/BMT ). Log-binomial models, adjusted for clinical and demographic factors, compared outcomes between groups using prevalence ratios (PR) with 95% confidence intervals (CI)., Results: Among 5,119 survivors and 4,693 siblings, survivors were more likely to report poor health status in each domain including poor general health (13.5% vs. 7.4%; PR = 1.92; 95% CI, 1.69-2.19). Compared with 70s , 90sSR and 90sHR were less likely to report poor general health ( 90sSR : PR = 0.75; 95% CI, 0.57-0.98; 90sHR : PR = 0.58; 95% CI, 0.39-0.87), functional impairment ( 90sSR : PR = 0.56; 95% CI, 0.42-0.76; 90sHR : PR = 0.63; 95% CI, 0.42-0.95), and activity limitations ( 90sSR : 0.61; 95% CI, 0.45-0.83; 90sHR : PR = 0.59; 95% CI, 0.38-0.91). An added adjustment for chronic conditions in multivariable models partially attenuated 90sSR risk estimates., Conclusions: Risk-stratified ALL therapy has succeeded in reducing risk for poor general health, functional impairment, and activity limitations among more recent survivors of standard- and high-risk therapy., Impact: Future research into the relationship between risk-stratified therapy, health status, and late health outcomes may provide new opportunities to further improve late morbidity among survivors., (©2021 American Association for Cancer Research.)

Background: Lung cancer, the most common cause of cancer-related death in adults, has not been well studied as a subsequent malignant neoplasm (SMN) in childhood cancer survivors. We assessed prevalence, risk factors, and outcomes for lung SMN in the Childhood Cancer Survivor Study (CCSS) cohort., Methods: Among 25,654 5-year survivors diagnosed with childhood cancer (<21 years), lung cancer was self-reported and confirmed by pathology record review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, comparing survivors to the general population, and hazard ratios (HR) were estimated using Cox regression for diagnosis and treatment exposures., Results: Forty-two survivors developed a lung SMN [SIR, 4.0; 95% confidence interval (CI), 2.9-5.4] with a cumulative incidence of 0.16% at 30 years from diagnosis (95% CI, 0.09%-0.23%). In a treatment model, chest radiation doses of 10-30 Gy (HR, 3.4; 95% CI, 1.05-11.0), >30-40 Gy (HR, 4.6; 95% CI, 1.5-14.3), and >40 Gy (HR, 9.1; 95% CI, 3.1-27.0) were associated with lung SMN, with a monotone dose trend ( P trend < 0.001). Survivors of Hodgkin lymphoma (SIR, 9.3; 95% CI, 6.2-13.4) and bone cancer (SIR, 4.4; 95% CI, 1.8-9.1) were at greatest risk for lung SMN., Conclusions: Survivors of childhood cancer are at increased risk for lung cancer compared with the general population. Greatest risk was observed among survivors who received chest radiotherapy or with primary diagnoses of Hodgkin lymphoma or bone cancer., Impact: This study describes the largest number of observed lung cancers in childhood cancer survivors and elucidates need for further study in this aging and growing population., (©2021 American Association for Cancer Research.)

Background: Given the relatively small population of Asians or Pacific Islanders (API) in the United States, studies describing long-term outcomes in API survivors of childhood cancer are limited. This study compared functional outcomes between API versus non-Hispanic White (NHW) survivors., Methods: This study included 203 API 5-year survivors [age at follow-up: 29.2 (SD = 6.3) years] and 12,186 NHW survivors [age at follow-up 31.5 (SD = 7.3) years] from the Childhood Cancer Survivor Study. Self-reported functional outcomes of neurocognitive function, emotional distress, quality of life, and social attainment were compared between the two groups using multivariable regression, adjusted for sex, age at diagnosis and evaluation, cancer diagnosis, and neurotoxic treatment., Results: No statistically significant race/ethnicity-based differences were identified in neurocognitive and emotional measures. API survivors reported, on average, less bodily pain than NHW survivors [mean 54.11 (SD = 8.98) vs. 51.32 (SD = 10.12); P < 0.001]. NHW survivors were less likely to have attained at least a college degree than API survivors [OR = 0.50; 95% confidence interval (CI) = 0.34-0.73]. API survivors were more likely than NHW survivors to be never-married (OR = 2.83; 95% CI = 1.93-4.13) and to live dependently (OR = 3.10; 95% CI = 2.02-4.74). Older age (>45 years), brain tumor diagnosis, and higher cranial radiation dose were associated with poorer functional outcomes in API survivors (all, P < 0.05)., Conclusions: We observed differences in social attainment between API and NHW survivors, although statistically significant differences in neurocognitive and emotional outcomes were not identified., Impact: Future studies should evaluate whether racial/ethnic differences in environmental and sociocultural factors may have differential effects on health and functional outcomes., (©2021 American Association for Cancer Research.)

Background: Subsequent thyroid cancer (STC) is one of the most common malignancies in childhood cancer survivors. We aimed to evaluate the polygenic contributions to STC risk and potential utility in improving risk prediction., Methods: A polygenic risk score (PRS) was calculated from 12 independent SNPs associated with thyroid cancer risk in the general population. Associations between PRS and STC risk were evaluated among survivors from St. Jude Lifetime Cohort (SJLIFE) and were replicated in survivors from Childhood Cancer Survivor Study (CCSS). A risk prediction model integrating the PRS and clinical factors, initially developed in SJLIFE, and its performance were validated in CCSS., Results: Among 2,370 SJLIFE survivors with a median follow-up of 28.8 [interquartile range (IQR) = 21.9-36.1] years, 65 (2.7%) developed STC. Among them, the standardized PRS was associated with an increased rate of STC [relative rate (RR) = 1.57; 95% confidence interval (CI) = 1.24-1.98; P < 0.001]. Similar associations were replicated in 6,416 CCSS survivors, among whom 121 (1.9%) developed STC during median follow-up of 28.9 (IQR = 22.6-34.6) years (RR = 1.52; 95% CI = 1.25-1.83; P < 0.001). A risk prediction model integrating the PRS with clinical factors showed better performance than the model considering only clinical factors in SJLIFE ( P = 0.004, AUC = 83.2% vs. 82.1%, at age 40), which was further validated in CCSS ( P = 0.010, AUC = 72.9% vs. 70.6%)., Conclusions: Integration of the PRS with clinical factors provided a statistically significant improvement in risk prediction of STC, although the magnitude of improvement was modest., Impact: PRS improves risk stratification and prediction of STC, suggesting its potential utility for optimizing screening strategies in survivorship care., (©2021 American Association for Cancer Research.)

Background: Children treated for cancer are at risk for neuromuscular dysfunction, but data are limited regarding prevalence, longitudinal patterns, and long-term impact., Methods: Longitudinal surveys from 25,583 childhood cancer survivors ≥5 years from diagnosis and 5,044 siblings from the Childhood Cancer Survivor Study were used to estimate the prevalence and cumulative incidence of neuromuscular dysfunction. Multivariable models adjusted for age, sex, race, and ethnicity estimated prevalence ratios (PR) of neuromuscular dysfunction in survivors compared with siblings, and associations with treatments and late health/socioeconomic outcomes., Results: Prevalence of neuromuscular dysfunction was 14.7% in survivors 5 years postdiagnosis versus 1.5% in siblings [PR, 9.9; 95% confidence interval (CI), 7.9-12.4], and highest in survivors of central nervous system (CNS) tumors (PR, 27.6; 95% CI, 22.1-34.6) and sarcomas (PR, 11.5; 95% CI, 9.1-14.5). Cumulative incidence rose to 24.3% in survivors 20 years postdiagnosis (95% CI, 23.8-24.8). Spinal radiotherapy and increasing cranial radiotherapy dose were associated with increased prevalence of neuromuscular dysfunction. Platinum exposure (vs. none) was associated with neuromuscular dysfunction (PR, 1.8; 95% CI, 1.5-2.1), even after excluding survivors with CNS tumors, cranial/spinal radiotherapy, or amputation. Neuromuscular dysfunction was associated with concurrent or later obesity (PR, 1.1; 95% CI, 1.1-1.2), anxiety (PR, 2.5; 95% CI, 2.2-2.9), depression (PR, 2.1; 95% CI, 1.9-2.3), and lower likelihood of graduating college (PR, 0.92; 95% CI, 0.90-0.94) and employment (PR, 0.8; 95% CI, 0.8-0.9)., Conclusions: Neuromuscular dysfunction is prevalent in childhood cancer survivors, continues to increase posttherapy, and is associated with adverse health and socioeconomic outcomes., Impact: Interventions are needed to prevent and treat neuromuscular dysfunction, especially in survivors with platinum and radiation exposure., (©2021 American Association for Cancer Research.)

Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiotherapy; n = 246) were compared with cardiotoxic-exposed survivors of European ancestry ( n = 1,645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2-4 and grade 3-4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF (rs6689879*C: EF reduction = 4.2%; P = 2.8 × 10 -8 ) in 246 survivors of African ancestry, which was successfully replicated in 1,645 survivors of European ancestry but with attenuated magnitude (EF reduction = 0.4%; P = 0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2-4 cardiomyopathy, the PHTF1 promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2-4 cardiomyopathy. PHTF1 was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry. SIGNIFICANCE: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry, and a novel locus at 1p13.2 is associated with therapy-related cardiomyopathy specifically in African-American survivors. See related commentary by Brown and Richard, p. 2272 ., (©2020 American Association for Cancer Research.)

Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival in pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data-sharing ecosystem for accessing, analyzing, and visualizing genomic data from >10,000 pediatric patients with cancer and long-term survivors, and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes, and 2,202 transcriptomes. The resource is expanding rapidly, with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem-Genomics Platform, Pediatric Cancer Knowledgebase, and Visualization Community-enable simultaneously performing advanced data analysis in the cloud and enhancing the Pediatric Cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes. SIGNIFICANCE: To advance research and treatment of pediatric cancer, we developed St. Jude Cloud, a data-sharing ecosystem for accessing >1.2 petabytes of raw genomic data from >10,000 pediatric patients and survivors, innovative analysis workflows, integrative multiomics visualizations, and a knowledgebase of published data contributed by the global pediatric cancer community. This article is highlighted in the In This Issue feature, p. 995 ., (©2021 American Association for Cancer Research.)

Exposure to high doses of alkylating agents is associated with increased risk of impaired spermatogenesis among nonirradiated male survivors of childhood cancer, but there is substantial variation in this risk. Here we conducted a genetic study for impaired spermatogenesis utilizing whole-genome sequencing data from 167 nonirradiated male childhood cancer survivors of European ancestry from the St. Jude Lifetime Cohort treated with cyclophosphamide equivalent dose (CED) ≥4,000 mg/m 2 . Sperm concentration from semen analysis was assessed as the primary outcome. Common variants (MAF > 0.05) were adjusted for age at cancer diagnosis, CED, and top principal components. Rare/low-frequency variants (MAF ≤ 0.05) were evaluated jointly by various functional annotations and 4-kb sliding windows. A novel locus at 7q21.3 containing TAC1 / ASNS was associated with decreased sperm concentration (rs7784118: P = 3.5 × 10 -8 ). This association was replicated in two independent samples of SJLIFE survivors of European ancestry, including 34 nonirradiated male survivors treated with 0 < CED < 4,000 mg/m 2 ( P = 3.1 × 10 -4 ) and 24 male survivors treated with CED ≥4,000 mg/m 2 and radiotherapy <40 Gray ( P = 0.012). No association was observed among survivors not exposed to alkylating agents included in the CED ( P > 0.29). rs7784118 conferred 3.48- and 9.73-fold increases in risk for clinically defined oligospermia and azoospermia and improved prediction of normospermic, oligospermic, and azoospermic states by 13.7%, 5.3%, and 21.7%. rs7784118 was associated with decreased testosterone level, increased levels of follicle stimulating and luteinizing hormones, and 8.52-fold increased risk of Leydig cell failure. Additional research is warranted to determine how this SNP influences spermatogenesis and to assess its clinical utility in characterizing high-risk survivors and guiding intervention strategies. SIGNIFICANCE: The identified genetic markers harbor potential clinical utility in characterizing high-risk survivors and guiding intervention strategies including pretreatment patient counseling and use of fertility preservation services., (©2020 American Association for Cancer Research.)

Background: The optimal lifestyle for breast cancer prevention over the long term is unclear. We aimed to determine whether or not the amount of exercise prescribed in a year-long exercise intervention influences breast cancer biomarker levels 1 year later., Methods: We conducted a 24-month follow-up study (2012-2014) to the Breast Cancer and Exercise Trial in Alberta (BETA), a 12-month, two-armed (1:1), two-center randomized controlled trial of exercise in 400 cancer-free, postmenopausal women. The exercise prescription was moderate-vigorous aerobic exercise, 5 days/week (3 days/week supervised) for 30 minutes/session (MODERATE) or 60 minutes/session (HIGH). Participants were asked not to change their usual diet. We used linear mixed models to compare biomarker concentrations (C-reactive protein, insulin, glucose, HOMA-IR, estrone, sex hormone binding globulin, total estradiol, and free estradiol) over time (0, 12, and 24 months) by group (MODERATE, HIGH), using group-time interactions., Results: After 12 months of no intervention, 24-month fasting blood samples were available for 84.0% and 82.5% of MODERATE and HIGH groups, respectively ( n = 333/400). We found no evidence that 0 to 24- or 12 to 24-month biomarker changes differed significantly between randomized groups (HIGH:MODERATE ratio of mean biomarker change ranged from 0.97 to 1.06, P values >0.05 for all). We found more favorable biomarker profiles among participants who experienced greater than the median fat loss during the trial., Conclusions: Prescribing aerobic exercise for 300 versus 150 minutes/week for 12 months to inactive, postmenopausal women had no effects on longer-term biomarkers., Impact: Exercise may lead to larger improvements in breast cancer biomarkers after intervention among women who also experience fat loss with exercise., (©2019 American Association for Cancer Research.)

Background: Given the inverse relationship described previously between telomere content and thyroid subsequent malignant neoplasm (thyroid SMN) in survivors of childhood cancer, we investigated the relationship between known genetic determinants of leukocyte telomere length (LTL) and thyroid SMN among survivors., Methods: Leveraging data from a large, genotyped survivor cohort, the Childhood Cancer Survivor Study, we used a well-described genetic risk score method to estimate the HR for thyroid SMN among 5,324 genotyped survivors., Results: We identified 118 survivors with thyroid SMN and 5,206 without thyroid SMN. No association between genetically estimated LTL and risk for thyroid SMN was identified., Conclusions: Our results suggest that variation in common SNPs influencing LTL is not strongly associated with risk for thyroid SMN in survivors of childhood cancer., Impact: The previously observed inverse relationship between LTL and thyroid SMN risk in survivors of childhood cancer may be related to alternative molecular mechanisms and warrants further study., (©2018 American Association for Cancer Research.)

Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAE v4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAE v4.03. This article describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained. Cancer Epidemiol Biomarkers Prev; 26(5); 666-74. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Background: Cancer survivors exposed to therapeutic radiation are at increased risk for basal cell carcinoma (BCC). Despite the notable influence of race on rates of BCC in the general population, the same is not clearly defined in previously irradiated cancer survivors. We investigated the influence of race on the development of BCC in adult survivors of childhood cancer., Methods: Using a retrospective cohort study, outcomes were collected through June 30, 2015, for 1,746 irradiated childhood cancer survivors participating in the St. Jude Lifetime Cohort Study (SJLIFE), comprising a total of 33,147 person-years of follow-up. Subsequent neoplasms identified in survivors through self-report and prospective clinical assessment were validated by pathology reports. Expected numbers of each type of radiation-associated neoplasm, including BCC, were calculated for irradiated black survivors based on rates in irradiated white survivors, accounting for primary cancer diagnosis, diagnosis year, attained age, and sex., Results: On the basis of the rate of BCC in previously irradiated white survivors, 56.1 BCCs were expected among 237 black survivors, yet none observed. In contrast, the observed-to-expected ratio of non-BCC radiation-associated neoplasms (melanoma, brain, breast, thyroid cancer) was 0.88 (30 observed/34.2 expected, 95% confidence interval, 0.59-1.25)., Conclusions: We identified an unexpected absence of BCC in irradiated black survivors in SJLIFE. We observe a similar absence of BCC in black individuals among two additional cohorts treated with irradiation for childhood cancer., Impact: Black survivors are at a substantially reduced or absent risk for BCC from therapeutic radiation for reasons not yet fully understood. Cancer Epidemiol Biomarkers Prev; 25(9); 1356-60. ©2016 AACR., Competing Interests: The authors declare no competing interests., (©2016 American Association for Cancer Research.)

This randomized dose comparison trial examined if higher exercise volume decreased inflammatory biomarkers, associated with postmenopausal breast cancer risk, more than moderate exercise volume. The Breast Cancer and Exercise Trial in Alberta was a two-center, two-armed randomized trial in 400 inactive, healthy, postmenopausal women, aged 50 to 74 years, with a body mass index of 22 to 40 kg/m(2). Participants were randomized to high (300 minutes/week) or moderate (150 minutes/week) volumes of aerobic exercise while maintaining usual diet. Fasting blood concentrations of C-reactive protein (CRP), IL6, and TNFα were measured at baseline, 6 and 12 months. Intention-to-treat (ITT) analysis was performed using linear mixed models adjusted for baseline biomarker concentrations. ITT analyses of 386 (97%) participants showed no statistically significant group differences for changes in biomarker levels at 6 and 12 months. In addition, we did not observe any modification of this effect by baseline characteristics of participants. In post hoc analyses based on self-selected exercise level (measured in minutes/week), CRP decreased by 22.45% for participants who exercised >246 minutes/week (highest quintile) and increased by 0.07% for those who exercised <110 minutes/week (lowest quintile, Ptrend = 0.04), adjusted for baseline covariates. When this analysis was restricted to include exercise time in the target heart rate zone only, statistically significant trends were observed for both CRP (P < 0.01) and IL6 (P = 0.04). Prescribing 300 minutes/week of moderate-to-vigorous aerobic exercise did not improve inflammatory markers compared with 150 minutes/week in postmenopausal women. Decreases in CRP were observed with higher self-selected exercise volume., (©2015 American Association for Cancer Research.)

Background: It is unclear how inequalities in survival among children with acute lymphoblastic leukemia (ALL) have changed over time in different race/ethnicity groups., Methods: Children diagnosed with a first primary malignant ALL at ages 0 to 19 years in 1975-2010 in the nine Surveillance, Epidemiology, and End Results cancer registries were included. Cumulative ALL mortalities were compared, and multivariable Cox regression analyses were applied to estimate ALL mortality HRs associated with race/ethnicity, age at diagnosis, and sex, adjusting for each other, within each diagnosis period (1975-1983, 1984-1991, 1992-1999, and 2000-2010)., Results: Compared with non-Hispanic-whites (NH-whites), the HR in non-Hispanic-blacks (NH-blacks) dropped to 1.21 [95% confidence interval (CI), 0.74-1.96] in 2000-2010 from the largest inequality in 1984-1991 (HR, 2.09; 95% CI, 1.57-2.79); the HR in Hispanics increased, however, from 1.28 (95% CI, 0.98-1.66) in 1975-1983 to 1.95 (95% CI, 1.48-2.58) in 2000-2010. Asian/Pacific Islanders (API) and American Indian/Alaska Natives (AIAN) had HRs of 1.39 (95% CI, 0.92-2.11) and 2.31 (95% CI, 1.13-4.74), respectively, in 2000-2010 with nonstatistically significant increases over time. In 2000-2010, compared with NH-white counterparts, NH-blacks and APIs diagnosed at 1-9 years, Hispanics diagnosed at 1-9 and 10-19 years, and AIANs diagnosed at 10-19 years all had about twice the ALL mortality hazard rates; inequality was observed among API boys (HR, 1.61; 95% CI, 1.00-2.60) but not API girls., Conclusions: Survival inequalities changed differently across subgroups of children with ALL., Impact: Underlying causes of the differential trends need to be examined, such that targeted interventions can be developed to reduce inequalities., (©2015 American Association for Cancer Research.)

Background: Exercise may improve psychosocial distress in patients with cancer; however, few studies have examined the effects of different types or doses of exercise, or whether exercise effects are related to baseline depression levels., Methods: In a multicenter trial in Canada, we randomized 301 patients with breast cancer initiating chemotherapy to thrice weekly, supervised exercise consisting of either a standard dose of 25 to 30 minutes of aerobic exercise (STAN; n = 96), a higher dose of 50 to 60 minutes of aerobic exercise (HIGH; n = 101), or a combined dose of 50 to 60 minutes of aerobic and resistance exercise (COMB; n = 104). The primary endpoint was depression assessed by the Center for Epidemiological Studies-Depression scale at baseline, twice during chemotherapy, and postchemotherapy. Secondary endpoints were anxiety, perceived stress, and self-esteem., Results: Repeated measures ANOVA indicated that neither HIGH [mean difference = -0.9; 95% confidence interval (CI), +0.0 to -1.8; P = 0.061] nor COMB (mean difference = -0.4; 95% CI, +0.5 to -1.3; P = 0.36) was superior to STAN for managing depressive symptoms. In a planned subgroup analysis, there was a significant interaction with baseline depression levels (P interaction = 0.027) indicating that COMB and HIGH were effective for managing depressive symptoms in patients with clinical levels of depressive symptoms at baseline., Conclusions: Compared with a standard volume of aerobic exercise, higher volumes of exercise did not help manage depressive symptoms in unselected patients with breast cancer receiving chemotherapy, but they were effective in patients with clinical levels of depressive symptoms at baseline., Impact: A phase III exercise trial targeting depressed patients with breast cancer is warranted., (©2014 AACR.)

Chronic low-grade inflammation is a possible risk factor for cancer that may be modifiable with long-term exercise. Very few randomized controlled trials (RCT) have studied the isolated effects of exercise on low-grade inflammation exclusively in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial, a 2-armed RCT in healthy postmenopausal women, examined how 1 year of moderate to vigorous aerobic exercise, compared with usual inactivity, influenced circulating inflammatory markers. Baseline, 6-month, and 12-month serum was analyzed by direct chemiluminescent immunoassays to measure high sensitivity C-reactive protein (CRP) and ELISAs to measure interleukin 6 (IL-6) and TNF-α. Intention to treat analyses were conducted with linear mixed models. Statistically significant differences in CRP were observed over 12 months for exercisers versus controls (treatment effect ratio = 0.87, 95% CI = 0.79-0.96, P = 0.005), but not in IL-6 or TNF-α. A statistically significant trend (P(trend) = 0.021) of decreasing CRP with increasing exercise adherence and stronger intervention effects on CRP in women with higher baseline physical fitness (P(heterogeneity) = 0.040) was found. The intervention effect on CRP became statistically nonsignificant with adjustment for dietary fiber intake change and seemed to be mediated by fat loss. Low-grade inflammation may be lowered with exercise, but confounding by dietary intake occurred and should be considered in future studies. Further trials are needed to corroborate our findings about the optimal dose of exercise required to lower CRP levels and effect modification of CRP changes by levels of body fatness and fitness., (©2011 AACR.)

Background: Metabolic syndrome may predict endometrial cancer risk better than diabetes, hypertension, dyslipidemia, dysglycemia, or weight alone, but few studies have examined this issue., Methods: We conducted a population-based case-control study in Alberta, Canada (2002-2006) that included 515 incident endometrial cancer cases and 962 frequency age-matched controls. Data were collected through in-person interviews, anthropometric measurements, and 8-hour fasting bloods drawn either pre- or postsurgery. Bloods were analyzed using quantitative colorimetric or absorbance-based assays (ELISA), specific to metabolic syndrome markers. Metabolic syndrome was defined using harmonized guidelines requiring presence of ≥ 3 of the following risk factors: waist circumference ≥ 88 cm, triglycerides ≥ 150 mg/dL, high-density lipoprotein cholesterol <50 mg/dL, treatment of previously diagnosed hypertension, and fasting blood glucose ≥ 100 mg/dL. OR and 95% CIs for endometrial cancer risk with presence of metabolic syndrome and individual metabolic syndrome components were estimated using logistic regression analysis., Results: Metabolic syndrome was significantly more prevalent among cases (62%) than controls (38%). A statistically significant increased risk for endometrial cancer was observed for metabolic syndrome (OR = 1.53; 95% CI: 1.17-2.00), as well as for some of the individual components of metabolic syndrome including waist circumference ≥ 88 cm (OR = 1.57; 95% CI: 1.18-2.08), hypertension (OR = 1.57; 95% CI: 1.18-2.09), and fasting blood glucose ≥ 100 mg/dL (OR = 1.31; 95% CI: 1.03-1.67). Some evidence for effect modification by menopausal status and body mass index was also found., Conclusion: Metabolic syndrome is clearly associated with increased endometrial cancer risk., Impact: Targeting the entire metabolic syndrome may optimize endometrial cancer risk reduction., (© 2011 AACR.)

The effects of sanyaku, a traditional Chinese medicine [freeze-dried powder of the yam tuber (Dioscorea)], and its major steroidal saponin constituent, diosgenin, on colon carcinogenesis were investigated. Male ICR mice were subjected to a single intraperitoneal injection of azoxymethane (AOM; 10 mg/kg body weight) followed by administration of 1.5% dextran sodium sulfate (DSS) in drinking water for 7 days to establish carcinogenesis. Commercial diosgenin or sanyaku, which contained diosgenin at 63.8 ± 1.2 mg/kg dry weight, was given in the diet at 20, 100, or 500 mg/kg for 17 weeks. Groups of mice that received diosgenin or sanyaku at all doses yielded significantly less number of colon tumors compared with the AOM/DSS-treated mice. Occurrence of colonic mucosal ulcer and dysplastic crypt induced by AOM/DSS treatment was also significantly decreased by the administration of diosgenin and sanyaku, which was in accordance with the significant reduction of AOM/DSS-mediated increases in expression of inflammatory cytokines such as IL-1β by diosgenin and sanyaku. Furthermore, elevated levels of serum triglyceride in the AOM/DSS-treated mice tended to be reduced in mice given diosgenin and sanyaku. Microarray and real-time reverse transcriptase PCR analyses revealed that diosgenin administration increased 12-fold the expression of lipoprotein lipase, which may contribute to reduced serum triglyceride levels. Other genes altered by diosgenin included those associated with antioxidative stress responses and apoptosis, such as heme oxygenase-1, superoxide dismutase-3, and caspase-6. Our results imply that the Chinese medicine sanyaku and the tubers of various yams containing diosgenin as food could be ingested to prevent colon carcinogenesis in humans.

Background: Childhood cancer survivors are at higher risk of morbidity and mortality from cardiovascular disease compared with the general population., Methods: Eight thousand five hundred ninety-nine survivors (52% male) and 2,936 siblings (46% male) from the Childhood Cancer Survivor Study, a retrospectively ascertained, prospectively followed study of persons who survived 5 years after childhood cancer diagnosed from 1970 to 1986, were evaluated for body mass index of > or =30 kg/m(2) based on self-reported heights and weights and self-reported use of medications for hypertension, dyslipidemia, and impaired glucose metabolism. The presence of three or more of the above constituted Cardiovascular Risk Factor Cluster (CVRFC), a surrogate for Metabolic Syndrome., Results: Survivors were more likely than siblings to take medications for hypertension [odds ratio (OR), 1.9; 95% confidence interval (95% CI), 1.6-2.2], dyslipidemia (OR, 1.6; 95% CI, 1.3-2.0) or diabetes (OR, 1.7; 95% CI, 1.2-2.3). Among these young adults (mean age of 32 years for survivors and 33 years for siblings), survivors were not more likely than siblings to be obese or have CVRFC. In a multivariable logistic regression analysis, factors associated with having CVRFC included older age at interview [> or =40 versus <30 years of age (OR, 8.2; 95% CI, 3.5-19.9)], exposure to total body irradiation (OR, 5.5; 95% CI, 1.5-15.8) or radiation to the chest and abdomen (OR, 2.3; 95% CI, 1.2-2.4), and physical inactivity (OR, 1.7; 95% CI, 1.1-2.6)., Conclusions: Among adult survivors of pediatric cancer, older attained age, exposure to total body irradiation or abdominal plus chest radiation, and a sedentary life-style are associated with CVRFC.

The flavone 4',5,7-trihydroxy-3',5'-dimethoxyflavone (tricin) present in rice, oats, barley, and wheat exhibits antigrowth activity in several human cancer cell lines and anti-inflammatory potential. However, the chemopreventive activity has not yet been elucidated in preclinical animal models of colorectal cancer. This study was designed to determine whether dietary tricin exerts inflammation-associated colon carcinogenesis induced by azoxymethane and dextran sulfate sodium in mice. Male Crj: CD-1 mice were initiated with a single i.p. injection of azoxymethane (10 mg/kg body weight) and followed by a 1-week exposure to dextran sulfate sodium (1.5%, w/v) in drinking water to induce colonic neoplasms. They were then given the experimental diet containing 50 or 250 ppm tricin. The experiment was terminated at week 18 to determine the chemopreventive efficacy of tricin. In addition, the effects of dietary tricin on the expression of several inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, were assayed. The development of colonic adenomas and adenocarcinomas was significantly reduced by feeding with 50 and 250 ppm tricin, respectively. Dietary tricin also significantly reduced the proliferation of adenocarcinoma cells as well as the numbers of mitoses/anaphase bridging in adenocarcinoma cells. The dietary administration with tricin significantly inhibited the expression of TNF-alpha in the nonlesional cypts. Our findings that dietary tricin inhibits inflammation-related mouse colon carcinogenesis by suppressing the expression of TNF-alpha in the nonlesional cyrpts and the proliferation of adenocarcinomas suggest a potential use of tricin for clinical trials of colorectal cancer chemoprevention.

Background: Few exercise trials in cancer patients have reported longer-term follow-up. Here, we report a 6-month follow-up of exercise behavior and patient-rated outcomes from an exercise trial in breast cancer patients., Methods: Breast cancer patients initiating adjuvant chemotherapy (n = 242) were randomly assigned to usual care (n = 82), resistance exercise training (RET; n = 82), or aerobic exercise training (AET; n = 78) for the duration of their chemotherapy. At 6-month follow-up, participants were mailed a questionnaire that assessed quality of life, self-esteem, fatigue, anxiety, depression, and exercise behavior., Results: Two hundred one (83.1%) participants provided 6-month follow-up data. Adjusted linear mixed-model analyses showed that, at 6-month follow-up, the RET group reported higher self-esteem [adjusted mean difference, 1.6; 95% confidence interval (95% CI), 0.1-3.2; P = 0.032] and the AET group reported lower anxiety (adjusted mean difference, -4.7; 95% CI, -0.0 to -9.3; P = 0.049) compared with the usual care group. Moreover, compared with participants reporting no regular exercise during the follow-up period, those reporting regular aerobic and resistance exercise also reported better patient-rated outcomes, including quality of life (adjusted mean difference, 9.5; 95% CI, 1.2-17.8; P = 0.025)., Conclusions: Improvements in self-esteem observed with RET during breast cancer chemotherapy were maintained at 6-month follow-up whereas reductions in anxiety not observed with AET during breast cancer chemotherapy emerged at 6-month follow-up. Moreover, adopting a combined aerobic and resistance exercise program after breast cancer chemotherapy was associated with further improvements in patient-rated outcomes. Exercise training during breast cancer chemotherapy may result in some longer-term and late effects for selected patient-rated outcomes.

Background: Epidemiologic studies provide evidence that exercise is associated with reduced risk of colon cancer. Exercise may exert protective effects on the colon by influencing prostaglandin production. We hypothesized that an exercise intervention would decrease prostaglandin E(2) concentrations and increase prostaglandin F(2alpha) in colon biopsies compared with controls., Methods: A 12-month randomized controlled trial testing the effects of exercise on colon mucosal prostaglandin concentrations was conducted in men (n=95) and women (n=89). The exercise intervention included moderate-to-vigorous aerobic activity, 60 min/d, 6 days/wk versus controls. Prostaglandin E(2) and F(2alpha) concentrations were measured in colon biopsies using an enzyme-linked immunoassay at baseline and at 12 months to assess changes in mean concentration for each group., Results: Baseline colon prostaglandin E(2) and F(2alpha) concentrations were not correlated with age, race, education, family history of colon cancer, previous polyps, body size, diet, smoking, nonsteroidal antiinflammatory drug use, metabolic factors, or sex hormone levels. For both men and women, the exercise and control groups showed no change in mean prostaglandin E(2) or F(2alpha) between the baseline and 12-month biopsies. There was no difference in mean prostaglandin concentrations between exercisers and controls when exercisers were grouped by level of intervention adherence. Results were not modified by baseline age, body mass index, percentage of body fat, nonsteroidal antiinflammatory drug use, history of adenomatous polyps, or family history of colon cancer., Conclusion: A 12-month moderate-to-vigorous intensity aerobic exercise intervention did not result in significant changes in colon mucosal prostaglandin concentrations.

Background: Cellular proliferation and apoptosis (cell death) are highly regulated in the colon as insufficient apoptosis may lead to polyps and cancer. Physical activity decreases risk of colon cancer in observational studies, but the biological basis is not well defined. The objective of this study is to examine the effects of a 12-month aerobic exercise program on expression of proteins that promote (Bax) or inhibit (Bcl-2) apoptosis in colon crypts., Methods: Two hundred two sedentary participants, 40 to 75 years, were randomly assigned to moderate-to-vigorous intensity exercise for 60 min per day, 6 days per week for 12 months, or usual lifestyle. Colon crypt samples were obtained at baseline and 12 months. Bcl-2 and Bax expression was measured by immunohistochemistry., Results: Bax density at the bottom of crypts increased in male exercisers versus controls (+0.87 versus -0.18; P = 0.05), whereas the ratio of Bcl-2 to Bax at the bottom and middle of crypts decreased as aerobic fitness (VO(2)max) increased (P trend = 0.02 and 0.05, respectively). In female exercisers, Bax density in the middle of crypts decreased (-0.36 versus +0.69; P = 0.03) and Bcl-2 to Bax ratio at the top of crypts increased versus controls (+0.46 versus -0.85; P = 0.03). Bax density in the middle of crypts also decreased as minutes per week of exercise increased (P trend = 0.03)., Conclusions: A 12-month exercise intervention resulted in greater expression of proteins that promote apoptosis at the bottom of colon crypts in men and decreased expression of proteins that promote apoptosis at the middle and top of colon crypts in women. The difference in effect by gender and location of observed changes warrants further study.

Background: Colon crypt architecture and proliferation may be appropriate biomarkers for testing prevention interventions. A hypothesized mechanism for exercise-induced colon cancer risk reduction might be through alterations in colon crypt cell architecture and proliferation., Methods: Healthy, sedentary participants with a colonoscopy within the previous 3 years were recruited through gastroenterology practices and media. We randomly assigned 100 women and 102 men, ages 40 to 75 years, to a control group or a 12-month exercise intervention of moderate-to-vigorous aerobic exercise, 60 minutes per day, 6 days per week, and assessed change in number and relative position of Ki67-stained cells in colon mucosal crypts., Results: Exercisers did a mean 370 min/wk (men) and 295 min/wk (women) of exercise (seven dropped the intervention). In men, the mean height of Ki67-positive nuclei relative to total crypt height was related to amount of exercise, with changes from baseline of 0.0% (controls), +0.3% (exercisers <250 min/wk), -1.7% (exercisers 250-300 min/wk), and -2.4% (exercisers >300 min/wk; P(trend) = 0.03). In male exercisers whose cardiopulmonary fitness (V(O(2))max) increased >5%, the mean height of Ki67-positive nuclei decreased by 2% versus 0.9% in other exercisers, and versus no change in controls (P(trend) = 0.05). Similar trends were observed in other proliferation markers. In women, increased amount of exercise or V(O(2))max did not result in notable changes in proliferation markers., Conclusions: A 12-month moderate-to-vigorous intensity aerobic exercise intervention resulted in significant decreases in colon crypt cell proliferation indices in men who exercised a mean of >/=250 min/wk or whose V(O(2))max increased by >/=5%.

We determined risk of cancer among first-degree relatives of 5-year survivors of childhood leukemia, lymphoma, central nervous system tumors, sarcomas, Wilms' tumor, and neuroblastoma. Subjects were 13,703 participants in the Childhood Cancer Survivor Study. Family history was collected on 56,759 first-degree relatives using a self-reported questionnaire. Incidence was compared with age- and sex-specific rates using the U.S. Surveillance, Epidemiology and End Results program. Siblings of the survivors had an increased risk of cancer [standardized incidence ratio (SIR), 1.5; 95% confidence interval (95% CI), 1.35-1.7]. Risk was elevated for siblings of probands of leukemia (SIR, 1.3; 95% CI, 1.0-1.6), Hodgkin's disease (SIR, 1.5; 95% CI, 1.2-1.9), non-Hodgkin's lymphoma (SIR, 1.8; 95% CI, 1.3-2.5), Wilms' tumor (SIR, 1.9; 95% CI, 1.2-3.2), soft tissue sarcoma (SIR, 1.5; 95% CI, 1.0-2.2), and bone tumors (SIR, 1.6; 95% CI, 1.2-2.2). Cancer risk was elevated in siblings (SIR, 2.4; 95% CI, 1.5-3.7) and offspring (SIR, 15.0; 95% CI, 5.3-42.9) of probands with second malignant neoplasms (SMN) compared with relatives of probands without SMNs. Siblings of probands with leukemia, Hodgkin's disease, neuroblastoma, and Wilms' tumor had elevated risks for the same malignancies. Parents had no increased risk (fathers' SIR, 0.7; 95% CI, 0.7-0.8; mothers' SIR, 0.9; 95% CI, 0.9-1.0). Seventy percent of siblings' cancers developed in adulthood. These findings suggest that familial cancer syndromes may be revealed as this cohort and family members age and with accrual of more offspring and subjects with SMNs.

Objective: Hormone therapy use has been positively associated with mammographic density in several studies. However, few studies have examined the association between endogenous hormone levels and mammographic density. Therefore, we evaluated the relationship of endogenous sex hormones, insulin-like growth factor (IGF), and lipids with mammographic density in 88 overweight, postmenopausal women not taking hormone therapy., Methods: Percent density and dense area were evaluated as continuous measures using a computer-assisted program. We used multiple linear regression to evaluate the associations of sex hormones, IGF, and cholesterol with mammographic density, adjusting for confounders, including adiposity. We evaluated stratification by history of hormone therapy use (former versus never) and hormone therapy latency (<5 versus > or = 5 years)., Results: Among former hormone therapy users, mammographic density was inversely associated with circulating levels of estrone (P = 0.01), estradiol (P = 0.003), free estradiol (P = 0.004), testosterone (P = 0.04), free testosterone (P = 0.02), androstenedione (P < 0.001), dehydroepiandrosterone (P = 0.01), and the ratio of IGF-I to its binding protein (IGF-I/IGFBP-3; P = 0.04). We found similar associations when we limited the analyses to women who had used hormone therapy within the past 5 years. We also noted positive associations of mammographic density with total cholesterol (P = 0.03) and low-density lipoprotein (P = 0.03) among former hormone therapy users. No associations were noted among women who had never used hormone therapy., Conclusions: These results suggest that there is an inverse relationship between endogenous sex hormones and mammographic density in postmenopausal women among former users of hormone therapy. This is not consistent with the hormone therapy literature and should be confirmed in larger studies.

Reproductive and menstrual characteristics, as well as high circulating estrogen concentrations, are associated with risk of hormone-related cancers in postmenopausal women. To explore possible etiologic relationships between menstrual/reproductive characteristics and risk of hormone-related cancers, we examined associations between menstrual/reproductive factors and serum concentrations of free estradiol, total estradiol, estrone, sex hormone binding globulin (SHBG), and follicle stimulating hormone (FSH). This study was conducted in 173 postmenopausal women using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, overweight/obese, and not on hormone therapy. Women > or =20 years past menopause had 23% lower total estradiol and 30% lower free estradiol concentrations than women within 4 years of menopause (P for trend = 0.04 and 0.02, respectively). Nulliparous women had 19% higher FSH concentrations than parous women (P = 0.02). Among parous women, parity was positively associated with SHBG and negatively associated with free estradiol concentrations. Women with > or =4 children had 20% lower free estradiol and 38% higher SHBG concentrations compared with women with one birth (P for trend = 0.02 and 0.01, respectively). Total number of months spent breast-feeding was modestly and inversely associated with serum FSH concentrations (P for trend = 0.07). Our results suggest that menstrual/reproductive characteristics may be associated with postmenopausal hormone concentrations; verification of these results in other studies may elucidate how these variables influence risk of hormone-related cancers.

It is important to understand specimen allocation factors that may impact the validity and reliability of results in longitudinal studies examining within-person changes in biomarker levels. Using data from a randomized clinical trial of an exercise intervention in 136 postmenopausal women, we determined the effect of assaying the baseline and follow-up samples of some subjects in different batches on the intervention effect estimates for serum concentrations of estrone, estradiol, testosterone, androstenedione, and dehydroepiandrosterone. Twenty-five subjects had their baseline and 3-month follow-up samples and 50 subjects had their baseline and 12-month samples assayed in different batches; all other subjects had their baseline, 3-month, and 12-month samples assayed in the same batch. Subjects with split samples were reassayed with all samples in the same batch. We compared the estimated regression coefficient for the intervention effect using the split sample data with one estimated excluding the split sample data and one estimated replacing the split sample data with the reassayed data. The median percentage difference in the intervention effect estimate was 59.6% between using versus excluding the split sample data and 74.6% between using the split sample versus using the reassayed data. In general, the coefficients from the model including the split sample data were closer to zero and statistically less significant than those from the models excluding the split sample data or using the reassayed data. These results suggest that bias can be artificially introduced into intervention effect estimates of longitudinal studies if samples from a subject are not assayed in the same batch.

Postmenopausal women with elevated circulating androgen concentrations have an increased risk of developing breast cancer, yet interventions to reduce androgen levels have not been identified. We examined the effects of a 12-month moderate intensity exercise intervention on serum androgens. The study was a randomized clinical trial in 173 sedentary, overweight (body mass index > or = 24.0 kg/m(2), body fat > 33%), postmenopausal women, ages 50 to 75 years, not using hormone therapy and living in the Seattle, WA area. The exercise intervention included facility-based and home-based exercise (45 minutes, 5 days per week of moderate intensity sports/recreational exercise). A total of 170 (98.3%) women completed the study, with exercisers averaging 171 minutes per week of exercise. Women in the exercise and control groups experienced similar, nonsignificant declines in most androgens. Among women who lost >2% body fat, testosterone and free testosterone concentrations fell by 10.1% and 12.2% between baseline and 12 months in exercisers compared with a decrease of 1.6% and 8.0% in controls (P = 0.02 and 0.03 compared with exercisers, respectively). Concentrations of testosterone and free testosterone among exercisers who lost between 0.5% and 2% body fat declined by 4.7% and 10.4%. In controls who lost this amount of body fat, concentrations of testosterone and free testosterone declined by only 2.8% and 4.3% (P = 0.03 and 0.01 compared with exercisers, respectively). In summary, given similar levels of body fat loss, women randomized to a 12-month exercise intervention had greater declines in testosterone and free testosterone compared with controls. The association between exercise and breast cancer risk may be partly explained by the effects of exercise on these hormones.

Physical activity has been associated with reduced breast cancer risk, potentially via hormonal pathways, and high urinary excretion of 2-hydroxyestrone (2-OH E(1)) relative to 16alpha-hydroxyestrone (16alpha-OH E(1)) also has been associated with reduced breast cancer risk. Studies suggest that body composition and exercise can influence estrogen metabolism. We determined the effects of a 12-month moderate intensity aerobic exercise intervention on urinary 2-OH E(1), 16alpha-OH E(1), and their ratio in overweight and obese, previously sedentary, postmenopausal women, ages 50-75 years. Women were randomized to a 12-month exercise intervention (n = 87) or stretching control group (n = 86); 170 completed the study. Urinary 2- and 16alpha-OH E(1) were measured in spot urines collected at baseline, 3, and 12 months. Body composition was measured at baseline and 12 months. Differences between exercisers and controls for excretion of estrogen metabolites were determined using general estimating equations. Further analyses assessed change in estrogen metabolites and their ratio by subgroups of change in body composition. Overall, there were no significant effects of the exercise intervention on 2-OH E(1), 16alpha-OH E(1), or their ratio (P > 0.05). There appeared to be an effect of change in intra-abdominal fat and adherence to the exercise intervention on change in the estrogen metabolites or their ratio. However, this did not reflect a potentially desirable change in estrogen metabolites associated with the exercise intervention. Thus, this 12-month moderate intensity exercise intervention did not significantly alter urinary excretion of 2-OH E(1), 16alpha-OH E(1), or their ratio in this population of women.

Two isoforms of prostaglandin H synthase (PTGS = COX) are key enzymes in prostaglandin synthesis and primary targets for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Use of aspirin or other NSAIDs is associated with a lower risk and reduced recurrence of colorectal adenomas, established precursors of adenocarcinoma. This study investigated risk of colorectal adenomatous and hyperplastic polyps associated with several polymorphisms in the coding region of PTGS1. Within the Minnesota polyp case-control study, patients with colorectal adenomatous (n = 521) or hyperplastic (n = 194) polyps and n = 621 polyp-free controls were genotyped for four PTGS1 polymorphisms (R8W, L15-L16del, P17L, L237M); these had been predicted to affect protein function based on sequence-homology software. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed. Whereas there was no appreciable difference in adenoma or hyperplastic polyp risk associated with R8W, P17L, and L237M, an increased risk was observed for individuals heterozygous for the L15-L16del polymorphism (OR = 3.6, 95% CI 1.2-11.2). The variant L15-L16del allele appeared to be associated with a stronger increase in adenoma risk among nonusers of aspirin/other NSAIDs. The reduced risk observed with aspirin/other NSAID use was limited to those wild type for P17L [PP users: OR = 0.6 (0.5-0.8) versus PP nonusers: 1.0 (referent) (P interaction = 0.03)]. To our knowledge, this study represents the first investigation of polymorphisms in PTGS1 and risk of colorectal polyps. The L15-L16del variant allele may result in an increased risk of colorectal adenomas, whereas P17L may be relevant to the pharmacogenetics of aspirin. These preliminary findings require confirmation in larger studies of colorectal neoplasia.

Elevated circulating estrogens and a sedentary lifestyle increase risk for breast cancer. The effect of exercise on circulating estrogens in sedentary postmenopausal women is unknown. The objective of this study was to examine the effects of a 12-month moderate-intensity exercise intervention on serum estrogens. We randomly assigned 173 sedentary, overweight (body mass index > 24.0 kg/m(2), body fat > 33%), postmenopausal women, ages 50-75 years, not using hormone therapy, living in the Seattle, Washington, area for the next year, and willing to be randomly assigned to an exercise intervention or stretching control group. The exercise intervention included facility and home-based exercise (45 min, 5 days/week moderate intensity sports/recreational exercise). A total of 170 (98.3%) women completed the study with exercisers averaging 171 min/week of exercise. After 3 months, exercisers experienced declines in estrone, estradiol, and free estradiol of 3.8, 7.7, and 8.2%, respectively, versus no change or increased concentrations in controls (P = 0.03, 0.07, and 0.02, respectively). At 12 months, the direction of effect remained the same, although the differences were no longer statistically significant. The effect was limited to women who lost body fat: women whose percentage of body fat [by dual energy x-ray absortiometry (DEXA)] decreased by >/==" BORDER="0">2% had statistically significant (comparing exercisers versus controls) decreases at 12 months of 11.9, 13.7, and 16.7% for serum estrone, estradiol, and free estradiol, respectively. We concluded that a 12-month moderate-intensity exercise intervention in postmenopausal women resulted in significant decreases in serum estrogens. The association between increased physical activity and reduced risk for postmenopausal breast cancer may be partly explained by effects on serum estrogens.

Objectives: Vietnamese American women are five times more likely to be diagnosed with cervical cancer than their White counterparts. Previous research has demonstrated low levels of Papanicolaou (Pap) testing among Vietnamese. Our study objective was to examine factors associated with interval Pap testing adherence., Methods: A population-based, in-person survey of Vietnamese women aged 18-64 years was conducted. Questionnaire content was guided by the Health Behavior Framework (HBF). The study sample was randomly selected from 1639 south Seattle households. Statistical methods included chi(2) tests and logistic regression., Results: The response rate among eligible households was 82%, and the study included 352 women. Sixty-eight percent of the participants had been screened during the preceding 3 years. The following HBF factors were associated (P < 0.05) with interval Pap testing in bivariate comparisons: believing Pap tests decrease the risk of cervical cancer and believing cervical cancer is curable if detected early (perceived effectiveness); knowing testing is necessary for women who are asymptomatic, sexually inactive, or postmenopausal (knowledge); reporting concern about pain/discomfort as a barrier to screening (barriers); family member(s) and friend(s) had suggested testing (social support); doctor(s) had recommended testing; and had asked doctor(s) for testing (communication with provider). In a multivariate analysis, being married, knowing Pap testing is necessary for asymptomatic women, doctor(s) had recommended testing, and had asked doctor(s) for testing were independently associated (P < 0.05) with screening participation., Conclusion: Our results confirm low levels of Pap testing among Vietnamese women and demonstrate the importance of physician-patient communication in increasing screening adherence. Health education efforts should target unmarried women and reinforce the importance of Pap testing for all Vietnamese women.

Women with high circulating estrogen concentrations have an increased risk of breast cancer; thus, it is important to understand factors, including genetic variability, that influence estrogen concentrations. Several genetic polymorphisms that may influence sex hormone concentrations have been identified, including CYP17 (5'-untranslated region T-->C), CYP19 [intron 4 (TTTA)(n = 7-13) and a 3-bp deletion (-3)], CYP1B1 (Val(432)Leu), and COMT (Val(108/158)Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2- and 16alpha-hydroxyestrone in 171 postmenopausal women, using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, not taking hormone therapy, and had a body mass index >24.0. Compared with noncarriers, women carrying two CYP19 7r(-3) alleles had 26% lower estrone (P < 0.001), 19% lower estradiol (P = 0.01), 23% lower free estradiol (P = 0.01), and 22% higher sex hormone-binding globulin concentrations (P = 0.06). Compared with noncarriers, women carrying at least one CYP19 8r allele had 20% higher estrone (P = 0.003), 18% higher estradiol (P = 0.02), and 21% higher free estradiol concentrations (P = 0.01). Women with the COMT Met/Met genotype had 28% higher 2-hydroxyestrone (P = 0.08) and 31% higher 16alpha-hydroxyestrone concentrations (P = 0.02), compared with Val/Val women. Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations. This study provides further evidence that genetic variation may appreciably alter sex hormone concentrations in postmenopausal women not taking hormone therapy.

The prostate-specific antigen test has been a major factor in increasing awareness and better patient management of prostate cancer (PCA), but its lack of specificity limits its use in diagnosis and makes for poor early detection of PCA. The objective of our studies is to identify better biomarkers for early detection of PCA using protein profiling technologies that can simultaneously resolve and analyze multiple proteins. Evaluating multiple proteins will be essential to establishing signature proteomic patterns that distinguish cancer from noncancer as well as identify all genetic subtypes of the cancer and their biological activity. In this study, we used a protein biochip surface enhanced laser desorption/ionization mass spectrometry approach coupled with an artificial intelligence learning algorithm to differentiate PCA from noncancer cohorts. Surface enhanced laser desorption/ionization mass spectrometry protein profiles of serum from 167 PCA patients, 77 patients with benign prostate hyperplasia, and 82 age-matched unaffected healthy men were used to train and develop a decision tree classification algorithm that used a nine-protein mass pattern that correctly classified 96% of the samples. A blinded test set, separated from the training set by a stratified random sampling before the analysis, was used to determine the sensitivity and specificity of the classification system. A sensitivity of 83%, a specificity of 97%, and a positive predictive value of 96% for the study population and 91% for the general population were obtained when comparing the PCA versus noncancer (benign prostate hyperplasia/healthy men) groups. This high-throughput proteomic classification system will provide a highly accurate and innovative approach for the early detection/diagnosis of PCA.

Recruitment into public health intervention trials can be costly and time-consuming. We examined two components of recruitment for an exercise trial: (a) a randomized pilot study of mailing strategies; and (b) the results from the entire recruitment process. In the pilot study, 4,999 women were randomized into one of four groups using a factorial design. The first factor was the inclusion or exclusion of a personal invitation letter, and the second was the use of first-class stamps versus bulk mail. We received 580 (11.6%) responses. Responses from interested women were nonsignificantly higher (odds ratio, 1.19; P = 0.10) for first-class versus bulk-rate postage. However, the cost to randomize one participant using first-class mail was $56.14 (in 1998 dollars) more than for bulk mail. We found no difference in response when including the invitation letter (odds ratio, 1.00; P > 0.50). The general recruitment process identified potentially eligible women primarily through mass mailings but also through media and other sources. We mailed recruitment materials, via bulk mail and including an invitation letter, to 103,577 women in the Seattle area over 2 years. Response rates were different (P < 0.001) between age groups: 6.2% for 50-59-year-old women; 7.9% for 60-69-year-old women; and 7.4% for 70-75-year-old women. The proportion of respondents eventually randomized did not differ by recruitment strategy (mail, media, other). Our study indicates that bulk mail may be more cost-effective than first-class mail for recruitment into intervention trials and that older women are willing to participate in such studies.

There is an increasing need for accurate prediction methods of assessing individual risk for breast cancer for both clinical and research purposes. The purpose of this study is to compare the Gail and Claus model risk estimates of breast cancer among women with a family history of breast cancer. This study presents risk estimates from two models of breast cancer risk in 491 women 18 to 74 years of age with a family history of breast cancer who were recruited to risk counseling clinical trials in Seattle, Washington between 1996 and 1997. These trials included women from the general population and additional samples of Ashkenazi Jewish, African-American, and lesbian women. We estimated and compared lifetime (to age 79) and 5-year risk for developing breast cancer using the National Surgical Adjuvant Breast and Bowel Project adaptation of the Gail model and the Claus model. About one-quarter of participants fell into the Gail "high" risk category (> or =1.7% risk of developing breast cancer in the next 5 years). The average lifetime risk was estimated at 13.2% by the Gail model and 11.2% by the Claus model. Estimates from the two models were moderately and positively correlated (r = 0.55) with the Gail model yielding a higher estimate than the Claus model for most participants. If women with a family history of breast cancer are being counseled regarding decisions on genetic testing, tamoxifen use, or other preventive measures, presenting both Claus and Gail estimates may be the best option.

Parallel to its established causal association with both infectious mononucleosis (IM) and young adulthood Hodgkin disease (YAHD), we propose a hypothesis that "delayed" primary EBV infection (i.e., primary infection occurring during adolescence or adulthood) is associated with elevated breast cancer risk. We evaluated this hypothesis with two investigations, one descriptive and the other analytic. The descriptive study used international/United States cancer registry data to assess the association between incidence rates of breast cancer and those of YAHD. The incidence rates of the seemingly unrelated neoplasms were strongly correlated (correlation coefficients of 0.74 and 0.88 for international and United States data, respectively; these were higher than the correlation coefficients of YAHD with two other cancers that we considered). Populations with higher incidence rates corresponded to those with higher likelihood of delayed primary EBV infection. The analytical study was based on a population-based case-control study of breast cancer in middle-aged women. Age-adjusted odds ratios of breast cancer in women who reported a history of IM, relative to women who did not, increased monotonically from 0.55 [95% confidence interval (CI), 0.05-6.17] for women with 0-9 years of age at IM onset to 2.67 (CI, 1.04-6.89) for women with > or =25 years of age at IM onset (P = 0.016). An older age at tonsillectomy, another surrogate of delayed EBV exposure, was also associated with increased risk of breast cancer: odds ratios, 0.92 (CI, 0.57-1.48) and 1.76 (CI, 1.15-2.69) for women with tonsillectomy at 0-4 years of age and > or =15 years of age, respectively (P = 0.018). Adjusting for additional potential confounders did not modify the associations appreciably. The implications of the findings and a potential biological mechanism are presented.

Colorectal hyperplastic polyps are benign lesions that share many risk factors with colorectal adenomas and cancers. Low folate intakes are associated with an increased risk of colon cancer. The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) may be linked to DNA methylation and nucleotide synthesis and thus play a role in the etiology of colorectal neoplasia. We investigated an association between the common MTHFR polymorphism (C677T) and colorectal hyperplastic polyps within the Minnesota Cancer Prevention Research Unit case-control study. Cases (n = 200) were diagnosed with colonoscopically confirmed hyperplastic polyps; controls (n = 645) were derived from the same gastroenterology practice and were polyp-free at colonoscopy. Dietary intakes were estimated from a self-administered food-frequency questionnaire prior to colonoscopy. Multivariate adjusted odds ratios (ORs) and 95% confidence intervals for MTHFR status were 0.8 (0.6-1.2; CT versus CC wild-type) and 0.9 (0.5-1.6; TT versus CC). In subgroup analyses stratified on dietary intakes of folate, vitamin B12, vitamin B6, or methionine, those with the TT genotype and either low intakes of folate or vitamin B6 were at increased risk relative to those with normal or high vitamin intake. However, most 95% confidence intervals included 1.0, and no consistent trends were observed. In contrast to our findings on colorectal adenomas, increasing alcohol consumption was associated with an elevated risk of colorectal hyperplastic polyps, regardless of genotype. The MTHFR (C677T) variant genotype does not appear to be related to risk of colorectal hyperplastic polyps, and there is no convincing evidence that MTHFR shows a different relation to risk, dependent on dietary intakes of nutrients related to its pathway.

5,10-Methylene-tetrahydrofolate reductase (MTHFR), an enzyme in folate metabolism, may play a role in the etiology of colorectal adenomas via effects on DNA methylation and nucleotide synthesis. We investigated the association between a common polymorphism (C677T, reduced MTHFR activity) and colorectal adenomas within the Minnesota CPRU case-control study. Cases (n = 527) were diagnosed with colonoscopically confirmed adenomas; controls (n = 645) were derived from the same gastroenterology practice and were polyp free at colonoscopy. Dietary intakes were obtained from a self-administered food-frequency questionnaire prior to colonoscopy. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals for the MTHFR genotype were 0.9 (0.7-1.2; CT versus CC wild-type) and 0.8 (0.6-1.3; TT versus CC). The associations between dietary intakes of folate, vitamin B12, vitamin B6, or methionine and risk of adenomas showed consistent patterns dependent upon MTHFR genotype. Individuals with the TT genotype and intakes of any of these nutrients in the lowest tertile were at elevated risk for adenomas (about 2-3-fold when compared with TT genotype with high intakes). These trends were more pronounced among individuals over age 60, resulting in a 3-6-fold increase for low intakes of folate, B12, and B6. An increased risk with increasing alcohol consumption was observed only among those with the CC genotype (P-trend = 0.005); among those with the TT genotype, those with moderate alcohol consumption were at lowest risk (P for interaction P = 0.02). In conclusion, nutrients involved in the MTHFR metabolic pathway may modify the relationship between the MTHFR C677T polymorphism and colorectal adenomas. Low intakes of folate, vitamin B12, and vitamin B6 increase risk among those (particularly the elderly) with the MTHFR TT genotype.