Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group.

BACKGROUND: The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials. METHODS: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods. RESULTS: In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m2 ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m2 ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2 ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35). CONCLUSIONS: Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.

Association of HSD3B1 Genotype and Clinical Outcomes in Postmenopausal Estrogen-Receptor-Positive Breast Cancer.

BACKGROUND: Homozygous inheritance of a single-nucleotide polymorphism (1245A > C) in HSD3B1 results in an adrenal permissive phenotype of increased adrenal steroid precursor conversion to potent androgens. This is associated with poor outcomes in prostate cancer. We hypothesized that inheritance of the HSD3B1 adrenal permissive genotype would similarly negatively impact breast cancer outcomes. PATIENTS AND METHODS: Germline HSD3B1 was sequenced in 644 postmenopausal women diagnosed between 2004 and 2015 with stage I-III estrogen receptor-positive (ER+), HER2/neu-negative (HER2-) breast cancer enrolled in a population-based study in western Washington. Primary endpoint was distant metastatic recurrence according to genotype. Secondary endpoint was breast cancer-specific survival. Hazard ratios (HR) were calculated using cause-specific Cox regression accounting for competing risks. RESULTS: Adrenal restrictive genotype (homozygous wild type) was most prevalent (47%), followed by heterozygous (44%) and adrenal permissive (9%). There were no significant differences comparing demographic, tumor, or treatment characteristics apart from higher frequency of adrenal permissive genotype among non-Hispanic white participants (p = 0.04). After accounting for competing risks, the cumulative incidence of distant metastatic recurrence (15 events) was significantly higher among participants with adrenal permissive compared with the adrenal restrictive genotype (HR 4.9, 95% CI 1.32-18.4, p = 0.02). The adrenal permissive genotype was also predictive of breast cancer-specific mortality (HR 3.5, 95% CI 1.27-9.59, p = 0.02). CONCLUSIONS: Inheritance of the HSD3B1 adrenal permissive genotype is associated with increased incidence of distant metastasis and higher cause-specific mortality in postmenopausal ER+/HER2- breast cancer. Further research is necessary to understand the effect of excess adrenal androgen metabolism in promoting breast cancer growth and progression.

Morbidity and rehospitalization postpartum among women with epilepsy and their infants: A population-based study.

OBJECTIVE: We compared the relative occurrence of selected pregnancy outcomes and postpartum rehospitalizations among women with and without epilepsy and their infants. Using linked vital-hospital discharge records of women with deliveries in Washington State 1987-2014, comparisons were made overall, by epilepsy type, and by time periods related to antiepileptic drug (AED) marketing changes. METHODS: This population-based retrospective cohort study identified women with, and without epilepsy per diagnosis codes in the hospital discharge record from among all deliveries during 1987-2014 to examine maternal and infant outcomes, rehospitalization and mortality <2 years postpartum. Relative risks (RRs) and 95 % confidence intervals (CI) overall, and by epilepsy type were calculated using Poisson regression. We assessed the validity of epilepsy identification based on diagnosis codes by conducting a medical chart review for a sample of women. RESULTS: Women with epilepsy had increased risks of preeclampsia (RR 1.23; 95 % CI 1.08-1.41) and gestational diabetes (RR 1.18; 95 % CI 1.02-1.36). Their infants had increased malformation (RR 1.23; 95 % C: 1.08-1.42) and small for gestational age (SGA, RR 1.39; 95 % CI 1.25-1.54) risks, and were nearly three times as likely to not be breastfed. Affected mothers (RR 5.25; 95 % CI 2.46-11.23) and their infants (RR 1.64, 95 % CI 1.41-1.89) required more ICU admissions during the delivery hospitalizations, and more postpartum rehospitalization, with greatest risk in the first six months. Maternal mortality < 2 years after delivery was increased (RR 7.11; 95 % CI 2.47-20.49). Increased risks were observed for all epilepsy subtypes for nearly all outcomes examined. Risks of preterm delivery and low birthweight increased over time (p <.05). Suggestive, but not statistically significant temporal decreases in risks of gestational diabetes and malformations and increased risk of preterm labor were noted. We observed high sensitivity of diagnosis codes for identifying pregnant women with epilepsy. CONCLUSION: These population-based results emphasize the need for frequent postpartum monitoring of women with epilepsy. Increases in risks of low birthweight and preterm delivery over time are of concern. Possible temporal changes in other outcomes warrant further investigation.

Hospitalization and mortality outcomes in the first 5 years after a childhood cancer diagnosis: a population-based study.

PURPOSE: Children with cancer are frequently hospitalized. However, hospitalization and death by disease category are not well defined < 5 years from diagnosis. METHODS: We conducted a retrospective cohort study using linked cancer registry-hospital discharge-vital records to identify cancer cases < 20 years at diagnosis during 1987-2012 (n = 4,567) and comparison children without cancer, matched on birth year and sex (n = 45,582). Data linkage identified serious morbidities resulting in cancer- and non-cancer-related hospitalizations or deaths < 5 years from diagnosis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to compare relative hospitalization and mortality by disease category and after excluding cancer-related outcomes. Among cancer cases, relative risks of these outcomes for children with solid tumors compared with children with leukemia/lymphoma were also estimated. RESULTS: Greater rates of all-cause hospitalization (281.5/1,000 vs. 6.2/1,000 person years) and death (40.7/1,000 vs. 0.15/1,000 person years) were observed in childhood cancer cases than comparators and across all diagnosis categories. Increased hospitalization (31.0/1,000 vs. 6.2/1,000 person years; HR 5.0, 95% CI 4.5-5.5) and death (1.0/1,000 vs. 0.15/1,000 person years; HR 10.4, 95% CI 5.6-19.1) rates remained when cancer-related outcomes were excluded. Although HRs for hospitalization and death did not differ greatly by treatment era, absolute rates of hospitalization were greater (1987-1999: 233.3/1,000; 2000-2012: 320.0/1,000 person years) and death were lesser (1987-1999: 46.3/1,000; 2000-2012: 36.8/1,000 person years) in the later treatment era among cases. Children with solid tumors were less likely to have a cancer-related hospitalization than were those with leukemia/lymphoma (RR 0.91, 95% CI 0.84-0.98). CONCLUSION: Even after excluding cancer-related diagnoses, children with cancer experience greater rates of hospitalization and death in all disease categories. Results may guide future toxicity mitigation initiatives and inform anticipatory guidance for families of children with cancer.

Time and geographic variations in human papillomavirus vaccine uptake in Washington state.

This study examines geographic variations of human papillomavirus (HPV) vaccine uptake, the most significant disparity in HPV vaccination, in Washington State. We evaluated Washington State Immunization Information System (WA-IIS) data on target age (11-12 year old adolescents) between 2008 and 2018. A Bayesian spatio-temporal analysis was conducted to examine uptake at the census tract level. Urban-rural disparities in vaccine rates were assessed using t-tests. Persistently high and low vaccine areas and their contributing sociodemographic factors were then identified using a multinomial logistic regression. HPV vaccine uptake gradually increased after 2010, but remained persistently low. Average vaccine uptake rates from 2010 through 2018 in urban areas were 11%-34% for initiation and 4-19% for completion. These rates were 9-22% initiation and 3-11% completion in rural areas. We observed statistically significant (p < 0.05) differences between the estimated vaccine rates for urban and rural census tracts. Race/ethnicity and socioeconomic status were associated with this urban-rural disparity. The odds of being in low vaccine rural areas increased with increase in Area Deprivation Index (ADI) (OR = 1.14, CI = (1.10, 1.19)), and decreased with percentage increase in Black (OR = 0.43, CI = (0.02, 0.85)) and Hispanic (OR = 0.97, CI = (0.94, 1.00)) population. Bayesian spatial analysis was effective in capturing spatio-temporal patterns in HPV vaccine rates and identifying areas with persistently low vaccination over time. This analytic approach can be used to guide public health policies and geographically target interventions to reduce HPV vaccine disparities and to prevent future HPV-related cancers.

Assessment of the Accuracy of Identification of Selected Disabilities and Conditions in Hospital Discharge Data for Pregnant Women.

BACKGROUND: Linked birth certificate-hospital discharge records are a valuable resource for examining pregnancy outcomes among women with disability conditions. Few studies relying on these data have been able to assess the accuracy of identification of preexisting disability conditions. We assessed the accuracy of International Classification of Diseases version 9 (ICD9) codes for identifying selected physical, sensory, and intellectual conditions that may result in disability. As ICD9 codes were utilized until recently in most states, this information is useful to inform analyses with these records. METHODS: We reviewed 280 of 311 (90%) medical records of pregnant women with disabilities based on ICD9 codes and 390 of 8,337 (5%) records of pregnant women without disabilities who had deliveries at a large university medical center. We estimated sensitivity, specificity, and positive predictive values (PPV) using the medical record as gold standard. We adjusted for verification bias using inverse probability weighting and imputation. RESULTS: The estimated sensitivity of ICD9 codes to identify women with disabilities with deliveries 2009-2012 was 44%; PPV was 98%, improving over time. Although sensitivity was <50% for some conditions, PPVs were 87%-100% for all conditions except intellectual disability (67%). Many physical conditions had complete verification and no underreporting. CONCLUSIONS: These results are helpful for new studies using historical data comparing outcomes among women with and without these conditions and to inform interpretation of results from earlier studies. Assessment of the accuracy of disabilities as identified by ICD version 10 codes is warranted.

Birthweight and all-cause mortality after childhood and adolescent leukemia: a cohort of children with leukemia from Denmark, Norway, Sweden, and Washington State.

Background: High birthweight may predispose children to acute lymphoid leukemia, whereas low birthweight is associated with childhood morbidity and mortality. Low and high birthweight have been inconsistently associated with mortality in children with leukemia.Material and methods: In a cohort of childhood and adolescent leukemia (0-19 years) patients from registries in Denmark, Norway, Sweden, and Washington State in the United States (1967-2015), five-year all-cause mortality was assessed by birthweight and other measures of fetal growth using the cumulative incidence function and Cox regression with adjustment for sex, diagnosis year, country, the presence of Down's syndrome or other malformations, and type of leukemia.Results: Among 7148 children and adolescents with leukemia (55% male), 4.6% were low (<2500 g) and 19% were high (≥4000 g) birthweight. Compared with average weight, hazard ratios (HRs) of death associated with low birthweight varied by age at leukemia diagnosis: 1.5 (95% confidence interval (CI): 0.7, 3.2) for patients 0-1 year old, 1.6 (95% CI: 1.0, 2.6) for >1-2 years old; 1.0 (95% CI: 0.6, 1.5) for 3-8 years old; 1.0 (95% CI: 0.6, 1.8) for 9-13 years old; and 1.2 (95% CI: 0.7, 2.1) for 14-19 years old, and were similar for size for gestational age and Ponderal index. In analyses restricted to children born full term (37-41 weeks of gestation), results were only slightly attenuated but risk was markedly increased for infants aged ≤1 year (HR for low birthweight = 3.2, 95% CI: 1.2, 8.8).Conclusion: This cohort study does not suggest that low birthweight or SGA is associated with increased five-year all-cause mortality risk among children with any type of childhood leukemia or acute lymphoblastic leukemia, specifically, beyond infancy.

CYP2D6-inhibiting medication use and inherited CYP2D6 variation in relation to adverse breast cancer outcomes after tamoxifen therapy.

PURPOSE: Tamoxifen is widely used to reduce the risk of breast cancer (BC) recurrence and extend disease-free survival among women with estrogen-sensitive breast cancers. Tamoxifen efficacy is thought to be attributable to its active metabolite, which is formed through a reaction catalyzed by the P450 enzyme, CYP2D6. Inhibition of tamoxifen metabolism as a result of germline genetic variation and/or use of CYP2D6-inhibiting medications ("inhibitors") is hypothesized to increase the risk of adverse BC outcomes among women taking tamoxifen. METHODS: The present cohort study of 960 women diagnosed with early-stage BC between 1993 and 1999 examined the association between concomitant use of CYP2D6 inhibitors and adjuvant tamoxifen and the risk of adverse BC outcomes (recurrence, second primary BC, BC mortality), both overall and according to CYP2D6 metabolic phenotype. RESULTS: Six or more months of CYP2D6 inhibitor use concomitant with tamoxifen was not associated with any appreciable increase in risk of recurrence or second primary BC or BC mortality, and there was no clear evidence of variation by CYP2D6 metabolic phenotype. CONCLUSIONS: These results are consistent with the relatively few other large, population-based studies conducted to date that have not observed an increased risk of adverse BC outcomes associated with CYP2D6 inhibition.

CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study.

BACKGROUND: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown. METHODS: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS. RESULTS: Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02). CONCLUSION: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.

Hospitalization and mortality among pediatric cancer survivors: a population-based study.

PURPOSE: We examined serious long-term outcomes among childhood cancer survivors using population-based data. METHODS: We used 1982-2014 Washington State data to compare hospitalization and/or death (including cause-specific) during up to 27 years follow-up among all 5+ year childhood cancer survivors < 20 years at diagnosis (n = 3,152) and a sample of comparison children within birth cohorts, with assessment by cancer type and child/family characteristics. RESULTS: During follow-up (9 years median), 12% of survivors had hospitalizations; 4% died. Greatest absolute risks/1,000 person-years were for hospitalization/deaths due to cancers (8.1), infection (6.2), injuries (6.0), and endocrine/metabolic disorders (5.8). Hazard ratios (HR) and 95% confidence intervals (CI) for hospitalization (2.7, 95% CI 2.4-3.0) and any-cause death (14.7, 95% CI 11.3-19.1) were increased, and for all cause-specific outcomes examined, most notably cancer- (35.1, 95% CI 23.7-51.9), hematological- (6.7, 95% CI 5.3-8.5), nervous system- (6.4, 95% CI 5.2-7.8), and circulatory- (5.2, 95% CI 4.1-6.5) related outcomes. Hospitalizations occurred more often among females and those receiving radiation, with modest differences by urban/rural birth residence and race/ethnicity. Cause-specific outcomes varied by cancer type. CONCLUSIONS: This study suggests increased risks for the rarely-studied outcomes of long-term fracture and injury, and confirms increased risks of selected other conditions among survivors. Multi-state pooling of population-based data would increase the ability to evaluate outcomes for uncommon cancer types and by racial/ethnic groups under-represented in many studies.

Advanced parental age as risk factor for childhood acute lymphoblastic leukemia: results from studies of the Childhood Leukemia International Consortium.

Advanced parental age has been associated with adverse health effects in the offspring including childhood (0-14 years) acute lymphoblastic leukemia (ALL), as reported in our meta-analysis of published studies. We aimed to further explore the association using primary data from 16 studies participating in the Childhood Leukemia International Consortium. Data were contributed by 11 case-control (CC) studies (7919 cases and 12,942 controls recruited via interviews) and five nested case-control (NCC) studies (8801 cases and 29,690 controls identified through record linkage of population-based health registries) with variable enrollment periods (1968-2015). Five-year paternal and maternal age increments were introduced in two meta-analyses by study design using adjusted odds ratios (OR) derived from each study. Increased paternal age was associated with greater ALL risk in the offspring (ORCC 1.05, 95% CI 1.00-1.11; ORNCC 1.04, 95% CI 1.01-1.07). A similar positive association with advanced maternal age was observed only in the NCC results (ORCC 0.99, 95% CI 0.91-1.07, heterogeneity I2 = 58%, p = 0.002; ORNCC 1.05, 95% CI 1.01-1.08). The positive association between parental age and risk of ALL was most marked among children aged 1-5 years and remained unchanged following mutual adjustment for the collinear effect of the paternal and maternal age variables; analyses of the relatively small numbers of discordant paternal-maternal age pairs were not fully enlightening. Our results strengthen the evidence that advanced parental age is associated with increased childhood ALL risk; collinearity of maternal with paternal age complicates causal interpretation. Employing datasets with cytogenetic information may further elucidate involvement of each parental component and clarify underlying mechanisms.

Consumption of alcoholic beverages in adolescence and adulthood and risk of testicular germ cell tumor.

The etiology of testicular germ cell tumor (TGCT) remains obscure and accumulating evidence suggests that postnatal environmental or lifestyle factors may play a role. To investigate whether consumption of alcoholic beverages during adolescence or adulthood is associated with TGCT risk, we analyzed data from a USA population-based case-control study of 540 18-44 year-old TGCT cases and 1,280 age-matched controls. Participants were queried separately about consumption of beer, wine and liquor during grades 7-8, grades 9-12 and the 5 years before reference date (date of diagnosis for cases and corresponding date for controls). We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of TGCT risk with alcoholic beverage consumption during the different periods, both total and by specific beverage types and separately for seminomas and nonseminomas. Compared with nondrinkers in the 5 years before reference date, the OR (95% CI) for 1-6, 7-13 and ≥14 drinks per week were 1.20 (0.85, 1.69), 1.23 (0.81, 1.85) and 1.56 (1.03, 2.37), respectively (p-trend = 0.04). The corresponding results for alcohol consumption in grades 9-12 were 1.39 (1.06, 1.82), 1.07 (0.72, 1.60), 1.53 (1.01, 2.31) (p-trend = 0.05). Alcohol consumption in grades 7-8 was uncommon and no statistically significant associations with TGCT were observed. Associations with alcohol consumption in the 5 years before reference date appeared stronger for nonseminomas than for seminomas, but the differences were not statistically significant (p≥0.10). Associations were similar across different alcoholic beverage types. Consumption of alcoholic beverages may be associated with an increased TGCT risk.

Parental Tobacco Smoking and Acute Myeloid Leukemia: The Childhood Leukemia International Consortium.

The association between tobacco smoke and acute myeloid leukemia (AML) is well established in adults but not in children. Individual-level data on parental cigarette smoking were obtained from 12 case-control studies from the Childhood Leukemia International Consortium (CLIC, 1974-2012), including 1,330 AML cases diagnosed at age <15 years and 13,169 controls. We conducted pooled analyses of CLIC studies, as well as meta-analyses of CLIC and non-CLIC studies. Overall, maternal smoking before, during, or after pregnancy was not associated with childhood AML; there was a suggestion, however, that smoking during pregnancy was associated with an increased risk in Hispanics (odds ratio = 2.08, 95% confidence interval (CI): 1.20, 3.61) but not in other ethnic groups. By contrast, the odds ratios for paternal lifetime smoking were 1.34 (95% CI: 1.11, 1.62) and 1.18 (95% CI: 0.92, 1.51) in pooled and meta-analyses, respectively. Overall, increased risks from 1.2- to 1.3-fold were observed for pre- and postnatal smoking (P < 0.05), with higher risks reported for heavy smokers. Associations with paternal smoking varied by histological type. Our analyses suggest an association between paternal smoking and childhood AML. The association with maternal smoking appears limited to Hispanic children, raising questions about ethnic differences in tobacco-related exposures and biological mechanisms, as well as study-specific biases.

Integrative genomics in combination with RNA interference identifies prognostic and functionally relevant gene targets for oral squamous cell carcinoma.

In oral squamous cell carcinoma (OSCC), metastasis to lymph nodes is associated with a 50% reduction in 5-year survival. To identify a metastatic gene set based on DNA copy number abnormalities (CNAs) of differentially expressed genes, we compared DNA and RNA of OSCC cells laser-microdissected from non-metastatic primary tumors (n = 17) with those from lymph node metastases (n = 20), using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR)<5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Of these, 114 were found to have a significant correlation between DNA copy number and gene expression (FDR<0.01). Among these 114 correlated transcripts, the corresponding genomic regions of each of 95 transcripts had CNAs differences between primary and metastatic OSCC (FDR<0.01). Using an independent dataset of 133 patients, multivariable analysis showed that the OSCC-specific and overall mortality hazards ratio (HR) for patients carrying the 95-transcript signature were 4.75 (95% CI: 2.03-11.11) and 3.45 (95% CI: 1.84-6.50), respectively. To determine the degree by which these genes impact cell survival, we compared the growth of five OSCC cell lines before and after knockdown of over-amplified transcripts via a high-throughput siRNA-mediated screen. The expression-knockdown of 18 of the 26 genes tested showed a growth suppression ≥ 30% in at least one cell line (P<0.01). In particular, cell lines derived from late-stage OSCC were more sensitive to the knockdown of G3BP1 than cell lines derived from early-stage OSCC, and the growth suppression was likely caused by increase in apoptosis. Further investigation is warranted to examine the biological role of these genes in OSCC progression and their therapeutic potentials.

Natural Antibodies to Human Papillomavirus 16 and Recurrence of Vulvar High-Grade Intraepithelial Neoplasia (VIN3).

OBJECTIVES: Approximately 30% of women treated for squamous high-grade intraepithelial neoplasia (VIN3), often associated with human papillomavirus (HPV), have recurrent disease. In this study, we assess predictors of recurrence that may provide targets for early prevention or treatment. MATERIALS AND METHODS: Women with VIN3 who participated in a previous population-based case-control study with blood and tumor samples completed a follow-up telephone interview an average of 5 years after initial diagnosis. The risk of recurrence was determined by proportional hazards modeling. RESULTS: Women with VIN3 in the follow-up study (n = 65) were similar to women with VIN3 in the parent study (n = 215) with regard to age at primary diagnosis, level of current cigarette smoking (>60%), and lifetime number of partners. We found that 22 (33.8%) of 65 participants had a vulvar recurrence and that 73.4% recurred within 3 years of treatment. Recurrences occurred more often among women with common warts in the decade before diagnosis (hazard ratio [HR] = 2.5, 95% CI = 1.1-5.8) and among those with a previous anogenital cancer (HR = 2.7, 95% CI = 1.2-6.3). Interestingly, recurrence was less frequent among women who mounted a natural antibody response to HPV16 (HR = 0.4, 95% CI = 0.2-0.9). CONCLUSIONS: These data provide strong preliminary evidence that VIN3 recurrence was less frequent among those with HPV16 antibodies. Vaccination with the currently licensed HPV vaccine as part of adjunctive therapy for VIN3 would increase antibody response and may decrease risk of recurrence. Randomized controlled trials are needed to determine whether HPV vaccination is effective against VIN3 recurrence.

Neonatal vitamin D and childhood brain tumor risk.

Vitamin D deficiency among pregnant women is common. Compelling animal evidence suggests carcinogenic effects of vitamin D deficiency on the brains of offspring; however, the impact of circulating vitamin D [25(OH)D] on childhood brain tumor (CBT) risk has not been previously evaluated. Using linked birth-cancer registry data in Washington State, 247 CBT cases (<15 years at diagnosis; born 1991 or later) were identified. A total of 247 birth year-, sex- and race-matched controls were selected from the remaining birth certificates. Liquid chromatography-tandem mass spectrometry was used to measure circulating levels of vitamin D3 [25(OH)D3] in neonatal dried blood spots. Overall, no significant associations were observed. However, when stratified by median birth weight (3,458 g), there was evidence of increasing risk of CBT with increasing 25(OH)D3 among children in the higher birth weight category. Compared to the lowest quartile (2.8-7.7 ng/mL), odds ratios (ORs) and 95% confidence intervals (CIs) for the second (7.7-<11.0 ng/mL), third (11.0-<14.7 ng/mL) and fourth (14.7-37.0) quartiles of 25(OH)D3 were 1.7 (1.0-3.3), 2.4 (1.2-4.8) and 2.6 (1.2-5.6), respectively. Among children in the lower birth weight category, there was suggestive evidence of a protective effect: ORs and 95% CIs for the second, third and fourth quartiles were 0.9 (0.4-1.9), 0.7 (0.3-1.4) and 0.6 (0.3-1.3), respectively. Any associations of neonatal vitamin D with CBT may be birth weight-specific, suggesting the possible involvement of insulin-like growth factor 1, circulating levels of which have been associated with vitamin D and accelerated fetal growth.

Mortality After Major Cardiovascular Events in Survivors of Childhood Cancer.

BACKGROUND: Adult survivors of childhood cancer are at risk for cardiovascular events. OBJECTIVES: In this study, we sought to determine the risk for mortality after a major cardiovascular event among childhood cancer survivors compared with noncancer populations. METHODS: All-cause and cardiovascular cause-specific mortality risks after heart failure (HF), coronary artery disease (CAD), or stroke were compared among survivors and siblings in the Childhood Cancer Survivor Study (CCSS) and participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Cox proportional hazard regression models were used to estimate HRs and 95% CIs between groups, adjusted for demographic and clinical factors. RESULTS: Among 25,658 childhood cancer survivors (median age at diagnosis 7 years, median age at follow-up or death 38 years) and 5,051 siblings, 1,780 survivors and 91 siblings had a cardiovascular event. After HF, CAD, and stroke, 10-year all-cause mortalities were 30% (95% CI: 26%-33%), 36% (95% CI: 31%-40%), and 29% (95% CI: 24%-33%), respectively, among survivors vs 14% (95% CI: 0%-25%), 14% (95% CI: 2%-25%), and 4% (95% CI: 0%-11%) among siblings. All-cause mortality risks among childhood cancer survivors were increased after HF (HR: 7.32; 95% CI: 2.56-20.89), CAD (HR: 5.54; 95% CI: 2.37-12.93), and stroke (HR: 3.57; 95% CI: 1.12-11.37). CAD-specific mortality risk was increased (HR: 3.70; 95% CI: 1.05-13.02). Among 5,114 CARDIA participants, 345 had a major event. Although CARDIA participants were on average decades older at events (median age 57 years vs 31 years), mortality risks were similar, except that all-cause mortality after CAD was significantly increased among childhood cancer survivors (HR: 1.85; 95% CI: 1.16-2.95). CONCLUSIONS: Survivors of childhood cancer represent a population at high risk for mortality after major cardiovascular events.

A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility.

Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus. In combined analysis that mutually conditions on both DMRT1 single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) = 1.48, 95% confidence interval (CI) 1.23, 1.78; P = 2.52 × 10(-5)] compared with controls, while the association with rs755383 persisted (per allele OR = 1.26, 95% CI 1.08, 1.47, P = 0.0036). In similar analyses, the association of rs7040024 among men with seminomatous tumors did not differ from that among men with non-seminomatous tumors. In combination with KITLG, the strongest TGCT susceptibility locus found to date, men with TGCT had greatly elevated odds (OR = 14.1, 95% CI 5.12, 38.6; P = 2.98 × 10(-7)) of being double homozygotes for the risk (major) alleles at DMRT (rs7040024) and KITLG (rs4474514) when compared with men without TGCT. Our findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility.