Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI.

OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population. SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models. RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10-7). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue. CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

Genetic predisposition to radiation-related cancer and potential implications for risk assessment.

Several lines of evidence suggest that risk estimates for cancer associated with radiation exposure incorporate individuals who are more and less inherently susceptible to the carcinogenic effects of radiation, and the technology to further evaluate this issue is now available. For example, genome-wide association scan studies could be undertaken to address, at least in part, the direction of causality in the observations of differential sensitivity to radiomimetic agents in cancer cases compared with normal individuals, thereby building on previous observations that sensitivity to these agents is higher in apparently normal individuals carrying gene mutations in NBS and ATM. Direct studies of risk of second cancers in relation to radiation are underway, and some results have been reported (e.g. for the PRDM1 gene as related to sensitivity to radiation-related cancers after treatment for Hodgkin's lymphoma). It is important to understand the risk synergies between variants affecting associations with various cancers defining susceptibility in unexposed populations and the excess risk in populations therapeutically or occupationally exposed to radiation for the purpose of risk protection, especially as additional baseline risk variants are discovered in increasingly large-scale analyses. While there are studies that are beginning to address these questions, there have been no compelling new discoveries, to date, to indicate that predisposition information should be included in risk assessment. The conclusions in ICRP Publications 79 and 103 appear relevant today.

Diagnostic radiography and adult acute myeloid leukaemia: an interview and medical chart review study.

BACKGROUND: Aetiology of acute myeloid leukaemia (AML) is not well understood, perhaps because of its distinct subtypes. High-dose ionising radiation is a known risk factor, but less is known about risk from low-dose exposure such as from diagnostic radiography. METHODS: Subjects were 412 matched case-control pairs. Ten-year subject histories of diagnostic radiography were based on interview and medical records. RESULTS: There was no convincing association between AML risk and ionising radiation exposure from diagnostic imaging procedures, either for AML overall or for any AML subtype. CONCLUSION: The association between diagnostic radiography and AML risk remains uncertain.

The association of diabetes with colorectal cancer risk: the Multiethnic Cohort.

BACKGROUND: Diabetics have been found to have a greater risk of colorectal cancer than non-diabetics. METHODS: We examined whether this relationship differed by ethnic group, cancer site or tumour stage in a population-based prospective cohort, including 3549 incident colorectal cancer cases identified over a 13-year period (1993-2006) among 199 143 European American, African American, Native Hawaiian, Japanese American and Latino men and women in the Multiethnic Cohort. RESULTS: Diabetics overall had a significantly greater risk of colorectal cancer than did non-diabetics (relative risk (RR)=1.19, 95% confidence interval (CI)=1.09-1.29, P-value (P)<0.001). Positive associations were observed for colon cancer, cancers of both the right and left colon, and cancers diagnosed at a localised and regional/distant stage. The association with colorectal cancer risk was significantly modified by smoking status (P(Interaction)=0.0044), with the RR being higher in never smokers (RR=1.32, 95% CI=1.15-1.53, P<0.001) than past (RR=1.19, 95% CI=1.05-1.34, P=0.007) and current smokers (RR=0.90, 95% CI=0.70-1.15, P=0.40). CONCLUSION: These findings provide strong support for the hypothesis that diabetes is a risk factor for colorectal cancer.

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis.

There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.

A candidate gene approach to searching for low-penetrance breast and prostate cancer genes.

Most cases of breast and prostate cancer are not associated with mutations in known high-penetrance genes, indicating the involvement of multiple low-penetrance risk alleles. Studies that have attempted to identify these genes have met with limited success. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium--a pooled analysis of multiple large cohort studies with a total of more than 5,000 cases of breast cancer and 8,000 cases of prostate cancer--was therefore initiated. The goal of this consortium is to characterize variations in approximately 50 genes that mediate two pathways that are associated with these cancers--the steroid-hormone metabolism pathway and the insulin-like growth factor signalling pathway--and to associate these variations with cancer risk.

Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group.

BACKGROUND: The International Neuroblastoma Pathology Classification (International Classification), which was established in 1999, is significant prognostically and is relevant biologically for the evaluation and analysis of patients with neuroblastic tumors (NTs). MYCN amplification is a known molecular marker for aggressive progression of NTs. These have been used together as important prognostic factors to define risk groups for patient stratification and protocol assignment. METHODS: A total of 628 NTs (535 neuroblastomas [NBs]); 21 ganglioneuroblastoma, intermixed [GNBi]; 9 ganglioneuromas [GN]; and 63 ganglioneuroblastoma, nodular [GNBn]) from the Children's Cancer Group studies were evaluated histologically (favorable histology [FH] tumors vs. unfavorable histology [UH] tumors) according to the International Classification and were tested molecularly for MYCN status (amplified vs. nonamplified). Four tumor subsets (FH-nonamplified, FH-amplified, UH-nonamplified, and UH-amplified) were defined by histopathology and MYCN status, and their prognostic effects were analyzed. Detailed analysis between morphologic indicators (grade of neuroblastic differentiation and mitosis-karyorrhexis index [MKI]) and MYCN status was done by using tumors in the NB category. RESULTS: There were 339 FH-nonamplified tumors (5-year event free survival [EFS], 92.1%); 8 FH-amplified tumors (EFS, 37.5%); 172 UH-nonamplified tumors (EFS, 40.9%); and 109 UH-amplified tumors (EFS, 15.0%). The prognostic effects on patients with tumors in the four subsets were independent from the factors of patient age and disease stage (P < 0.0001). MYCN amplification was seen almost exclusively in tumors of the NB category, and no patients with tumors in either the GNBi category or in the GN category and only two patients with tumors in the GNBn category had amplified MYCN. Among the patients with tumors in the NB category, patients with FH-nonamplified tumors (309 patients) had an excellent prognosis, and patients with UH-amplified tumors (107 patients) had the poorest clinical outcome in any age group. The prognosis for children with UH-nonamplified tumors (111 patients) was poor when they were diagnosed at age > 1.5 years. It was also noted that patients with UH-amplified tumors (median age, 2.14 years) were diagnosed at a significantly younger age compared with the patients with UH-nonamplified tumors (median age, 3.55 years). Histologically, MYCN-amplified tumors lacked neuroblastic differentiation regardless of the age of patients. MYCN amplification also was linked generally to increased mitotic and karyorrhectic activities. However, MKI classes in patients with MYCN-amplified tumors varied significantly, depending on the age at diagnosis, and younger patients had higher MKI classes. CONCLUSIONS: The combination of histopathologic evaluation and MYCN status distinguishes four clinical and biologic tumor subsets in patients with NTs. MYCN amplification seems to be the powerful driving force for preventing cellular differentiation regardless of patient age and for increasing mitotic and karyorrhectic activities in an age dependent manner.

International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group.

BACKGROUND: The International Neuroblastoma Pathology Classification was established in 1999 for the prognostic evaluation of patients with neuroblastic tumors (NTs). METHODS: Pathology slides from 746 NTs (the Children's Cancer Group [CCG]-3881 and CCG-3891 studies) were evaluated according to the International Classification. First, prognostic effects of the morphologic indicators (grade of neuroblastic differentiation: undifferentiated [U], poorly differentiated [PD] and differentiating [D]; and mitosis-karyorrhexis index [MKI]: low [L-MKI], intermediate [I-MKI], and high [H-MKI]) for tumors in the neuroblastoma (NB) category were tested. Then, prognostic significance of the International Classification for all NTs in four categories (neuroblastoma [NB]; ganglioneuroblastoma, intermixed [GNBi]; ganglioneuroma [GN]; and ganglioneuroblastoma, nodular [GNBn]) was analyzed. Finally, age distribution of the patients in the four categories as well as three subtypes (based on the grade of differentiation) in the NB category was compared. RESULTS: There were 630 NB tumors, 30 GNBi tumors, 10 GN tumors, and 76 GNBn tumors. In the NB category, prognostic effects of the indicators (three grades of differentiation and three mitosis-karyorrhexis index [MKI] classes: low [L], intermediate [I], and high [H]) were affected significantly by the age of the patients. The age-linked evaluation of the indicators according to the International Classification successfully distinguished two prognostic subgroups: the favorable histology (FH) subgroup (PD/D and L/I-MKI tumors in patients age < 1.5 years, D and L-MKI tumors in patients ages 1.5-5.0 years; 90.4% 5-year event free survival [EFS]) and the unfavorable histology (UH) subgroup (U and/or H-MKI tumors in patients of any age, PD and/or I-MKI tumors in patients ages 1.5-5.0 years, any grade of differentiation, and any MKI class in patients age > or = 5 years; 26.9% EFS) (P < 0.0001). The International Classification also distinguished the FH group (FH subgroup with NB, GNBi, and GN tumors) and the UH group (UH subgroup with NB and GNBn tumors) for all NTs (90.8% EFS and 31.2% EFS, respectively; P < 0.0001) and provided independent prognostic information on both patient age and disease stage (P < 0.0001). Among patients with FH tumors, the median ages of patients with the PD and D subtype tumors in the NB category were 0.43 years (range, 0-1.50 years) and 1.50 years (range, 0.02-4.65 years), respectively, and the median ages of patients with GNBi and GN tumors were 3.51 years (range, 0.96-14.85 years) and 4.80 years (range, 1.94-17.05 years), respectively. In contrast, patients with UH tumors generally were older when they were diagnosed, and with median ages of 2.99 years (range, 1.30-8.84 years) for patients with U subtype tumors, 2.59 years (range, 0.0-12.57 years) for patients with PD subtype tumors, 2.16 years (range, 0.35-9.90) for patients with D subtype tumors, and 3.26 years (range, 0.57-15.90 years) for patients with GNBn tumors. CONCLUSIONS: This study confirmed the prognostic significance of the International Classification, substantiated age-linked prognostic effects of the morphologic indicators for patients with the tumors in the NB category, and supported the concept of an age-appropriate framework of maturation for patients with the tumors in the FH group.

Risk factors for cardiovascular and cerebrovascular death among African Americans and Hispanics in Los Angeles, California.

OBJECTIVE: To describe the risk factors associated with cardiovascular mortality in the African American (AA) and Hispanic populations in Los Angeles County in an effort to define causes for the excess mortality seen in AAs. METHODS: This was a longitudinal analysis of all-cause, cardiovascular, and cerebrovascular mortality in a large, prospective multiethnic cohort of individuals aged 45-74 years. Death rates between AA and Hispanic men and women during the six-year period from 1993 to 1998 due to hypertension, cardiomyopathy, acute myocardial infarction (AMI), ischemic heart disease, and stroke were compared. RESULTS: There were 1,157 deaths due to cardiovascular disease (CVD) or cerebrovascular disease among the 71,798 eligible members of the cohort included in these analyses. Age-adjusted mortality rates were two to five times higher in AAs as compared with Hispanics (e.g., 373.15 in AAs for hypertensive disease vs 50.37 in Hispanics). A history of hypertension was the most common significant risk factor for CVD; other risk factors significantly associated with CVD mortality included cigarette smoking and a past history of diabetes and stroke. Adjusting for these factors did not remove the significance of AA ethnicity as a risk factor for CVD mortality in either subjects reporting or subjects not reporting hypertension at baseline. CONCLUSIONS: The evidence for both higher relative severity and higher incidence of hypertensive disease among AAs, and the consistency of the effect across gender, suggests that a major determinant of risk may be a gene environment interaction.

Regression calibration in studies with correlated variables measured with error.

Regression calibration is a technique that corrects biases in regression results in situations where exposure variables are measured with error. The existence of a calibration substudy, where accurate and crude measurement methods are related by a second regression analysis, is assumed. The cost of measurement error in multivariate analyses is loss of statistical power. In this paper, calibration data from California Seventh-day Adventists are used to simulate study populations and new calibration studies. Applying regression calibration logistic analyses, the authors estimate power for pairs of nutritional variables. The results demonstrate substantial loss of power if variables measured with error are strongly correlated. Biases in estimated effects in cases where regression calibration is not performed can be large and are corrected by regression calibration. When the true coefficient has zero value, the corresponding coefficient in a crude analysis will usually have a nonzero expected value. Then type I error probabilities are not nominal, and the erroneous appearance of statistical significance can readily occur, particularly in large studies. Major determinants of power with use of regression calibration are collinearity between the variables measured with error and the size of correlations between crude and corresponding true variables. Where there is important collinearity, useful gains in power accrue with calibration study size up to 1,000 subjects.

Allelic deletion at chromosome bands 11q14-23 is common in neuroblastoma.

BACKGROUND: Neuroblastoma tumorigenesis may involve the differential inactivation of multiple tumor suppressor genes. Recent data have suggested that a neuroblastoma suppressor gene may be located on the long arm of chromosome 11 (11q). PROCEDURE: We therefore analyzed 295 primary neuroblastomas from a representative group of patients for loss of heterozygosity (LOH) at 25 polymorphic markers spanning 11q. RESULTS: LOH was observed in 129 primary neuroblastomas (44%), and a common region of LOH mapped to 11q14-23. No correlation was found between 11q LOH and adverse prognostic variables, but a strong inverse relationship between 11q LOH and MYCN amplification (P < 0.001) was observed. There was no difference in overall survival when patients were stratified by 11q LOH status. However, 11q LOH was associated with a decreased overall survival probability when patients whose tumors had a single copy of MYCN were analyzed separately (P = 0.008). CONCLUSION: These data support the hypothesis that a tumor suppressor gene mapping within 11q14-23 is frequently inactivated during the malignant evolution of neuroblastoma.

Loss of heterozygosity for chromosome 14q in neuroblastoma.

BACKGROUND: Neuroblastoma is a genetically heterogeneous disease, with subsets of tumors demonstrating rearrangements of several genomic regions. Preliminary studies from several groups have identified loss of heterozygosity (LOH) for the long arm of chromosome 14 (14q) in 20-25% of primary neuroblastomas. PROCEDURE: To determine precisely the frequency and extent of 14q deletions, we performed LOH analysis for a large series of primary neuroblastomas using a panel of 11 highly polymorphic markers. RESULTS: LOH was detected in 83 of 372 tumors (22%). Although the majority of tumors with allelic loss demonstrated allelic loss for all informative markers, 13 cases showed LOH for only a portion of 14q. A single consensus region of deletion, which was shared by all tumors with 14q LOH, was defined within 14q23-q32 between D14S588 and the 14q telomere. Allelic loss for 14q was strongly correlated with the presence of 11q LOH (P < 0.001 ) and inversely correlated with MYCN amplification (P= 0.04). CONCLUSIONS: LOH for 14q was evident in all clinical risk groups, indicating that this abnormality may be a universal feature of neuroblastoma tumor development. These findings suggest that a tumor suppressor gene involved in the initiation or progression of neuroblastoma is located within distal 14q.

Comprehensive analysis of chromosome 1p deletions in neuroblastoma.

BACKGROUND: Chromosome 1p deletions are common in advanced neuroblastomas, but the biological and clinical implications of this clonal rearrangement remain controversial. Previous studies of chromosome 1p loss of heterozygosity (LOH) have been limited by analyses of relatively small number of tumors derived from heterogeneously assessed and treated patient populations. Therefore, a strictly representative cohort of 288 Children's Cancer Group neuroblastoma patients treated on the most recent phase III therapeutic trials was identified. PROCEDURE: Primary tumors from these patients were analyzed for LOH at precisely mapped and highly informative 1p polymorphic loci located from 1p32 to 1p36.3 by multiplex PCR. RESULTS: Ninety-three primary tumor specimens (32%) had LOH at multiple 1p36 marker loci. All 1p deletions overlapped the previously determined smallest region of overlap (SRO). One tumor had a small terminal deletion completely within 1p36.3, allowing for further refinement of the 1p36 SRO. We found no evidence to support an additional, nonoverlapping region of LOH within 1p32-36. We confirmed the strong correlation of 1p36 LOH with MYCN amplification (P < 0.001), advanced disease stage (P < 0.001), and decreased both 3-year event-free survival and overall survival probabilities (P< 0.001). When stratified for MYCN amplification status or entered into a multivariate analysis, 1p36 LOH remained predictive for decreased event-free survival, but not overall survival probability. CONCLUSIONS: These data support the hypothesis that inactivation of a tumor suppressor gene within 1p36.3 is associated with an increased risk for disease relapse.

Bone marrow leukemic progenitor cell content in pediatric T-lineage acute lymphoblastic leukemia patients with an isolated extramedullary first relapse.

Isolated extramedullary relapse in childhood acute lymphoblastic leukemia (ALL) is associated frequently with the T-lineage immunophenotype and may be accompanied by occult bone marrow disease. We employed highly sensitive multiparameter flow cytometry and blast colony assays to quantify the leukemic progenitor cell (LPC) burden in the pretreatment bone marrows of 15 pediatric T-lineage ALL patients with an isolated extramedullary first relapse. Sites of extramedullary relapse were CNS (11 patients), testes (3 patients), and both CNS and testes (1 patient). Bone marrow LPC were detectable in 8 patients (53%) and undetectable in 7 patients (47%) at day 0 of post-relapse induction therapy, with LPC counts ranging from 0/10(6) mononuclear cells (MNC) to 518/10(6) MNC (mean +/- SEM, 50+/-34/10(6) MNC). Five of 9 patients with an early relapse (< 18 months after achieving a first complete remission [CR1]) and 3 of 6 patients with a late relapse (> or = 18 months from CR1) had detectable bone marrow LPC at day 0. Five of 8 patients with NCI-defined poor risk ALL and 3 of 7 patients with NCI-defined standard risk ALL had detectable LPC at day 0. Following post-relapse induction chemotherapy. LPC counts were detectable in bone marrows of 4 of 6 evaluated patients. Thus, approximately half of the extramedullary relapse T-lineage ALL patients studied had substantial occult involvement of the bone marrow. These findings may partly explain the previously observed poor prognosis of T-lineage patients following a CNS relapse.

Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies-a report from the Children's Cancer Group Study.

BACKGROUND: Opsoclonus-myoclonus-ataxia (OMA) is a paraneoplastic neurologic syndrome affecting 2-3% of children with neuroblastoma. Although children with OMA and neuroblastoma may have higher survival, many experience a significant amount of late neurologic impairment, which may be immunologically mediated. The aim of this study was to compare the outcome of neuroblastoma patients with and without OMA, relating to prognostic factors, treatment, and the presence or absence of anti-neuronal antibodies. PROCEDURE: Questionnaires were mailed out requesting information on the current neurologic status of patients who submitted sera at diagnosis to the Children's Cancer Group serum bank from 1980 to 1994. Information was requested on clinical and biological patient characteristics as well as clinical aspects of the patients identified as having OMA syndrome, including presentation and treatment for OMA, late sequelae of OMA, the presence or absence of antineuronal antibodies, and survival. Sera from 16 of the OMA patients and 48 case-controls with neuroblastoma were assayed for anti-neuronal antibodies. RESULTS: Of the 675 responses received, 21 patients had OMA. Ninety percent of OMA patients presented with non-metastatic disease, vs. 35% of non-OMA patients. Estimated 3-year survival for the OMA patients with nonmetastatic disease (stage I, II, III) greater than 1 year of age was 100% vs. 77% for similar non-OMA patients (P = 0.0222). At follow-up, 14/19 evaluable OMA patients displayed some form of developmental or neurologic abnormality. There was no significant correlation of late sequelae with antineuronal antibodies, age, time between OMA symptoms and diagnosis, or treatment given for tumor or OMA. There was a significant correlation of late sequelae with lower stage disease (I and II) compared to more advanced disease (III and IV). CONCLUSIONS: Patients with OMA and neuroblastoma have excellent survival but a high risk of neurologic sequelae. Favorable disease stage correlates with a higher risk for development of neurologic sequelae. The role of anti-neuronal antibodies in late sequelae of OMA needs further clarification.

Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: histopathologic features-a report from the Children's Cancer Group.

BACKGROUND: Opsoclonus-myoclonus-ataxia (OMA) is a paraneoplastic syndrome that occurs in about 2-3% of all cases of neuroblastoma. The histopathologic characteristics of neuroblastoma tumors associated with this syndrome were evaluated in a series of cases and controls. PROCEDURE: Pathology slides from a total of 54 neuroblastoma tumors were reviewed blindly. They included 13 tumors associated with opsoclonus-myoclonus and 41 age- and stage-matched controls. All tumors were classified into either the favorable (FH) or unfavorable histology (UH) group according to the International Neuroblastoma Pathology Classification (the Shimada system). Grade of lymphocytic infiltration was evaluated and presence or absence of lymphoid follicles was recorded in the individual tumor tissues. RESULTS: Twelve of 13 cases with opsoclonus-myoclonus were in the FH group. Twelve of 13 cases had diffuse (found in every section prepared from the multiple portions of the primary tumor) and extensive (occupying more than 50% of a single of multiple microscopic fields with x 100 magnification) lymphocytic infiltration with lymphoid follicles. Of the 41 control cases (27 FH and 14 UH tumors), 18 had focal areas of lymphocytic infiltration and six showed lymphoid follicles, but none had diffuse or extensive infiltration in their primary tumors. CONCLUSIONS: Diffuse and extensive lymphocytic infiltration with lymphoid follicles is a characteristic histologic feature of neuroblastic tumors with opsoclonus-myoclonus. This observation suggests an immune-mediated mechanism for this rare paraneoplastic syndrome.

Duration of hospitalization as a measure of cost on Children's Cancer Group acute lymphoblastic leukemia studies.

PURPOSE: We used duration of hospitalization as a surrogate for cost and event-free survival as a measure of effectiveness to estimate the cost-effectiveness ratios of various treatment regimens on Children's Cancer Group trials for acute lymphoblastic leukemia. PATIENTS AND METHODS: The analyses included 4,986 children (2 to 21 years of age) with newly diagnosed acute lymphoblastic leukemia enrolled onto risk-adjusted protocols between 1988 and 1995. Analyses were based on a model of 100 patients. The marginal cost-effectiveness ratio (hospital days per additional patient surviving event-free) was the difference in total duration of hospitalization divided by the difference in number of event-free survivors at 5 years for two regimens. Relapse-adjusted marginal cost of frontline therapy was the difference in total duration of hospitalization for frontline therapy plus relapse therapy divided by the difference in number of event-free survivors at 5 years on the frontline therapy for two regimens. RESULTS: One or two delayed intensification (DI) phases, augmented therapy, and dexamethasone all improved outcome. Marginal cost-effectiveness of these regimens compared with the control regimens was 133 days per patient for DI, 117 days per patient for double DI, and 41 days per patient for augmented therapy. Dexamethasone resulted in 17 fewer days per patient. Relapse-adjusted marginal costs were 68 days per patient for DI and 52 days for double DI. Augmented therapy and dexamethasone-based therapy resulted in 16 and 82 fewer hospital days, respectively. The estimated cost-effectiveness for treating any first relapse was 250 days per patient. CONCLUSION: DI, double DI, augmented therapy, and dexamethasone-based therapy are cost-effective strategies compared with current treatment of first relapse.

Building a multigenic model of breast cancer susceptibility: CYP17 and HSD17B1 are two important candidates.

We conducted a nested case-control study to evaluate whether polymorphisms in two genes involved in estrogen metabolism, CYP17 and HSD17B1, were useful in developing a breast cancer risk model that could help discriminate women who are at higher risk of breast cancer. If polymorphisms in these genes affect the level of circulating estrogens, they may directly influence breast cancer risk. The base population for this study is a multiethnic cohort study that includes African-American, Non-Latina White, Japanese, Latina, and Native Hawaiian women. For this analysis, 1508 randomly selected controls and 850 incident breast cancer cases of the first four ethnic groups who agreed to provide a blood specimen were included (76 and 80% response rates, respectively). The CYP17 A2 allele and the HSD17B1 A allele were considered "high-risk" alleles. Subjects were then classified according to number of high-risk alleles. After adjusting for age, weight, and ethnicity, we found that carrying one or more high-risk alleles increases the risk of advanced breast cancer in a dose-response fashion. The risk among women carrying four high-risk alleles was 2.21 [95% confidence interval (CI), 0.98-5.00; P for trend = 0.03] compared with those who carried none. This risk was largely limited to women who were not taking hormone replacement therapy (relative risk, 2.60; 95% CI, 0.95-7.14) and was most pronounced among those weighing 170 pounds or less (RR, 3.05; 95% CI, 1.29-7.25). These findings suggest that breast cancer risk has a strong genetic component and supports the theory that the underlying mechanism of "complex traits" can be understood using a multigenic model of candidate genes.

Singapore Chinese Health Study: development, validation, and calibration of the quantitative food frequency questionnaire.

This report describes the development and validation/calibration of a structured food frequency questionnaire for use in a large-scale cohort study of diet and health in Chinese men and women aged 45-74 years in Singapore, the development of a food composition database for analysis of the dietary data, and the results of the dietary validation/calibration study. The present calibration study comparing estimated intakes from 24-hour recalls with those from the food frequency questionnaires revealed correlations of 0.24-0.79 for energy and nutrients among the Singapore Chinese, which are comparable to the correlation coefficients reported in calibration studies of other populations. We also report on the nutritional profiles of Singapore Chinese on the basis of results of 1,880 24-hour dietary recalls conducted on 1,022 (425 men and 597 women) cohort subjects. Comparisons with age-adjusted corresponding values for US whites and blacks show distinct differences in dietary intakes between the Singapore and US populations. The Singapore cohort will be followed prospectively to identify dietary associations with cancer risk and other health outcomes.

Deletion of 11q23 is a frequent event in the evolution of MYCN single-copy high-risk neuroblastomas.

BACKGROUND: Deletions of the long arm of chromosome 11 are frequently identified in human neuroblastomas. PROCEDURE: We screened 394 primary neuroblastomas and 52 tumor-derived cell lines with a panel of 11q and 11p polymorphic markers to determine the frequency of chromosome 11 allelic deletion, and to differentiate partial deletions of chromosome 11q (unb[11q] LOH) from whole chromosome loss. RESULTS: Allelic deletion occurred most frequently at cytogenetic band 11q23 and was detected in 161 primary neuroblastomas (41%) and 18 cell lines (35%). Eighty-seven tumors (22%) had unb[11q] LOH with a heterogeneous distribution of deletion breakpoints. Unb[11q] LOH was highly correlated with age > 1 year at diagnosis (P = 0.008), stage 4 disease (P = 0.001), unfavorable Shimada histopathology (P < 0.001), and assignment to a high-risk therapeutic protocol (P < 0.001), and was inversely correlated with MYCN amplification (P = 0.018). Patients whose tumors showed unb[11q] LOH were less likely to survive (P < 0.001), but there was only a trend towards an independent prognostic influence in multivariate analyses. CONCLUSIONS: Thus, structural rearrangements resulting in unb[11q] LOH commonly occur during the malignant evolution of high-risk neuroblastomas with single-copy MYCN.