ORCID Profile
0000-0002-5525-0598
Current Organisation
University of Minnesota Medical School Twin Cities
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Publications
Genome-Wide Association Study Identifies ROBO2 as a Novel Susceptibility Gene for Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-03-2023
DOI: 10.1200/JCO.22.01527
Abstract: Interin idual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests a modifying role of genetic susceptibility. Few previous studies have examined gene-anthracycline interactions. We addressed this gap using the Childhood Cancer Survivor Study (discovery) and the Children's Oncology Group (COG) study COG-ALTE03N1 (replication). A genome-wide association study (Illumina HumanOmni5Exome Array) in 1,866 anthracycline-exposed Childhood Cancer Survivor Study participants (126 with heart failure) was used to identify single-nucleotide polymorphisms (SNPs) with either main or gene-environment interaction effect on anthracycline-related cardiomyopathy that surpassed a prespecified genome-wide threshold for statistical significance. We attempted replication in a matched case-control set of anthracycline-exposed childhood cancer survivors with (n = 105) and without (n = 160) cardiomyopathy from COG-ALTE03N1. Two SNPs (rs17736312 [ ROBO2]) and rs113230990 (near a CCCTC-binding factor insulator [ 750 base pair]) passed the significance cutoff for gene-anthracycline dose interaction in discovery. SNP rs17736312 was successfully replicated. Compared with the GG/AG genotypes on rs17736312 and anthracyclines ≤ 250 mg/m 2 , the AA genotype and anthracyclines 250 mg/m 2 conferred a 2.2-fold (95% CI, 1.2 to 4.0) higher risk of heart failure in discovery and an 8.2-fold (95% CI, 2.0 to 34.4) higher risk in replication. ROBO2 encodes transmembrane Robo receptors that bind Slit ligands (SLIT). Slit-Robo signaling pathway promotes cardiac fibrosis by interfering with the transforming growth factor-β1/small mothers against decapentaplegic (Smad) pathway, resulting in disordered remodeling of the extracellular matrix and potentiating heart failure. We found significant gene-level associations with heart failure: main effect ( TGF-β1, P = .007) gene*anthracycline interaction ( ROBO2*anthracycline, P = .0003) and gene*gene*anthracycline interaction ( SLIT2* TGF-β1*anthracycline, P = .009). These findings suggest that high-dose anthracyclines combined with genetic variants involved in the profibrotic Slit-Robo signaling pathway promote cardiac fibrosis via the transforming growth factor-β1/Smad pathway, providing credence to the biologic plausibility of the association between SNP rs17736312 ( ROBO2) and anthracycline-related cardiomyopathy.
Methods for tracing, contacting, and recruiting a cohort of survivors of childhood cancer
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1997
DOI: 10.1097/00043426-199705000-00007
Abstract: Due to the use of combined modalities of multiagent chemotherapy, radiation therapy, and surgery, many children with a diagnosis of cancer are now surviving into adulthood. This pilot study sought to determine the feasibility of establishing a cohort of childhood cancer survivors and then to develop methods to trace and contact eligible participants. A retrospective cohort design was used. Four hundred and forty subjects who were treated for cancer at the University of Minnesota Hospital before the age of 21, between 1970 and 1986, had survived 5 years, and were alive at last contact were eligible. Tracing efforts were undertaken if the address was more than 2 years old or if a letter was returned by the post office. Contact procedures in this study were designed to determine whether participation rates differed according to the method of contact. In this cohort of 440 in iduals, 11 had died and were not traced. Of the remaining 429 eligible in iduals, 408 (95.1%) were successfully contacted. Successful tracing efforts differed by both current age and age at diagnosis. Once contacted, 370 (90.6%) agreed to participate in this study and returned a baseline health questionnaire. Each method of participation, and the combination of methods, showed similar percentages of participation. Results from this pilot study show that appropriate methods exist to establish a cohort of adults who have not been contacted since childhood.
XRCC1 and glutathione‐S‐transferase gene polymorphisms and susceptibility to radiotherapy‐related malignancies in survivors of Hodgkin disease
Publisher: Wiley
Date: 13-08-2004
DOI: 10.1002/CNCR.20520
Abstract: One of the most serious late effects of treatment for childhood cancer is the occurrence of subsequent malignancy. Survivors of Hodgkin disease (HD), in particular, have been shown to be at high risk of subsequent malignancy, the occurrence of which has been associated strongly with exposure to radiotherapy. In the current study, the authors investigated the association between polymorphisms in 3 genes--glutathione-S-transferase M1 (GSTM1), glutathione-S-transferase T1 (GSTT1), and XRCC1, with roles in protection from a variety of DNA-damaging agents-and the risk of subsequent malignancy in 650 survivors of HD enrolled in the Childhood Cancer Survivor Study who had received radiotherapy. In iduals lacking GSTM1 but not GSTT1 were at increased risk of any subsequent malignancy (odds ratio [OR], 1.5 95% confidence interval [CI], 1.0-2.3), and for subsequent cancer within the radiation field (OR, 1.4 95% CI, 0.9-2.1). A nonsignificant increased risk of thyroid carcinoma was observed in in iduals lacking either GSTM1 (OR, 2.9 95% CI, 0.8-10.9) or GSTT1 (OR, 3.7 95% CI, 0.6-23.5). In iduals having the genotype of the arginine/glutamine polymorphism at codon 399 in the XRCC1 gene (R399) showed a nonsignificant increased risk of breast carcinoma compared with those without (OR, 1.4 95% CI, 0.7-2.7), and a nonsignificant decreased risk against a subsequent thyroid carcinoma (OR, 0.6 95% CI, 0.2-1.6). No differences in genotype frequencies were observed between survivors with basal cell carcinoma when compared with survivors without a subsequent cancer. These data illustrated the potential value of incorporating the collection of genomic DNA in longitudinal cohort studies of populations with well defined, potentially carcinogenic exposures. Evaluation of additional genetic polymorphisms in this cohort may help define genes that influence in idual sensitivity to radiotherapy.
Study design and cohort characteristics of the childhood cancer survivor study: A multi-institutional collaborative project
Publisher: Wiley
Date: 12-03-2002
DOI: 10.1002/MPO.1316
Abstract: Increased attention has been directed toward the long-term health outcomes of survivors of childhood cancer. To facilitate such research, a multi-institutional consortium established the Childhood Cancer Survivor Study (CCSS), a large, erse, and well-characterized cohort of 5-year survivors of childhood and adolescent cancer. Eligibility for the CCSS cohort included a selected group of cancer diagnoses prior to age 21 years between 1970-1986 and survival for at least 5 years. A total of 20,276 eligible subjects were identified from the 25 contributing institutions, of whom 15% are considered lost to follow-up. Currently, 14,054 subjects (69.3% of the eligible cohort) have participated by completing a 24-page baseline questionnaire. The distribution of first diagnoses includes leukemia (33%), lymphoma (21%), neuroblastoma (7%), CNS tumor (13%), bone tumor (8%), kidney tumor (9%), and soft-tissue sarcoma (9%). Abstraction of medical records for chemotherapy, radiation therapy, and surgical procedures has been successfully completed for 98% of study participants. Overall, 78% received radiotherapy and 73% chemotherapy. The CCSS represents the largest and most extensively characterized cohort of childhood and adolescent cancer survivors in North America. It serves as a resource for addressing important issues such as risk of second malignancies, endocrine and reproductive outcome, cardiopulmonary complications, and psychosocial implications, among this unique and ever-growing population.
Twenty years of follow‐up among survivors of childhood and young adult acute myeloid leukemia
Publisher: Wiley
Date: 21-04-2008
DOI: 10.1002/CNCR.23405
Abstract: Limited data exist on the comprehensive assessment of late medical and social effects experienced by survivors of childhood and young adult acute myeloid leukemia (AML). This analysis included 272 5-year AML survivors who participated in the Childhood Cancer Survivor Study (CCSS). All patients were diagnosed at age < or =21 years between the years 1970 and 1986, and none underwent stem cell transplantation. Rates of survival, relapse, and late outcomes were analyzed. The average follow-up was 20.5 years (range, 5-33 years). The overall survival rate was 97% at 10 years (95% confidence interval [95%CI], 94%-98%) and 94% at 20 years (95% CI, 90%-96%). Six survivors reported 8 recurrences. The cumulative incidence of recurrent AML was 6.6% at 10 years (95% CI, 3.7%-9.6%) and 8.6% at 20 years (95% CI, 5.1%-12.1%). Ten subsequent malignant neoplasms (SMN) were reported, including 4 with a history of radiation therapy, for a 20-year cumulative incidence of 1.7% (95% CI, 0.02%-3.4%). Six cardiac events were reported, for a 20-year cumulative incidence 4.7% (95% CI, 2.1%-7.3%). Half of the survivors reported a chronic medical condition and, compared with siblings, were at increased risk for severe or life-threatening chronic medical conditions (16% vs 5.8% P or =25 years, the age-adjusted marriage rates were similar among survivors and the general United States population (57% for both) and lower compared with siblings (67% P < .01). Survivors' college graduation rates were lower compared with siblings but higher than the general population (40% vs 52% vs 34%, respectively P or =5-years after diagnosis was favorable. Late-occurring medical events remained a concern with socioeconomic achievement lower than expected within the in idual family unit, although it was not different from the general United States population.
Polygenic Risk and Chemotherapy-Related Subsequent Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study Report
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-09-2023
DOI: 10.1200/JCO.23.00428
Abstract: Chemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases. SMNs among long-term childhood cancer survivors of European (EUR N = 9,895) and African (AFR N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models. A total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22 P = .048 n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% v 6% HR, 2.46 P .01), anthracyclines (20% v 8% HR, 2.86 P .001), epipodophyllotoxins (23% v 1% HR, 12.20 P .001), or platinums (46% v 7% HR, 8.58 P .01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414 P .01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 v 0.63) and platinum-exposed (AUC,0.68 v 0.58) survivors. A pleiotropic cancer PRS has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer-susceptibility mutations.
Allergic disorders and the risk of childhood acute lymphoblastic leukemia (United States)
Publisher: Springer Science and Business Media LLC
Date: 2000
Abstract: To test the hypothesis that childhood acute lymphoblastic leukemia (ALL) is associated with allergic disorders. We compared the histories of selected allergic disorders (asthma, hay fever, food or drug allergies, eczema, and hives) of 1842 cases of ALL with those of 1986 in idually matched controls. The histories of the allergic disorders among siblings of cases and controls were also compared. The combined history of any one or more of the five allergic disorders evaluated was associated with a significant reduced risk of ALL (adjusted OR = 0.7, 95% CI 0.6-0.8), as were histories of four specific allergic disorders (asthma, hay fever, food or drug allergies, and eczema). The combined history of any one or more of the five allergic disorders among any of the siblings of the study subjects also revealed a significantly inverse association (adjusted OR = 0.9, 95% CI 0.8-1.0). The results from this study, in agreement with most previous studies on adult cancer, suggest that allergic disorders may be associated with a reduced risk of childhood ALL.
Related Organisations
University Of Minnesota Medical School Twin Cities
Location: United States of America
University Of Minnesota School Of Public Health
Location: United States of America
Related Funding Activities
No related grants have been discovered for Joseph Neglia.