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Paediatric leukaemia has a long tail of driver mutations each of which must be 'backtracked' to samples taken at birth to identify the prenatal origin of a subtype. Presently, Bardini et al. describe the first successful backtracking of an NUTM1 rearrangement, which sheds light on the biology of this particular alteration. Continued backtracking of NUTM1 rearrangements, and all leukaemia-typical somatic alterations, is necessary to fully understand the prenatal origin of these diseases. Commentary on: Bardini et al. Prenatal origin of NUTM1 gene rearrangement in infant B-cell precursor acute lymphoblastic leukaemia. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19685.
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INTRODUCTION: Children with congenital heart defects (CHD) have shorter life expectancy than the general population. Previous studies also suggest that patients with CHD have higher risk of cancer. This study aims to describe cancer-related mortality among patients with a history of CHD interventions using the Pediatric Cardiac Care Consortium (PCCC), a large US cohort of such patients. METHODS: We performed a retrospective cohort study of individuals (<21 years) who underwent interventions for CHD in the PCCC from 1982 to 2003. Patients surviving their first intervention were linked to the National Death Index through 2020. Multivariable models assessed risk of cancer-related death, adjusting for age, sex, race, and ethnicity. Patients with/without genetic abnormalities (mostly Down syndrome [DS]) were considered separately, due to expected differential risk in cancer. RESULTS: Among the 57,601 eligible patients in this study, cancer was the underlying or contributing cause of death for 208; with 20% among those with DS. Significantly increased risk of cancer-related death was apparent among patients with DS compared to the non-genetic group (aHR: 3.63, 95% confidence interval [CI]: 2.52-5.24, p < .001). For the group with non-genetic abnormalities, the highest association with cancer-related death compared to those with mild CHD was found among those with more severe CHD (severe two-ventricle aHR: 1.82, 95% CI: 1.04-3.20, p = .036, single-ventricle aHR: 4.68, 95% CI: 2.77-7.91, p < .001). CONCLUSIONS: Patients with more severe forms of CHD are at increased risk for cancer-related death. Despite our findings, we are unable to distinguish whether having CHD raises the risk of cancer or reduces survival.
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BACKGROUND: We examined association between late stage diagnosis and individual- and community-level characteristics among pediatric Hodgkin lymphoma (HL) and rhabdomyosarcoma (RMS) patients. METHODS: We obtained Children's Oncology Group (COG) data from 1999-2021 including summary stage (local (L), regional (R), distant (D)), tumor subtype, demographics, and ZIP code at diagnosis. We linked ZIP codes to county-level redlining scores (C,D=greatest redlining), Child Opportunity Index (COI), and measures of segregation (racial dissimilarity indices (DI)). Logistic regressions calculated odds ratios for late stage diagnosis, and by race within tumor subtype. RESULTS: 5,933 HL and 2,800 RMS patients were included. Late stage diagnosis of HL was correlated with Black race (ORDistant(D) vs regional/local(R&L)=1.38 [1.13-1.68]), being uninsured (ORD vs R&L=1.38 [1.09-1.75]), and subtype (Nodular sclerosis vs Other HL: ORD vs R&L=1.64 [1.34-2.01], Untyped: ORD vs R&L=1.30 [1.04-1.63]). Late stage rhabdomyosarcoma was correlated with bilingual households (ORDistant/regional(D&R) vs local(L)=2.66 [1.03-6.91]) and tumor type (Alveolar vs Embryonal ORD vs R&L=6.16 [5.00-7.58]. Community-level factors associated with late stage HL were greater Black (OR80-100%=1.83; 95% CI=1.11-3.02) and Hispanic (OR60-79%=1.30; 95%CI=1.05-1.60) DI. Late stage diagnosis for RMS was associated with more redlined census tracts within counties (OR=1.54; 95% CI =1.02-2.35) and low/very low COI (OR=1.21; 95% CI=1.02-1.45). CONCLUSION: Novel markers of community deprivation, such as redlining and racial segregation, likely affect cancer outcomes for children with HL and RMS in this first disparities study using COG registries. IMPACT: The interplay of multilevel risk factors provides important consideration for efforts to improve early detection of pediatric cancer diagnosis.
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BACKGROUND: Prenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results. METHODS: We evaluated whether â¼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software. RESULTS: None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups. CONCLUSIONS: This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups. IMPACT: Genetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.
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Folic Acid , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Folic Acid/metabolism , Folic Acid/administration & dosage , Child , Case-Control Studies , Female , Male , Genome-Wide Association Study , Risk Factors , Genetic Predisposition to Disease , Child, PreschoolABSTRACT
BACKGROUND: Canine and human osteosarcoma are similar in clinical presentation and tumor genomics. Giant breed dogs experience elevated osteosarcoma incidence, and taller stature remains a consistent risk factor for human osteosarcoma. Whether evolutionarily conserved genes contribute to both human and canine osteosarcoma predisposition merits evaluation. METHODS: A multi-center sample of childhood osteosarcoma patients and controls underwent genome-wide genotyping and imputation. Ancestry-adjusted SNP associations were calculated within each dataset using logistic regression, then meta-analyzed across the three datasets, totaling 1091 patients and 3026 controls. Ten regions previously associated with canine osteosarcoma risk were mapped to the human genome, spanning â¼6â¯Mb. We prioritized association testing of 5985 human SNPs mapping to candidate osteosarcoma risk regions detected in Irish wolfhounds, the largest dog breed studied. Secondary analyses explored 6289 additional human SNPs mapping to candidate osteosarcoma risk regions identified in Rottweilers and greyhounds. RESULTS: Fourteen SNPs were associated with human osteosarcoma risk after adjustment for multiple comparisons, all within a 42â¯kb region of human Chromosome 7p12.1. The lead variant was rs17454681 (OR=1.25, 95â¯%CI: 1.12-1.39; P=4.1×10-5), and independent risk variants were not observed in conditional analyses. While the associated region spanned 2.1â¯Mb and contained eight genes in Irish wolfhounds, associations were localized to a 50-fold smaller region of the human genome and strongly implicate GRB10 (growth factor receptor-bound protein 10) in canine and human osteosarcoma predisposition. PheWAS analysis in UK Biobank data identified noteworthy associations of the rs17454681 risk allele with varied measures of height and pubertal timing. CONCLUSIONS: Our comparative oncology analysis identified a novel human osteosarcoma risk allele near GRB10, a growth inhibitor that suppresses activated receptor tyrosine kinases including IGF1R, PDGFRB, and EGFR. Epidemiologists may benefit from leveraging cross-species comparisons to identify haplotypes in highly susceptible but genetically homogenous populations of domesticated animals, then fine-mapping these associations in diverse human populations.
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We evaluated whether socioeconomic status (SES), race/ethnicity, and their interaction were associated with the presentation of advanced stage at diagnosis in embryonal tumors. Children 0 to 19 years of age diagnosed with embryonal tumors between 2006 and 2018 were identified from the US Surveillance, Epidemiology, and End Results program database specialized with Census Tract SES/Rurality. SES quintile was derived from a composite index for census tracts. We performed logistic regression to estimate odds ratios (ORs) and 95% confidence intervals by SES and race/ethnicity, adjusting for sex, age, and diagnosis year. Overall, no significant associations were found between either SES or race/ethnicity and the risk of presenting with advanced stage at diagnosis, although patterns of risk reductions were observed in atypical teratoid/rhabdoid tumors and embryonal rhabdomyosarcoma with increasing SES. In the stratified analysis, decreased odds of presenting with advanced-stage embryonal rhabdomyosarcoma were observed for Hispanics with higher SES (OR: 0.24, 95% Confidence Interval: 0.08-0.75) compared with Hispanics with lower SES. Future studies incorporating individual-level SES, cancer-specific staging information, and potential demographic, clinical, epidemiological, and genetic risk factors are warranted to confirm our findings.
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Neoplasms, Germ Cell and Embryonal , Social Class , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Young Adult , Ethnicity/statistics & numerical data , Hispanic or Latino , Neoplasm Staging , Neoplasms, Germ Cell and Embryonal/epidemiology , Neoplasms, Germ Cell and Embryonal/diagnosis , Neoplasms, Germ Cell and Embryonal/pathology , Neoplasms, Germ Cell and Embryonal/ethnology , Racial Groups , Risk Factors , SEER Program , United States/epidemiologyABSTRACT
BACKGROUND: Osteosarcoma displays a bimodal peak in incidence in adolescence and later adulthood. Males are more frequently diagnosed with osteosarcoma in both periods. Males have worse survival than females, which is generally poor at 30-70% 5-years post diagnosis, depending on age, but treatment received is often unaccounted for in survival analyses. METHODS: Therefore, we estimated sex differences in survival for children and adults stratifying by treatment received and other disease characteristics using the National Cancer Database (2004-2016, n=9017). We estimated sex differences in long-term survival using Kaplan Meier survival curves and Log-Rank p-values. We also estimated hazard ratios (HR) and 95% confidence intervals (CIs) as the measure of association between sex and death using Cox regression. RESULTS: In all age groups, cases were predominantly male (52-58%). In Kaplan-Meier analyses, males had worse overall survival than females for 0-19, 20-39, and ≥60-year-olds (Log-Rank p<0.05). Females had higher 5- and 10-year survival percentages in all age groups. In adjusted Cox models, males had a higher risk of death among 0-19-year-olds (HRoverall: 1.24, 95% CI: 1.06-1.44; HRnon-metastatic disease: 1.35, 95% CI: 1.12, 1.63, HRlower limb tumors: 1.31, 95% CI: 1.09-1.59). Among 20-39-year-olds, males had an increased risk of death when receiving surgery only (HR: 4.67, 95% CI: 1.44, 15.09). Among those ≥60-year-olds, males had a suggestive increased risk of death overall (HR: 1.17, 95% CI: 0.99-1.39) and a higher risk of death based on some tumor locations, (HRupper limb: 2.52, 95% CI: 1.24, 5.11; HRmidline: 1.36, 95% CI: 1.02, 1.82). CONCLUSIONS: Our findings suggest that the worse survival among young males compared to females with osteosarcoma persisted after accounting for many major disease characteristics, including treatment received. Collectively, our work points toward other unexplored mechanisms beyond treatment, potentially biologic or otherwise, which may be driving the observed sex differences in long-term survival.
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Acute leukemias, mainly consisting of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), comprise a major diagnostic group among hematologic cancers. Due to the early age at onset of ALL, particularly, it has long been suspected that acute leukemias of childhood may have an in utero origin. This supposition has motivated many investigations seeking direct proof of prenatal leukemogenesis, in particular, twin and "backtracking studies". The suspected in utero origin has also focused on gestation as a critical window of risk, resulting in a rich literature on prenatal risk factors for pediatric acute leukemias. In this narrative review, we recount the circumstantial and direct evidence for an in utero origin of childhood acute leukemias.
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Knowledge of Ewing sarcoma (EWS) risk factors is exceedingly limited; however, multiple small, independent studies have suggested a possible connection between hernia and EWS. By leveraging hernia summary statistics from the UK Biobank and a recently published genome-wide association study of EWS (733 EWS cases and 1,346 controls), we conducted a genetic investigation of the relationship of 5 hernia types (diaphragmatic, inguinal, umbilical, femoral, and ventral) and EWS. We discovered a positive causal relationship between inguinal hernia and EWS (OR 1.27, 95% confidence interval [CI] 1.01-1.59, and p = 0.041) through Mendelian randomization analysis. Further analyses suggested shared pathways through three genes: HMGA2, LOX, and FBXW7. Diaphragmatic hernia showed a stronger causal relationship with EWS among all of the hernia types (OR 2.26, 95% CI 1.30-3.95, p = 0.004), but no statistically significant local correlation pattern was observed. No evidence of a causal or genetic relationship was observed between EWS and the other three hernia types, including umbilical hernia, despite a previous report indicating an OR as high as 3.3. The finding of our genetic analysis provided additional support to the hypothesis that EWS and hernias may share a common origin.
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Hernia, Inguinal , Sarcoma, Ewing , Humans , Sarcoma, Ewing/epidemiology , Genome-Wide Association Study , Hernia, Inguinal/epidemiologyABSTRACT
BACKGROUND: Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk. PROCEDURE: Information on cases (n = 517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n = 784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including whether their child had been born with a non-chromosomal birth defect. To test the association between birth defects and HL risk, conditional logistic regression was applied to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: Children born with any non-chromosomal birth defect were not more likely to be diagnosed with HL at 0-14 years of age (aOR: 0.91; 95% CI: 0.69-1.21). No associations were detected between major or minor birth defects and HL (aOR: 1.34; 95% CI: 0.67-2.67 and aOR: 0.88; 95% CI: 0.57-1.34, respectively). Similarly, no association was observed for children born with any birth defect and EBV-positive HL (aOR: 0.57; 95% CI: 0.25-1.26). CONCLUSIONS: Previous assessments of HL in children with non-chromosomal birth defects have been limited. Using data from the largest case-control study of HL in those <15 years of age, we did not observe strong associations between being born with a birth defect and HL risk.
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Hodgkin Disease , Child , Humans , Case-Control Studies , Ethnicity , Extremities , Hodgkin Disease/epidemiology , Hodgkin Disease/etiology , Risk Factors , Male , FemaleABSTRACT
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.
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Leukemia, Myeloid, Acute , Child , Humans , Infant , Risk Factors , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/genetics , Birth Weight , Logistic Models , Case-Control Studies , Surveys and QuestionnairesABSTRACT
INTRODUCTION: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma. METHODS: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene. RESULTS: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma. CONCLUSION: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.
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The Children's Oncology Group (COG) Epidemiology Committee has a primary focus on better understanding the etiologies of childhood cancers. Over the past 10 years, the committee has leveraged the Childhood Cancer Research Network, and now more recently Project:EveryChild (PEC), to conduct epidemiologic assessments of various childhood cancers, including osteosarcoma, neuroblastoma, germ cell tumors, Ewing sarcoma, rhabdomyosarcoma, and Langerhans cell histiocytosis. More recent studies have utilized questionnaire data collected as part of PEC to focus on specific characteristics and/or features, including the presence of congenital disorders and the availability of stored cord blood. Members of the COG Epidemiology Committee have also been involved in other large-scale National Institutes of Health efforts, including the Childhood Cancer Data Initiative and the Gabriella Miller Kids First Pediatric Research Program, which are improving our understanding of the factors associated with childhood cancer risk. Future plans will focus on addressing questions surrounding health disparities, utilizing novel biospecimens in COG epidemiology studies, exploring the role of environmental factors on the etiologies and outcomes of childhood cancer, collaborating with other COG committees to expand the role of epidemiology in childhood cancer research, and building new epidemiologic studies from the Molecular Characterization Initiative-all with the ultimate goal of developing novel prevention and intervention strategies for childhood cancer.
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Bone Neoplasms , Neoplasms , Osteosarcoma , Rhabdomyosarcoma , Sarcoma, Ewing , Child , Humans , Neoplasms/epidemiology , Medical OncologyABSTRACT
Background: Familial aggregation in childhood leukemia is associated with epidemiological and genomic factors. Albeit epidemiological studies on the familial history of hematological malignancies (FHHMs) are scarce, genome-wide studies have identified inherited gene variants associated with leukemia risk. We revisited a dataset of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients to explore the familial aggregation of malignancies among their relatives. Methods: A series of 5,878 childhood leukemia (≤21 years of age) from the EMiLI study (2000-2019) were assessed. Lack of well-documented familial history of cancer (FHC) and 670 cases associated with genetic phenotypic syndromes were excluded. Leukemia subtypes were established according to World Health Organization recommendations. Logistic regression-derived odds ratios (ORs) and 95% confidence intervals (CIs) were performed and adjusted by age as a continuous variable, where ALL was the reference group for AML and conversely. The pedigree of 18 families with excess hematological malignancy was constructed. Results: FHC was identified in 472 of 3,618 eligible cases (13%). Ninety-six of the 472 patients (20.3%) had an occurrence of FHHMs among relatives. Overall, FHC was significantly associated with AML (OR, 1.36; 95% CI, 1.01-1.82; p = 0.040). Regarding the first-degree relatives, the OR, 2.92 95% CI,1.57-5.42 and the adjOR, 1.16 (1.03-1.30; p0.001) were found for FHC and FHHM, respectively. Conclusion: Our findings confirmed that AML subtypes presented a significant association with hematological malignancies in first-degree relatives. Genomic studies are needed to identify germline mutations that significantly increase the risk of developing myeloid malignancies in Brazil.
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PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Breast Neoplasms , Cancer Survivors , Neoplasms, Second Primary , Adult , Child , Humans , Female , Cohort Studies , Podophyllotoxin , Neoplasms, Second Primary/chemically induced , Neoplasms, Second Primary/epidemiology , Breast Neoplasms/epidemiology , Risk FactorsABSTRACT
A hallmark of osteosarcoma in both human and canine tumors is somatic fragmentation and rearrangement of chromosome structure which leads to recurrent increases and decreases in DNA copy number. The PTEN gene has been implicated as an important tumor suppressor in osteosarcoma via forward genetic screens. Here, we analyzed copy number changes, promoter methylation and transcriptomes to better understand the role of PTEN in canine and human osteosarcoma. Reduction in PTEN copy number was observed in 23 of 95 (25%) of the canine tumors examined leading to corresponding decreases in PTEN transcript levels from RNA-Seq samples. Unexpectedly, canine tumors with an intact PTEN locus had higher levels of PTEN transcripts than human tumors. This variation in transcript abundance was used to evaluate the role of PTEN in osteosarcoma biology. Decreased PTEN copy number and transcript level was observed in - and likely an important driver of - increases in cell cycle transcripts in four independent canine transcriptional datasets. In human osteosarcoma, homozygous copy number loss was not observed, instead increased methylation of the PTEN promoter was associated with increased cell cycle transcripts. Somatic modification of PTEN, either by homozygous deletion in dogs or by promoter methylation in humans, is clinically relevant to osteosarcoma, because the cell cycle related transcripts are associated with patient outcomes. The PTEN gene is part of a syntenic rearrangement unique to the canine genome, making it susceptible to somatic loss of both copies of distal chromosome 26 which also includes the FAS death receptor. SIGNIFICANCE STATEMENT: PTEN function is abrogated by different mechanisms in canine and human osteosarcoma tumors leading to uncontrolled cell cycling. Somatic loss of this canine specific syntenic region may help explain why the canine genome appears to be uniquely susceptible to osteosarcoma. Syntenic arrangement, in the context of copy number change, may lead to synergistic interactions that in turn modify species specific cancer risk. Comparative models of tumorigenesis may utilize different driver mechanisms.
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Bone Neoplasms , Osteosarcoma , Humans , Dogs , Animals , Homozygote , Sequence Deletion , Osteosarcoma/genetics , Osteosarcoma/pathology , Cell Division , Bone Neoplasms/genetics , Bone Neoplasms/pathology , PTEN Phosphohydrolase/geneticsABSTRACT
Previous studies have associated maternal diet during pregnancy with the development of sporadic unilateral retinoblastoma (RB), but few studies have focused on the role of individual nutrients. The aim of this study is to investigate the association between maternal nutrient intake during pregnancy and the development of sporadic unilateral RB in the offspring. A modified food frequency questionnaire, with additional questions on supplement use, was completed via a phone interview. Cases were recruited from hospitals and controls were comprised of friends and relatives of the patient without a history of cancer. Overall, 168 sporadic unilateral RB cases and 145 controls were included in case-control study. We performed logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI), adjusting for child's age, child's sex, parental race/ethnicity, maternal education, total calorie intake during pregnancy, maternal age at birth, maternal smoking during pregnancy, pre-pregnancy body mass index, maternal weight gain during pregnancy, paternal age at birth, and maternal multivitamin use in the year before pregnancy. In the adjusted model, the interquartile (IQR) increase in vitamin A intake, which was measured in retinol activity equivalent (RAE; OR: 0.64, 95 % CI: 0.46-0.90), and vitamin D intake (OR: 0.62, 95 % CI: 0.42-0.91) significantly reduced the risk of sporadic unilateral RB. These findings suggest that a higher intake of vitamins A and D can be a protective factor for sporadic unilateral RB. Further analyses in consideration of multi-exposures such as parental occupational exposures are warranted to discover the complex etiology of sporadic unilateral RB. In addition, the role of nutritional epigenetics for how maternal nutrient intake influences the risk of sporadic unilateral RB in the offspring still needs to be explored.
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Retinal Neoplasms , Retinoblastoma , Child , Female , Humans , Pregnancy , Eating , Energy Intake , Retinal Neoplasms/epidemiology , Retinal Neoplasms/etiology , Retinoblastoma/epidemiology , Retinoblastoma/etiology , Risk FactorsABSTRACT
Background: Medulloblastoma, the most common malignant pediatric brain tumor, displays marked sex differences in prevalence of the four main molecular subgroups: SHH, WNT, Group 3 and Group 4. Males are more frequently diagnosed with SHH, Group 3 and 4 tumors, which have worse prognoses than WNT tumors. Little is known about sex differences in methylation profiles within subgroups. Methods: Using publicly available methylation data (Illumina HumanMethylation450K array), we compared beta values for males versus females. Differentially methylated positions (DMP) by sex within medulloblastoma subgroups were identified on the autosomes. DMPs were mapped to genes and Reactome pathway analysis was run by subgroup. Kaplan-Meier survival curves (Log-Rank p-values) were assessed for each sex within subgroup. MethylCIBERSORT was used to investigate the tumor microenvironment using deconvolution to estimate the abundances of immune cell types using DNA methylation data. Results: There were statistically significant differences in sex by medulloblastoma subgroups (chi-squared p-value=0.00004): Group 3 (n=144; 65% male), Group 4 (n=326; 67% male), SHH (n=223; 57% male) and WNT (n=70; 41% male). Females had worse survival than males for SHH (p-value=0.02). DMPs by sex were identified within subgroups: SHH (n=131), Group 4 (n=29), Group 3 (n=19), and WNT (n=16) and validated in an independent dataset. Unsupervised hierarchical clustering showed that sex-DMPs in SHH did not correlate with other tumor attributes. Ten genes with sex DMPs (RFTN1, C1orf103, FKBP1B, COL25A1, NPDC1, B3GNT1, FOXN3, RNASEH2C, TLE1, and PHF17) were shared across subgroups. Significant pathways (p<0.05) associated with DMPs were identified for SHH (n=22) and Group 4 (n=4) and included signaling pathways for RET proto-oncogene, advanced glycosylation end product receptor, regulation of KIT, neurotrophic receptors, NOTCH, and TGF-ß. In SHH, we identified DMPs in four genes (CDK6, COL25A1, MMP16, PRIM2) that encode proteins which are the target of therapies in clinical trials for other cancers. There were few sex differences in immune cell composition within tumor subgroups. Conclusion: There are sexually dimorphic methylation profiles for SHH medulloblastoma where survival differences were observed. Sex-specific therapies in medulloblastoma may impact outcomes.