Health-Related quality of life and DNA Methylation-Based aging biomarkers among survivors of childhood cancer.

BACKGROUND: Childhood cancer survivors are at high risk for morbidity and mortality and poor patient-reported outcomes, typically health-related-quality-of-life (HRQOL). However, associations between DNA methylation (DNAm)-based aging biomarkers and HRQOL have not been evaluated. METHODS: DNAm was generated with Infinium EPIC BeadChip on blood-derived DNA (median[range] for age at blood draw = 34.5[18.5-66.6] years) and HRQOL was assessed with age at survey (32.3[18.4-64.5] years) from 2,206 survivors in the St Jude Lifetime Cohort. DNAm-based aging biomarkers, including epigenetic age using multiple clocks (eg, GrimAge) and others (eg, DNAmB2M beta-2-microglobulin; DNAmADM: adrenomedullin), were derived from the DNAm Age Calculator (https://dnamage.genetics.ucla.edu). HRQOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey to capture eight domains, and physical and mental component summaries (PCS and MCS). General linear models evaluated associations between HRQOL and epigenetic age acceleration (EAA, eg, EAA_GrimAge) or other age-adjusted DNAm-based biomarkers (eg, ageadj_DNAmB2M) after adjusting for age at blood draw, sex, cancer treatments, and DNAm-based surrogate for smoking pack-years. All P values were 2-sided. RESULTS: Worse HRQOL was associated with greater EAA_GrimAge (PCS ß[95%CI]=-0.18[-0.251,-0.11] years, P = 1.85 × 10-5; and four individual HRQOL domains), followed by ageadj_DNAmB2M (PCS: -0.08[-0.124,-0.037], P = .003; and three individual HRQOL domains), and ageadj_DNAmADM (PCS: -0.082[-0.125,-0.039], P = .002; and two HRQOL domains). EAA_Hannum (Hannum clock) was not associated with any HRQOL. CONCLUSIONS: Overall and domain-specific measures of HRQOL are associated with DNAm measures of biological aging. Future longitudinal studies should test biological aging as a potential mechanism underlying the association between poor HRQOL and increased risk of clinically assessed adverse health outcomes.

On the Overlap of Commercial Sexual Exploitation and Intimate Partner Violence: An Exploratory Examination of Trauma-Related Shame.

Every year, millions of people experience intimate partner violence (IPV) and commercial sexual exploitation (CSE), with researchers increasingly discussing the overlap between these two forms of interpersonal violence. However, researchers have not yet used quantitative methods to examine the link between IPV and CSE or to explore potential mechanisms underlying the overlap, including child maltreatment risk factors and psychological mechanisms. One potential mechanism is trauma-related shame, a symptom of post-traumatic stress disorder commonly experienced by both victims of CSE and IPV. The current study explores trauma-related shame, childhood maltreatment, and IPV and their associations with CSE using a sample of 174 primarily Black women. Binomial logistic regression is used to analyze the impact of IPV, child abuse and neglect, and trauma-related shame on CSE. Results indicate that IPV and trauma-related shame are both significant predictors of CSE. Implications for future research and the incorporation of shame in trauma-related treatment are discussed.

Revisiting the Calculation for a Novel Measure of Average Lifespan Shortened: Real-World Examples From Cervical and Ovarian Cancers in Alberta, Canada, 2000 - 2020.

In this technical note, we primarily demonstrate the computation of confidence limits for a novel measure of average lifespan shortened (ALSS). We identified women who had died from cervical and ovarian cancer between 2000 and 2020 from the Alberta cancer registry. Years of life lost (YLL) was calculated using the national life tables of Canada. We estimated the ALSS as a ratio of YLL in relation to the expected lifespan. We computed the confidence limits of the measure using various approaches, including the normal distribution, gamma distribution, and bootstrap method. The new ALSS measure shows a modest gain in lifespan of women, particularly women with ovarian cancer, over the study period.

A versatile pumpless multi-channel fluidics system for maintenance and real-time functional assessment of tissue and cells.

To address the needs of the life sciences community and the pharmaceutical industry in pre-clinical drug development to both maintain and continuously assess tissue metabolism and function with simple and rapid systems, we improved on the initial BaroFuse to develop it into a fully functional, pumpless, scalable multi-channel fluidics instrument that continuously measures changes in oxygen consumption and other endpoints in response to test compounds. We and several other laboratories assessed it with a wide range of tissue types including retina, pancreatic islets, liver, and hypothalamus with both aqueous and gaseous test compounds. The setup time was less than an hour for all collaborating groups, and there was close agreement between data obtained from the different laboratories. This easy-to-use system reliably generates real-time metabolic and functional data from tissue and cells in response to test compounds that will address a critical need in basic and applied research.

Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature.

Sequence-based genetic testing currently identifies causative genetic variants in ∼50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. Rare epigenetic variations ("epivariants") can drive disease by modulating gene expression at single loci, whereas genome-wide DNA methylation changes can result in distinct "episignature" biomarkers for monogenic disorders in a growing number of rare diseases. Here, we interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 516 individuals with genetically unsolved DEEs who had previously undergone extensive genetic testing. We identified rare differentially methylated regions (DMRs) and explanatory episignatures to discover causative and candidate genetic etiologies in 10 individuals. We then used long-read sequencing to identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and two copy number variants. We also identify pathogenic sequence variants associated with episignatures; some had been missed by previous exome sequencing. Although most DEE genes lack known episignatures, the increase in diagnostic yield for DNA methylation analysis in DEEs is comparable to the added yield of genome sequencing. Finally, we refine an episignature for CHD2 using an 850K methylation array which was further refined at higher CpG resolution using bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate genetic causes as ∼2% (10/516) for unsolved DEE cases.

Determining how MAFA and MAFB transcription factors activity is influenced by structural differences predicted by AlphaFold2.

MAFA and MAFB are related basic-leucine-zipper domain containing transcription factors which have important regulatory roles in a variety of cellular contexts, including pancreatic islet hormone producing α and ß cells. These proteins have similar as well as distinct functional properties, and here we first used AlphaFold2, an artificial intelligence-based structural prediction program, to obtain insight into the three-dimensional organization of their non-DNA binding/dimerization sequences. This analysis was conducted on the wildtype (WT) proteins as well the pathogenic MAFA Ser64Phe (MAFA S64F ) and MAFB Ser70Ala (MAFB S70A ) mutants, with structural differences revealed between MAFA WT and MAFB WT in addition to MAFA S64F and MAFA WT , but not MAFB S70A and MAFB WT . Functional analysis disclosed that the inability to properly phosphorylate at S70 in MAFB S70A , like S65 in MAFA S64F , greatly increased protein stability and enabled MAFB S70A to accelerate cellular senescence in cultured cells. Significant differences were also observed in the ability of MAFA, MAFA S64F , MAFB, and MAFB S70A to cooperatively stimulate Insulin enhancer-driven activity in the presence of other islet-enriched transcription factors. Experiments performed on protein chimeras disclosed that these properties were greatly influenced by structural differences found between the WT and mutant proteins. In general, these results revealed that AlphaFold2 predicts features essential to protein activity.

Toxicity of spray adjuvants and tank mix combinations used in almond orchards to adult honey bees (Apis mellifera).

Commercial beekeepers transporting honey bees across the United States to provide almond pollination services have reported honey bee deaths, possibly due to pesticide applications made during crop bloom. Pesticides are often applied as "tank mixes", or mixtures of fungicides and insecticides combined into a single application. Spray adjuvants are often added to tank mixes to improve the application characteristics of a pesticide and include spreaders, stickers, or surfactants. The goal of this research was to determine toxicity of adjuvants to adult worker honey bees, both when applied alone and in adjuvant-pesticide tank mixtures. Field-relevant combinations of formulated products were applied to 3-day-old adult worker honey bees using a Potter Spray Tower, and mortality was assessed 48 h following exposure. Adjuvants tested included Activator-90, Attach, Choice Weather Master, Cohere, Dyne-Amic, Induce, Kinetic, LI 700, Liberate, Nu-Film P, PHT Latron B-1956, and Surf-90; fungicides tested include Luna Sensation (Fluopyram and Trifloxystrobin), Pristine (Pyraclostrobin and Boscalid), Tilt (Propiconazole), and Vangard (Cyprodinil), and insecticides tested include Altacor (Chlorantraniliprole), Intrepid 2F (Methoxyfenozide), and a positive control Mustang Maxx (Zeta-cypermethrin). Results demonstrated that exposure to some adjuvants causes acute honey bee mortality at near-field application rates, both when applied alone and in combination with pesticides. Some adjuvant-pesticide combinations demonstrated increased toxicity compared with the adjuvant alone, while others demonstrated decreased toxicity. A better understanding of adjuvant and adjuvant-pesticide tank mixture toxicity to honey bees will play a key role in informing "Best Management Practices" for pesticide applicators using spray adjuvants during bloom when honey bee exposure is likely.

Species-specific roles for the MAFA and MAFB transcription factors in regulating islet ß cell identity.

Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet ß cells, characterized by inappropriate production of other islet cell-enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in ß cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human ß cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D ß cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human ß cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non-ß cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional ß cell signature.

The Incidence and Prevalence of Primary Central Nervous System (CNS) Tumours in Canada (2010-2017), and the Survival of Patients Diagnosed with CNS Tumours (2008-2017).

Primary central nervous system (CNS) tumours are heterogeneous, with different treatment pathways and prognoses depending on their histological and molecular classification. Due to their anatomical location, all CNS tumours, regardless of malignancy, can be debilitating. We used vital statistics linked to Canadian Cancer Registry data to estimate the age-standardized incidence rates (ASIR), Kaplan-Meier survival rates (SR), and limited-duration prevalence proportions (PP) of 25 histology-specific CNS tumour groups that were classified based on site and histology. During 2010-2017, 45,115 patients were diagnosed with 47,085 primary CNS tumours, of which 19.0% were unclassified. The average annual ASIR was 21.48/100,000 person-years and did not vary by sex. The ASIR increased with age, particularly for meningioma, unclassified tumours, and glioblastoma. The eight-year PP was 102.1/100,000 persons (index date 1 January 2018). The most common histology was meningioma (ASIR: 5.19; PP: 31.6). The overall five-year SR among 51,310 patients diagnosed during 2008-2017 was 57.2% (95% CI: 56.8-57.7%). SRs varied by tumour behaviour, histology, and patient age, with the lowest SR among glioblastoma patients (5-year SRs ranged from 1.3-25.7%). For non-malignant tumours, the 5-year SRs ranged from 37.4-100%. We provide the most up-to-date histology-specific surveillance estimates for primary CNS tumours in Canada.

Epigenetic Age in Peripheral Blood Among Children, Adolescent, and Adult Survivors of Childhood Cancer.

Importance: Certain cancer therapies are risk factors for epigenetic age acceleration (EAA) among survivors of childhood cancer, and EAA is associated with chronic health conditions (CHCs). However, small numbers of younger survivors (aged <20 years) previously evaluated have limited the ability to calculate EAA among this age group. Objective: To evaluate the change rate of epigenetic age (EA) and EAA in younger compared with older survivors and the possible association of EAA with early-onset obesity (aged <20 years), severity/burden of CHCs, and late mortality (>5 years from cancer diagnosis). Design, Setting, and Participants: Study participants were from the St Jude Lifetime Cohort, initiated in 2007 with ongoing follow-up. The present study was conducted from April 17, 2022, to March 23, 2023. Survivors in this cohort of European ancestry with DNA methylation data were included. Cross-sectional annual changes in EA and EAA were compared across 5 different chronologic age groups: age 0 to 9 (children), 10 to 19 (adolescents), 20 to 34 (younger adults), 35 to 49 (middle-aged adults), and greater than or equal to 50 (older adults) years. Logistic regression evaluated the association between EAA and early-onset obesity or severity/burden of CHCs. Cox proportional hazards regression assessed the association between EAA and late mortality. Main Outcomes and Measures: Early-onset obesity, severity/burden of CHCs (graded using the Common Terminology Criteria for Adverse Events (grade 1, mild; 2, moderate; 3, severe/disabling; 4, life-threatening) and were combined into high vs low severity/burden based on frequency and grade), and late mortality were the outcomes based on follow-up until April 2020. Expanded DNA methylation profiling increased the number of survivors younger than 20 years (n = 690). Epigenetic age was calculated primarily using the Levine clock, and EAA was derived from least squares regression of EA against chronologic age and was standardized to a z score (Levine EEA). Results: Among 2846 participants (median age, 30.3 [IQR, 9.3-41.5] years; 53% males), the cross-sectional annual change in EA_Levine was higher in children (1.63 years) and adolescents (1.14 years), and the adjusted least-squares mean of Levine EEA was lower in children (-0.22 years) and older adults (-1.70 years). Each 1-SD increase in Levine EEA was associated with increased risk of developing early-onset obesity (odds ratio [OR], 1.46; 95% CI, 1.19-1.78), high severity/burden of CHCs (OR, 1.13; 95% CI, 1.03-1.24), and late mortality (hazard ratio, 1.75; 95% CI, 1.35-2.26). Conclusions and Relevance: The findings of this study suggest that EAA measured in children and adolescent survivors of childhood cancer is associated with early-onset obesity, severity/burden of all CHCs, and late mortality. Evaluating EAA may help identify survivors of childhood cancer at increased risk for early-onset obesity, morbidity in general, and mortality.

Distinct DNA methylation signatures associated with blood lipids as exposures or outcomes among survivors of childhood cancer: a report from the St. Jude lifetime cohort.

BACKGROUND: DNA methylation (DNAm) plays an important role in lipid metabolism, however, no epigenome-wide association study (EWAS) of lipid levels has been conducted among childhood cancer survivors. Here, we performed EWAS analysis with longitudinally collected blood lipid data from survivors in the St. Jude lifetime cohort study. METHODS: Among 2052 childhood cancer survivors of European ancestry (EA) and 370 survivors of African ancestry (AA), four types of blood lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), were measured during follow-up beyond 5-years from childhood cancer diagnosis. For the exposure EWAS (i.e., lipids measured before blood draw for DNAm), the DNAm level was an outcome variable and each of the blood lipid level was an exposure variable; vice versa for the outcome EWAS (i.e., lipids measured after blood draw for DNAm). RESULTS: Among EA survivors, we identified 43 lipid-associated CpGs in the HDL (n = 7), TC (n = 3), and TG (n = 33) exposure EWAS, and 106 lipid-associated CpGs in the HDL (n = 5), LDL (n = 3), TC (n = 4), and TG (n = 94) outcome EWAS. Among AA survivors, we identified 15 lipid-associated CpGs in TG exposure (n = 6), HDL (n = 1), LDL (n = 1), TG (n = 5) and TC (n = 2) outcome EWAS with epigenome-wide significance (P < 9 × 10-8). There were no overlapping lipids-associated CpGs between exposure and outcome EWAS among EA and AA survivors, suggesting that the DNAm changes of different CpGs could be the cause or consequence of blood lipid levels. In the meta-EWAS, 12 additional CpGs reached epigenome-wide significance. Notably, 32 out of 74 lipid-associated CpGs showed substantial heterogeneity (Phet < 0.1 or I2 > 70%) between EA and AA survivors, highlighting differences in DNAm markers of blood lipids between populations with diverse genetic ancestry. Ten lipid-associated CpGs were cis-expression quantitative trait methylation with their DNAm levels associated with the expression of corresponding genes, out of which seven were negatively associated. CONCLUSIONS: We identified distinct signatures of DNAm for blood lipids as exposures or outcomes and between EA and AA survivors, revealing additional genes involved in lipid metabolism and potential novel targets for controlling blood lipids in childhood cancer survivors.

Incidence and survival of primary central nervous system tumors diagnosed in 4 Canadian provinces from 2010 to 2015.

Background: The Brain Tumor Registry of Canada was established in 2016 to enhance infrastructure for surveillance and clinical research on Central Nervous System (CNS) tumors. We present information on primary CNS tumors diagnosed among residents of Canada from 2010 to 2015. Methods: Data from 4 provincial cancer registries were analyzed representing approximately 67% of the Canadian population. Age-standardized incidence rates (ASIR) and 95% confidence intervals (CI) were calculated using the 2011 Canadian population age distribution. Net survival was estimated using the Pohar-Perme method. Results: A total of 31 644 primary tumors were identified for an ASIR of 22.8 per 100 000 person-years. Nonmalignant tumors made up 47.1% of all classified tumors, with mixed behaviors present in over half of histology groupings. Unclassified were 19.5% of all tumors. The most common histological subtypes are meningiomas (ASIR = 5.5 per 100 000 person-years); followed by glioblastomas (ASIR 4.0 per 100 000 person-years). The overall 5-year net survival rate for CNS tumors was 65.5%; females 70.2% and males 60.4%. GBMs continue to be the most lethal CNS tumors for all sex and age groups. Conclusions: The low annual frequency of most CNS tumor subtypes emphasizes the value of population-based data on all primary CNS tumors diagnosed among Canadians. The large number of histological categories including mixed behaviors and the proportion of unclassified tumors emphasizes the need for complete reporting. Variation in incidence and survival across histological groups by sex and age highlights the need for comprehensive and histology-specific reporting. These data can be used to better inform research and health system planning.

Average lifespan shortened due to cancer in selected countries of North America, Europe, Asia and Oceania, 2006 and 2016.

PURPOSE: We applied a novel measure of average lifespan shortened (ALSS) to examine changes in lifespan among patients who died of cancer over a 10-year period from 2006 to 2016 in 20 selected high-income countries from North America, Europe, Asia, and Oceania. METHODS: We retrieved cancer deaths in each country from the World Health Organization mortality database. We calculated ALSS as a ratio of years of life lost to the expected lifespan among patients who died from cancer. RESULTS: Between 2006 and 2016, we observed modest changes in ALSS for overall cancer deaths over the study in many countries. The changes in the ALSS over time due to any cancer ranged between -1.7 and +0.4 percentage points (pps) among men and between -1.9 and +0.6 pps among women. Across countries, overall cancer deaths led to an average loss between 16% and 22% of their lifespan in men, and between 18% and 24% in women. Across cancer sites, patients who died of central nervous system cancers, for instance, lost a large proportion of their lifespan. CONCLUSIONS: In this study, we demonstrated the use of ALSS across selected high-income countries, which enables population-level assessment of premature mortality among cancer patients over time.

Average lifespan shortened due to Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, and leukemia in Japan, 1990-2015.

We examined whether there were gains in lifespan among patients who died from hematological cancers in Japan between 1990 and 2015 using the novel average lifespan shortened (ALSS) measure. We obtained mortality data from the World Health Organization mortality database. Years of life lost (YLL) was calculated using Japanese life tables. ALSS measure was calculated as a ratio of YLL to the expected lifespan. The ALSS results showed that the lifespan of patients who died from hematological cancers has improved over time. For instance, women who died of leukemia in 1990 lost about 34% of their lifespan; conversely, those who died in 2015 lost about 20%. Likewise, men dying from non-Hodgkin lymphoma lost about 22% of their lifespan in 1990, whereas men lost about 14% in 2015. In summary, the new ALSS measure shows prolonged lifespans among patients who died from hematological cancers in Japan over the study period.

Implementation of a Nurse-Driven Spontaneous Awakening Trial Protocol in a Cardiac Intensive Care Unit.

BACKGROUND: In patients receiving mechanical ventilation, spontaneous awakening trials reduce morbidity and mortality when paired with spontaneous breathing trials. However, spontaneous awakening trials are not performed every day they are indicated and little is known about spontaneous awakening trial protocol use in cardiac intensive care units. LOCAL PROBLEM: Spontaneous awakening trial completion rate at the study institution was low and no trial protocol was regularly used. METHODS: A preintervention-postintervention retrospective cohort study was performed in adult patients with at least 24 hours of invasive mechanical ventilation in Michigan Medicine's cardiac intensive care unit. Patients with SARS-CoV-2 infection were excluded. Data included demographics, sedation, mechanical ventilation duration, and in-hospital mortality. A nurse-driven spontaneous awakening trial protocol modified for the cardiac intensive care unit was implemented in October 2020. RESULTS: Compared with the preintervention cohort (n = 29, May through July 2020), the postintervention cohort (n = 27, October 2020 through February 2021) had a higher ratio of number of trials performed to number of days eligible for trial (0.91 vs 0.52; P < .01). Median continuous sedative infusion duration was shorter after intervention (2.3 vs 3.6 days; P = .02). Median mechanical ventilation duration (3.8 vs 4.7 days; P = .18) and mortality (41% vs 41%; P = .95) were similar between groups. CONCLUSIONS: Spontaneous awakening trial protocol implementation led to a higher trial completion rate and a shorter duration of continuous sedative infusion. Larger studies are needed to assess the impact of protocolized spontaneous awakening trials on cardiac intensive care unit patient outcomes.

Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis.

The dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are essential for mitochondrial function, which has been principally attributed to their regulation of fission/fusion dynamics. Here, we report that Mfn1 and 2 are critical for glucose-stimulated insulin secretion (GSIS) primarily through control of mitochondrial DNA (mtDNA) content. Whereas Mfn1 and Mfn2 individually were dispensable for glucose homeostasis, combined Mfn1/2 deletion in ß-cells reduced mtDNA content, impaired mitochondrial morphology and networking, and decreased respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies unexpectedly revealed that Mfn1/2 control of glucose homeostasis was dependent on maintenance of mtDNA content, rather than mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient ß-cells. Thus, the primary physiologic role of Mfn1 and 2 in ß-cells is coupled to the preservation of mtDNA content rather than mitochondrial architecture, and Mfn1 and 2 may be promising targets to overcome mitochondrial dysfunction and restore glucose control in diabetes.

Brain Metastases among Cancer Patients Diagnosed from 2010-2017 in Canada: Incidence Proportion at Diagnosis and Estimated Lifetime Incidence.

The incidence of BM among Canadian cancer patients is unknown. We aimed to estimate IP of BM at the time of cancer diagnosis and during the lifetime of patients with selected primary cancers. Data on BM at diagnosis from 2010-2017 was obtained from the CCR. Site-specific IPs of BM were estimated from provincial registries containing ≥90% complete data on BM. The CCR IP estimates and the IP estimates from literature were applied to the total diagnosed primary cancers to estimate the number of concurrent BM and lifetime BM from 2010-2017 in Canada, respectively. The annual average number of patients with BM at diagnosis from all cancer sites was approximately 3227. The site-specific IPs of BM at diagnosis were: lung (9.42%; 95% CI: 9.16-9.68%), esophageal (1.58%; 95% CI: 1.15-2.02%), kidney/renal pelvis (1.33%; 95% CI: 1.12-1.54%), skin melanoma (0.73%; 95% CI: 0.61-0.84%), colorectal (0.22%; 95% CI: 0.18-0.26%), and breast (0.21%; 95% CI: 0.17-0.24%). Approximately 76,546 lifetime BM cases (or 5.70% of selected fifteen primary cancers sites) were estimated to have occurred from the 2010-2017 cancer patient cohort. These findings reflect results of population analyses in the US and Denmark. We recommend improved standardization of the collection of BM data within the CCR.

Genome-wide association studies identify novel genetic loci for epigenetic age acceleration among survivors of childhood cancer.

BACKGROUND: Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA. METHODS: Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability. RESULTS: For EAA-Horvath, a genome-wide significant association was mapped to the SELP gene with the strongest SNP rs732314 (meta-GWAS: ß=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS: ß=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (ß=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to the HLA locus with the strongest SNP rs28366133 (meta-GWAS: ß=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (ß=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (ß=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge. CONCLUSIONS: We identified novel genetic variants in the SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.