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This report describes an approach to regional anaesthesia of the dorsal nerves of the penis in a Great Dane, as part of an anaesthetic protocol for surgical urethral resection and anastomosis. Bupivacaine (0.5%) was infiltrated around the left and right dorsal nerves of the penis, with ultrasound guidance. The locoregional approach was trans-perineal, with the ultrasound probe orientated at a right angle to the anus, at the level of the ischial symphysis. The described technique provided good visualisation of the urethra and dorsal arteries of the penis. No adverse events relating to the nerve blockade were encountered and no additional analgesia, other than the methadone premedication, was required intra-operatively. The locoregional approach was subsequently repeated on a cadaver using the same technique and, on dissection, demonstrated deposition of injectate next to the target neurovascular bundles. The technique described may provide a simple method of distal penile anaesthesia in the dog, where ultrasound is available.

Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population. Science , this issue p. eabg2538 , p. 725

Purpose We examined if childhood socioeconomic status (SES) was related to adult leucocyte telomere length (TL) using the data of 361 African American (AA) participants from the GENE-FORECAST Study. We also assessed the mediating role of behavioral and psychosocial factors in the association between childhood SES and adult TL. Methods Childhood SES was assessed individually by using participant’s mother’s education and occupation, father’s education and occupation, parental home ownership, and family structure. TL was assessed using the quantitative polymerase chain reaction method. Information on potential confounders and mediators were collected. The associations of childhood SES with TL were assessed using multivariable linear regression models. We used path analysis to quantify and test the share of these associations that was statistically explained by each of the mediators (participant’s educational attainment, smoking status, physical activity, dietary habit, perceived stress, and depressive symptoms). Results Mother’s education was associated with longer average TL (β: 0.021; 95% CI: 0.001, 0.04, p=0.038) in confounder adjusted models. Once mediators were introduced in the model, the estimates were reduced and remained marginally significant (β: 0.017; 95% CI: −0.003, 0.038, p=0.061). According to path model, approximately 19% of the effect of mother’s education on TL (β: 0.004; 95% CI: −0.001, 0.01, p < 0.10) was mediated through participant’s own education level. No significant mediation effect was observed for any other mediators. Conclusions These data provide evidence that participant’s mother’s education was positively linked to adult TL in AA population. Participant’s own educational level partially explained this association.

PURPOSE Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown. PATIENTS AND METHODS We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based P values using a Bonferroni-corrected significance threshold of P < 8.06 × 10−5. RESULTS Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; P = 4.79 × 10−5), most notably but nonsignificantly for FANCM (patient cases, 4.0%; matched controls, 0.6%; P = 9.64 × 10−5). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; P = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with EXO1 variants (patient cases, 1.8%; controls, 0.4%; P = 3.31 × 10−5), another gene implicated in DNA double-strand break repair. CONCLUSION In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.

Background Myalgic Encephalomyelitis (ME) is a chronic condition whose status within medicine is the subject of on-going debate. Some medical professionals regard it as a contentious illness. Others report a lack of confidence with diagnosis and management of the condition. The genesis of this paper was a complaint, made by an ME patient, about their treatment by a general practitioner. In response to the complaint, Healthwatch Trafford ran a patient experience-gathering project. Method Data was collected from 476 participants (411 women and 65 men), living with ME from across the UK. Multinomial logistic regression investigated the predictive utility of length of time with ME; geographic location (i.e. Manchester vs. rest of UK); trust in GP; whether the patient had received a formal diagnosis; time taken to diagnosis; and gender. The outcome variable was number of GP visits per year. Results All variables, with the exception of whether the patient had received a formal diagnosis, were significant predictors. Conclusions Relationships between ME patients and their GPs are discussed and argued to be key to the effective delivery of care to this patient cohort. Identifying potential barriers to doctor patient interactions in the context of ME is crucial.

Background Oral microbiota may be related to pancreatic cancer risk because periodontal disease, a condition linked to multiple specific microbes, has been associated with increased risk of pancreatic cancer. We evaluated the association between oral microbiota and pancreatic cancer in Iran. Methods A total of 273 pancreatic adenocarcinoma cases and 285 controls recruited from tertiary hospitals and a specialty clinic in Tehran, Iran provided saliva samples and filled out a questionnaire regarding demographics and lifestyle characteristics. DNA was extracted from saliva and the V4 region of the 16S rRNA gene was PCR amplified and sequenced on the MiSeq. The sequencing data were processed using the DADA2 plugin in QIIME 2 and taxonomy was assigned against the Human Oral Microbiome Database. Logistic regression and MiRKAT models were calculated with adjustment for potential confounders. Results No association was observed for alpha diversity with an average of 91.11 (standard deviation [SD] 2.59) sequence variants for cases and 89.42 (SD 2.58) for controls. However, there was evidence for an association between beta diversity and case status. The association between the Bray‐Curtis dissimilarity and pancreatic cancer was particularly strong with a MiRKAT P‐value of .000142 and specific principal coordinate vectors had strong associations with cancer risk. Several specific taxa were also associated with case status after adjustment for multiple comparisons. Conclusion The overall microbial community appeared to differ between pancreatic cancer cases and controls. Whether these reflect differences evident before development of pancreatic cancer will need to be evaluated in prospective studies., Specific microbial taxa and periodontal pathogens have been found to be associated with pancreatic cancer in Western populations. In a case‐control study in Iran, we found distinct microbial communities in pancreatic cancer cases and controls in addition to associations with particular microbial taxa.

Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor that could cause telomere shortening through inhibition of telomerase. We examined the association between in utero exposure to ZDV and telomere length at birth in HIV-exposed-uninfected (HEU) newborns.We selected 94 ZDV-exposed HEU children and 85 antiretroviral therapy (ART)-unexposed HEU children from the Surveillance Monitoring for ART Toxicities Study and the Women and Infants Transmission Study. We assessed relative telomere length in stored peripheral blood mononuclear cells taken in the first 7 days of life using quantitative polymerase chain reaction. We used linear regression to compare relative telomere length between ZDV-exposed and ART-unexposed children. We additionally evaluated relative telomere length according to maternal and infant characteristics.Relative telomere length was longer in ZDV-exposed children compared with ART-unexposed individuals (adjusted mean ratio difference 0.21, 95% confidence interval 0.15-0.28, P 0.001). We found an inverse correlation between maternal HIV RNA levels and infant relative telomere length (-0.06 per log10 copies, 95% confidence interval -0.08 to -0.03, P 0.001). Relative telomere length was not associated with maternal CD4 cell count, maternal age, gestational age, sex, sample storage time, or maternal substance use (P 0.05).Relative telomere length was longer in ZDV-exposed infants. This difference may reflect beneficial health effects of ART during pregnancy, as we observed an inverse association with maternal HIV RNA levels.

Research on narcissism supports a multifactorial structure with each factor to be multidimensional. However, studies typically assess 1 factor of narcissism using scales such as the Short Dark Triad (SD3). The Five-Factor Narcissism Inventory and its short form (FFNI-SF) were developed recently to account for this issue. The extent to which the FFNI-SF assesses equivalent constructs across countries has, nonetheless, received little attention. This study evaluated the factor structure of the FFNI-SF in a Russian sample (N = 1,996) and compared the results with those derived from a UK sample (N = 1,292). Overall, the FFNI-SF evidenced satisfactory internal consistency (mean α = .82 and .79 for the Russian and UK sample for the factors of Antagonism, Extraversion and Neuroticism, respectively). Additionally, analyses yielded a 3-component model in both samples similar to that reported in the original validation study, which also demonstrated meaningful correlations with the SD3. Finally, Antagonism demonstrated significant differences between the 2 samples, perhaps reflecting societal differences between Russia and the United Kingdom. The study highlights the importance of using psychometrically sound measures to assess narcissism in its complexity and the need for additional research on how this trait operates within the personality sphere and across cultures.

This study examined whether scores on indices related to subclinical delusion formation and thinking style varied as a function of level of self-professed paranormal ability. To assess this, the researchers compared three groups differing in personal ascription of paranormal powers: no ability, self-professed ability, and paranormal practitioners (i.e., Mediums, Psychics, Spiritualists, and Fortune-Tellers). Paranormal practitioners (compared with no and self-professed ability conditions) were expected to score higher on paranormal belief, proneness to reality testing deficits, emotion-based reasoning, and lower on belief in science. Comparable differences were predicted between the self-professed and no ability conditions. A sample of 917 respondents (329 males, 588 females) completed self-report measures online. Multivariate analysis of variance (MANOVA) revealed an overall main effect. Further investigation, using discriminant descriptive analysis, indicated that paranormal practitioners scored higher on proneness to reality testing deficits, paranormal belief, and emotion-based reasoning. Belief in science did not meaningfully contribute to the discriminant function. Overall, results were consistent with previous academic work in the domains of paranormal belief and experience, which has reported that paranormal-related cognitions and perceptions are associated with factors related to subclinical delusion formation (i.e., emotion-based/intuitive thinking).

Concerns toward public well-being and mental health are increasing considering the COVID-19 pandemic's global societal and individual impact. The present study builds on the current body of COVID-19 literature by examining the role of mental toughness (MT) in predicting negative affective states (depression, anxiety and stress) during the pandemic. The study also examined the effects of changes in employment on mental health and MT. Participants (N = 723) completed a battery of questionnaires including the Mental Toughness Questionnaire 48-item, The State-Trait Anxiety Inventory, and the Depression, Anxiety and Stress Scale – 21 items. Participants reported relatively higher levels of depression, stress and anxiety in comparison to pre-COVID-19 samples from previous research, with respondents who had lost their jobs during the pandemic reporting higher levels of negative affective states. Despite this, mentally tough individuals appeared to report lower levels of depression, anxiety and stress. Moreover, moderation analyses identified some interaction between MT and employment status when predicting depression, anxiety and stress. Our findings suggest that MT may have some utility in reducing the adverse mental health effects of the pandemic on individuals, however, further longitudinal research is needed to support these implications.

Background Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study. Methods Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons. Results Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 × 10-4). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers. Conclusion In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.

Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population. Science , this issue p. eabg2538 , p. 725

BACKGROUND: Stress is common to the experience of TBI. Stressors challenge physical and psychological coping abilities and undermine wellbeing. Brain injury constitutes a specific chronic stressor. An issue that hinders the usefulness of a stress-based approach to brain injury is a lack of semantic clarity attaching to the term stress. A more precise conceptualisation of stress that embraces experienced uncertainty is allostasis. OBJECTIVE: An emerging body of research, collectively identifiable as ‘the social cure’ literature, shows that the groups that people belong to can promote adjustment, coping, and well-being amongst individuals confronted with injuries, illnesses, traumas, and stressors. The idea is deceptively simple, yet extraordinarily useful: the sense of self that individuals derive from belonging to social groups plays a key role in determining health and well-being. The objective of this research was to apply a social cure perspective to a consideration of an individual’s lived experience of TBI. METHODS: In a novel application of interpretative phenomenological analysis (IPA) this research has investigated one person’s lived experience in a single case study of traumatic brain injury. RESULTS: Paradox, shifting perspectives and self under stress, linked by uncertainty, were the themes identified. CONCLUSIONS: A relational approach must be key to TBI rehabilitation.

Background:Subclinical Narcissism (SN) is part of the Dark Triad (DT), which includes also Subclinical Psychopathy (SP) and Machiavellianism. SN comprises facets retained from the clinical syndrome, such as grandiosity and dominance. Previous cross-sectional and longitudinal research indicates that SN may increase Mental Toughness (MT) resulting in various positive outcomes, including lower levels of psychopathy.Method:The researchers conducted three studies (N = 364, 244 and 144 for Study 1, 2 and 3 respectively) to test if the path model from SN to higher MT predicted lower symptoms of depression (DS). An extension to the model considered Openness to Experience (OE) as a possible mediator. Participants completed self-report measures of SN, MT, OE and DS. In Study 3, participants responded to an additional measure of SN to allow differentiation between grandiose and vulnerable aspects.Results:SN exerted a negative indirect effect on DS through MT across studies; and a negative indirect effect on DS through MT and OE in Study 2. In Study 3, Grandiose SN increased MT contributing to lower DS. Vulnerable SN demonstrated the reverse pattern. MT subfactors of Control and Confidence had a mediating effect across studies.Conclusion:The current findings support the model that SN to MT predicts positive outcomes in various domains, including lower levels of psychiatric symptoms. Exploring the link between SN with prosocial traits can be particularly helpful when seeking to identify and promote SN’s adaptive tendencies against symptoms of psychopathology.

© Copyright © 2020 Drinkwater, Denovan and Dagnall. Focusing on lucid dreaming, this paper examined relationships between dissociated experiences related to rapid eye movement (REM) sleep (lucid dreaming, nightmares, and sleep paralysis), reality testing, and paranormal experiences/beliefs. The study comprised a UK-based online sample of 455 respondents (110 males, 345 females, Mean age = 34.46 years, SD = 15.70), who had all previously experienced lucid dreaming. Respondents completed established self-report measures assessing control within lucid dreaming, experience and frequency of nightmares, incidence of sleep paralysis, proneness to reality testing deficits (Inventory of Personality Organization subscale, IPO-RT), subjective experience of receptive psi and life after death (paranormal experience), and paranormal belief. Analysis comprised tests of correlational and predictive relationships between sleep-related outcomes, IPO-RT scores, and paranormal measures. Significant positive correlations between sleep and paranormal measures were weak. Paranormal measures related differentially to sleep indices. Paranormal experience correlated with lucid dreaming, nightmares, and sleep paralysis, whereas paranormal belief related only to nightmares and sleep paralysis. IPO-RT correlated positively with all paranormal and sleep-related measures. Within the IPO-RT, the Auditory and Visual Hallucinations sub-factor demonstrated the strongest positive associations with sleep measures. Structural equation modeling indicated that Auditory and Visual Hallucinations significantly positively predicted dissociated experiences related to REM sleep, while paranormal experience did not. However, paranormal experience was a significant predictor when analysis controlled for Auditory and Visual Hallucinations. The moderate positive association between these variables explained this effect. Findings indicated that self-generated, productive cognitive-processes (as encompassed by Auditory and Visual Hallucinations) played a significant role in conscious control and awareness of lucid dreaming, and related dissociative sleep states (sleep paralysis and nightmares).

Background:Neuroticism is associated with inflated somatic symptom reporting. Worry and rumination are a cognitive concomitant of neuroticism and potentially mediate the neuroticism–somatic complaint relationship.Aims:The present study examined the degree to which worry and rumination mediated the relationship between neuroticism and somatic complaints.Method:A sample of 170 volunteers, recruited via convenience sampling, took part. Participants completed a series of self-report measures: the Eysenck Personality Questionnaire Revised-Short Form, Penn State Worry Questionnaire, the Ruminative Response Scale and the Somatic Symptom Scale-8.Results:Analysis revealed significant positive correlations between neuroticism, rumination and worry. Neuroticism, rumination and worry also correlated positively with somatic complaints. Using structural equation modelling, a mediational model indicated that rumination fully mediated the relationship between neuroticism and somatic complaints.Conclusions:Findings are consistent with the symptom perception hypothesis and have implications for healthcare in terms of managing individuals who present with multiple somatic complaints. Future research would benefit from adopting a longitudinal approach to test how rumination interacts with neuroticism and somatic complaints over time.

Background Dyskeratosis congenita (DC) is a rare genetic disorder of bone marrow failure inherited in an X-linked, autosomal dominant or autosomal recessive pattern. It has a wide array of clinical features and patients may be cared for by many medical sub specialties. The typical clinical features consist of lacy reticular skin pigmentation, nail dystrophy and oral leukoplakia. As the disease advances, patients may develop progressive bone marrow failure, pulmonary fibrosis, oesophageal stenosis, urethral stenosis, liver cirrhosis as well as haematological and solid malignancies. Several genes have been implicated in the pathogenesis of dyskeratosis congenita, with the dyskerin pseudouridine synthase 1 (DKC1) gene mutations being the X-linked recessive gene. Case presentation Herein, we report a 31-year-old male with history of recurrent febrile episodes who was found to have reticulate skin pigmentation interspersed with hypopigmented macules involving the face, neck and extremities, hyperkeratosis of palms and soles, nail dystrophy, leukoplakia of the tongue, premature graying of hair, watery eyes and dental caries. Several of his male relatives, including two maternal uncles and three maternal cousins were affected with a similar type of disease condition. Pedigree analysis suggested a possible X-linked pattern of inheritance. Genetic testing in the proband showed a novel hemizygous, non-synonymous likely pathogenic variant [NM_001363.4: c.1054A > G: p.Thr352Ala] in the PUA domain of the DKC1 gene. Quantitative polymerase chain reaction for relative telomere length measurements performed in the proband showed that he had very short telomeres [0.38, compared to a control median of 0.71 (range 0.44–1.19)], which is consistent with the DC diagnosis. Co-segregation analysis of the novel mutation and telomere length measurements in the extended family members could not be performed as they were unwilling to provide consent for testing. Conclusions The novel variant detected in the DKC1 gene adds further to the existing scientific literature on the genotype-phenotype correlation of DC, and has important implications for the clinical and molecular characterization of the disease.

Background: It is important to identify inherited bone marrow failure syndromes (IBMFS) in patients with aplastic anemia in order to provide appropriate therapy. IBMFS are diagnosed through genetic or other diagnostic testing but can also go unrecognized, particularly in adults who may lack classic IBMFS features. This is particularly critical in light of increasing identification of individuals with variants of uncertain significance (VUS) and those with single pathogenic variants in an autosomal recessive (AR) gene or X-linked recessive (XLR) gene in females (SPVR) ("carriers") during evaluation. In this study of patients diagnosed with acquired severe aplastic anemia (SAA), we evaluated putatively causal variants in IBMFS genes to determine the frequency of patients with an unrecognized IBMFS or SPVR and assessed their association with outcomes after hematopoietic cell transplant (HCT). Methods: We used pre-HCT blood samples and clinical data from the Transplant Outcomes in Aplastic Anemia study (TOAA; a collaboration between the National Cancer Institute and the Center for International Blood and Marrow Transplant Research). Germline whole exome sequencing was performed on 732 patients with acquired SAA who received HCT between 1991-2015. A total of 104 IBMFS genes, (51 autosomal dominant (AD), 46 AR, 3 both AR and AD, 4 XLR) were evaluated for both single nucleotide (SNV) and copy number variants (CNV). All variants were curated using ACMG/AMP criteria, and a subset were validated by Sanger sequencing. Variants classified as VUS according to ACMG/AMP criteria and with a damaging score prediction in 3 of 5 in silico meta-predictors were categorized as deleterious VUS. Patients were divided into 3 groups based on known inheritance patterns of identified genes into those with 1) unrecognized IBMFS 2) SPVR or 3) neither (presumed acquired SAA). For telomere biology genes with AD/AR inheritance, we used telomeres Results: We identified 309 variants of them 156 were pathogenic or likely pathogenic (P/LP) (112 (71.8%) loss of function SNVs, and 10 CNVs), and 153 were deleterious VUS. Patients with deleterious VUS did not have different survival compared with those with no variants, and these were not considered for designating unrecognized IBMFS and SPVR cases Our analysis showed that 6.7% (N=49/732) of patients had variants consistent with an unrecognized IBMFS; 22 were AR (21 compound heterozygous, 1 homozygous), 26 AD and 1 XLR. Approximately half of those patients (22/49, 45%) had P/LP variants in hematopoiesis genes, and 31% in telomere biology genes (Figure 1A). We identified 79 patients with an SPVR, most in SBDS and FANCM. Patients with an unrecognized IBMFS had worse overall survival when compared with patients with presumed acquired SAA (log-rank p=0.0098) (Figure 1B). Multivariable analysis confirmed this association (HR=2.11, 95% confidence interval (CI)=1.38-3.22, p=0.001). The observed survival difference was not mitigated by lower conditioning regimen intensity (HR=2.1, p=0.01 in myeloablative condition (MAC), and HR=2.3, p=0.016, in reduced intensity regimens (RIC)). Patients with an SPVR had no post-HCT survival difference than presumed acquired SAA regardless of conditioning regimen (overall HR=0.96, p=0.85; MAC HR=1.4, p=0.27; RIC HR=0.3, p=0.1). Conclusions: A sizable subset of patients (6.7%) with reported immune mediated acquired SAA had unrecognized inherited disorder and 33% were adults at HCT. Unrecognized IBMFS was associated with statistically significant poorer survival after HCT. In contrast, post-HCT survival in patients with an SPVR ("carriers") was not different than those with acquired SAA. This work underscores the importance of identifying SAA patients with clinically meaningful underlying inherited disorders to enable the use therapeutic approaches to minimize regimen toxicity and late complications. It further highlights that identification of a single pathogenic variant in an autosomal recessive gene or X-linked gene in females and VUS are associated with post-HCT survival similar to acquired SAA. Figure 1 Figure 1. Disclosures Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; JANSSEN: Other; AstraZeneca: Research Funding; Takeda: Research Funding; Novartis: Other: clinical trials, Research Funding; Syndax: Research Funding; Pfizer: Research Funding; Incyte: Research Funding.

Introduction: Myelofibrosis (MF) is a rare myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, progressive bone marrow failure, and increased risk of acute myeloid leukemia. While MF arises from somatic driver mutations in JAK2, MPL, and CALR, some MPN patients may have a heritable component. To comprehensively examine the genetic etiology of MF, we performed the first integrative analysis of SNP array genotyping (using Infinium Global Screening Array), targeted long-read sequencing (using PacBio SMRT sequencing) and telomere length (TL, using qPCR assay). Methods: Our study included 937 MF patients who received an allogeneic hematopoietic cell transplant (HCT) between 2000 and 2016 and had an available pre-HCT blood sample at the Center for International Blood and Marrow Transplant Research Repository. Somatic mosaic chromosomal alterations (mCAs, including deletions, duplications, or copy-neutral losses-of-heterozygosity (CNLOH)) were called with the Mosaic Chromosomal Alteration (MoChA) algorithm using raw genotyping intensity data. A genome-wide association study (GWAS) was restricted to include 827 MF patients of European ancestry and utilized 4,135 genetically-matched healthy controls. Results: GWAS identified six independent MF susceptibility loci at genome-wide significance (P< 5×10 -8); four of which replicate prior MPN susceptibility loci [9p24.1(JAK2), 5p15.33(TERT), 3q25.33(IFT80), and 4q24(TET2)] and two novel MF loci [6p21.35(HLA-DQB1-AS1) and 17p13.1(TP53)] (Figure 1). A transcriptome-wide association analysis using whole blood GTEx data highlighted the 9p24.1 locus with increased JAK2 expression associated with elevated risk of MF (P= 2.18×10 -19). A strong colocalization statistic further indicated shared genetic component between eQTL and this JAK2 locus (HyPrColoc Posterior Probability= 0.6) (Figure 2). Based on the strong signal identified at TERT (Figure 1), we investigated the relationship between MF risk and genetically-inferred telomere length using a panel of 19 germline variants previously found to be associated with telomere length. Of the 19 telomere-length associated variants investigated, 7 were found to be associated with MF risk (binomial P= 2.31×10 -5, linear trend P= 5.48×10 -4) (Figure 3). Both Mendelian randomization and genome-wide genetic correlation analyses further indicated that increased risk of MF was associated with longer inherited telomere length. Utilizing available clinical mutation data on a subset of 185 patients, MF cases carrying the germline risk haplotype of the 9p24.1(JAK2) susceptibility locus were observed to more frequently have the JAK2 V617F mutation (71% vs 59%; P= 0.02). Targeted PacBio long-read sequencing around JAK2 provided further evidence of linkage between the germline risk allele and the JAK2 V617F mutation. Detectable autosomal mCAs were also abundant in MF cases with 67.4% having at least one mCA (compared to ~3% in the general population) and 27.6% having an mCA spanning JAK2 (mostly CNLOH) (Figure 4). In addition, using a binomial test for biased allelic imbalance, a cis relationship was identified at 9p24.1 in which the MF risk haplotype was predominantly duplicated by CNLOH (binomial P=1.36×10 -9). Regional sequencing of JAK2 further confirmed duplication of JAK2 V617F by CNLOH. Finally, we observed an inverse association between autosomal mCAs and qPCR measured telomere length (OR= 0.22, 95% CI= 0.07-0.65, P= 6.40×10 -3). These results were consistent by mCA chromosomal region and copy number state. Conclusion: Our results suggest a molecular framework for the genetic etiology of MF in which both genetically-inferred telomere length and germline variation at JAK2 are associated with increased MF risk. The 9p24.1 risk haplotype predisposes to the acquisition of a somatic JAK2 V617F mutation in cis and subsequent duplication of JAK2 V617F by mCAs (usually CNLOH). This process leads to aberrant JAK2 activity and increased clonal proliferation, accelerating telomere length shortening and increasing genomic instability in patients with MF. Figure 1 Figure 1. Disclosures Gupta: AbbVie: Consultancy, Honoraria; Constellation Pharma: Consultancy, Honoraria; Roche: Consultancy; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding. Lee: Janssen: Other; Incyte: Research Funding; AstraZeneca: Research Funding; Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding; Amgen: Research Funding. Saber: Govt. COI: Other.

PLOS ONE 15(9), e0237792 (2020). doi:10.1371/journal.pone.0237792, Published by PLOS, San Francisco, California, US

The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) defines schizotypy as a multidimensional psychopathology construct comprising Unusual Experiences, Cognitive Disorganisation, Impulsive Nonconformity, and Introvertive Anhedonia. Previous research indicates that schizotypy is associated with various risky behaviours. Urgency (emotional impulsivity) has a unique and clinically important effect on risk-taking. However, the interplay between schizotypy and urgency in relation to risk-taking has not received adequate consideration. A sample of 204 participants completed self-report scales measuring Schizotypy, Urgency and Risk-taking behaviour. Using structural equation modelling, a mediational model tested the degree to which O-LIFE subfactors directly and indirectly (via urgency) predicted self-reported likelihood to engage in Risk-taking behaviour. Results indicated that Cognitive Disorganisation and Introvertive Anhedonia negatively predicted engagement in Risk-taking behaviour, whereas Impulsive Nonconformity positively predicted engagement in Risk-taking behaviour. Unusual Experiences, Cognitive Disorganisation and Impulsive Nonconformity had indirect effects on Risk-taking through Urgency. Inclusion of Urgency added explanatory power to the schizotypy-risk relationship.

Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of pre-transplant short (10th percentile-for-age) or very short (5th or1st percentile-for-age) leucocyte telomere length on survival after unrelated donor haematopoietic cell transplantation (HCT) for acquired severe aplastic anaemia (SAA). Patient pre-transplant blood samples and clinical data were available at the Center for International Blood and Marrow Transplant Research. We used quantitative real time polymerase chain reaction to measure relative telomere length (RTL) in 490 SAA patients who received HCT between 1990 and 2013 (median age = 20 years). One hundred and twelve patients (22·86%) had pre-HCT RTL10th percentile-for-age, with the majority below the 5th percentile (N = 80, 71·43%). RTL10th percentile-for-age was associated with a higher risk of post-HCT mortality (hazard ratio [HR] = 1·78, 95% confidence interval [CI]=1·18-2·69, P = 0·006) compared with RTL ≥50th percentile; no survival differences were noted in longer RTL categories (P 0·10). Time-dependent effects for post-HCT mortality were only observed in relation to very short RTL; HR comparing RTL5th versus ≥5th percentile = 1·38, P = 0·15 for the first 12 months after HCT, and HR = 3·91, P 0·0001, thereafter, P-heterogeneity = 0·008; the corresponding HRs for RTL1st versus ≥1st percentile = 1·29, P = 0·41, and HR = 5·18, P 0·0001, P-heterogeneity = 0·005. The study suggests a potential role for telomere length in risk stratification of SAA patients in regard to their HCT survival.

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid cancer (PTC) incidence in surrounding regions, particularly for 131I-exposed children. To investigate the contribution of environmental radiation to PTC characteristics and improve understanding of radiation-induced carcinogenesis, we analyzed genomic, transcriptomic, and epigenomic characteristics of 440 pathologically-confirmed fresh-frozen PTCs from Ukraine (359 with estimated childhood or in utero 131I exposure and 81 from unexposed children born after March 1987) and matched normal tissue (non-tumor thyroid tissue and/or blood). Mean age at PTC was 28.0 years (range: 10.0-45.6). Among 131I-exposed individuals, mean radiation dose was 250 mGy (range: 11.0-8,800). In multivariable models adjusted for age at PTC and sex, we observed radiation dose-dependent enrichment of fusion drivers (P=6.6 × 10−8), nearly all occurring in the MAPK pathway, as well as increases in small deletions (P=8.0 × 10−9) and simple/balanced structural variants (P=1.2 × 10−14). Further analyses demonstrated even stronger associations for those small deletions and simple/balanced structural variants that were clonal and bore hallmarks of non-homologous end-joining repair (deletions: P=4.9 × 10−31; simple/balanced structural variants: P=5.5 × 10−19). In contrast, radiation dose was not associated with subclonal small deletions (P=0.82) or subclonal simple/balanced structural variants (P=0.91). Additionally, radiation dose was not associated with TINS (locally templated insertions), which are characteristic of alt-end-joining repair (P=0.69). The effects of radiation on genomic alterations with more pronounced for those younger at exposure. Analyses generally were consistent with a linear radiation dose-response for all molecular characteristics except clonal small deletions. Analyses of transcriptomic and epigenomic features demonstrated strong associations with the PTC driver gene but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth following environmental radiation exposure. Citation Format: Lindsay M. Morton, Danielle Karyadi, Chip Stewart, Tetiana Bogdanova, Eric Dawson, Mia Steinberg, Jieqiong Dai, Stephen Hartley, Sara Schonfeld, Joshua Sampson, Yosi Maruvka, Vidushi Kapoor, Dale Ramsden, Juan Carvajal-Garcia, Chuck Perou, Joel Parker, Marko Krznaric, Meredith Yeager, Joseph Boland, Amy Hutchinson, Belynda Hicks, Casey Dagnall, Julie Gastier-Foster, Jay Bowen, Olivia Lee, Mitchell Machiela, Elizabeth Cahoon, Alina Brenner, Kiyohiko Mabuchi, Vladimir Drozdovitch, Sergii Masiuk, Mykola Chepurny, Liudmyla Yu Zurnadzhy, Maureen Hatch, Amy Berrington de Gonzalez, Gerry Thomas, Mykola Tronko, Gad Getz, Stephen Chanock. Molecular characterization of papillary thyroid cancer in relation to ionizing radiation dose following the Chernobyl accident [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-055.

A few studies have examined the association between vitamin D and telomere length, and fewer still have examined the relationship in black or male populations. We investigated the cross-sectional association between the vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) concentration in plasma and relative leucocyte telomere length (LTL) in 1154 US radiologic technologists who were 48–93 years old (373 white females, 278 white males, 338 black females, 165 black males). Plasma 25(OH)D concentration was measured by the chemiluminescence immunoassay, and relative LTL was measured by quantitative PCR. Logistic regression was used to obtain OR and 95 % CI for long v. short (based on median) LTL in relation to continuous 25(OH)D, quartiles of 25(OH)D and 25(OH)D deficiency. We found no significant association between continuous 25(OH)D and long LTL in all participants (Ptrend=0·440), nor in white females (Ptrend=0·845), white males (Ptrend=0·636), black females (Ptrend=0·967) or black males (Ptrend=0·484). Vitamin D deficiency (defined as 25(OH)DP=0·024), but not in other groups. In this population, we found little evidence to support associations between 25(OH)D and long LTL over the entire range of 25(OH)D in the overall study population or by sex and race.

Myotonic dystrophy type I (DM1) is an autosomal dominant disease of which clinical manifestations resemble premature aging. We evaluated the contribution of telomere length in pathogenesis in 361 DM1 patients (12 with serial measurements) and 223 unaffected relative controls using qPCR assay. While no differences in baseline leukocyte relative telomere length (RTL) was noted, the data suggested an accelerated RTL attrition in DM1 (discovery cohort: T/S change/year = -0.013 in DM1 vs. -0.005 in controls, P = 0.04); similar trend was noted in validation cohort. Further investigations are needed to examine the role of TL in the pathophysiology of DM1. The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.

Background: The oral microbiota may be associated with lung cancer risk through direct mechanisms, including infection, immune responses, and periodontal disease, and through indirect mechanisms such as the modification of the oral microbiota by tobacco. We conducted a case-cohort study nested within three US prospective cohort studies to evaluate the association between oral microbiota ascertained years before a cancer diagnosis and risk of lung cancer. Methods: Incident lung cancer cases within the Agricultural Health Study (AHS; N=244), NIH-AARP Diet and Health Study (N=376), and the Prostate, Lung, Colorectum, and Ovarian Cancer Screening Trial (PLCO; N=700) who provided an oral wash sample were identified. The median time between oral sample collection and diagnosis was approximately 6.6 years, 3.4 years, and 4.5 years for AHS, NIH-AARP, and PLCO, respectively. A referent subcohort was randomly selected by strata of age, sex, and cigarette smoking history. We extracted DNA using the DSP DNA Virus Pathogen kit, and the V4 region of the 16S rRNA gene was PCR amplified and sequenced using the MiSeq. The sequencing data were processed using QIIME2 with the DADA2 plugin and we generated alpha and beta diversity metrics. Cox proportional hazards models were used to evaluate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between the oral microbial measures and the risk of lung cancer with adjustment for known lung cancer risk factors, and estimates from the three cohorts were meta-analyzed. Results: Increased alpha diversity was associated with decreased lung cancer risk, although only the association with the Shannon Index reached statistical significance (HR for 5th quintile versus 1st quintile 0.74; 95% CI 0.60, 0.92) with no evidence of between-study heterogeneity (p = 0.5968). Specific principal coordinate vectors from the beta diversity matrices were also significantly associated with lung cancer risk, suggesting differing bacterial communities between future lung cancer cases. When stratified by histologic subtypes, the inverse association with alpha diversity was restricted to squamous cell carcinoma, with all alpha diversity metrics reaching statistical significance (e.g., Faith’s phylogenetic diversity HR for 5th quintile versus 1st quintile 0.57; 95% CI: 0.37, 0.87). Similarly, when stratified by smoking history, the inverse association with alpha diversity was restricted to former smokers (e.g., observed species HR for 5th quintile versus 1st quintile 0.63; 95% CI: 0.44, 0.89). Conclusions: In oral wash samples collected years before diagnosis, we found significant associations between both alpha and beta diversity metrics of the oral microbial communities and risk of lung cancer. Additional work is required to understand the associations by histologic subtype and smoking history. Citation Format: Emily Vogtmann, Xing Hua, Guoqin Yu, Autumn Hullings, Yunhu Wan, Casey L Dagnall, Kristine Jones, Belynda D. Hicks, Amy Hutchinson, Shalabh Suman, Bin Zhu, Barry Graubard, Mitchell H. Gail, J. Gregory Caporaso, William Wheeler, Dale Sandler, Laura E. Beane Freeman, Linda Liao, Neal D. Freedman, Neil Caporaso, Rashmi Sinha, Jianxin Shi, Christian C Abnet. The human oral microbiota and risk of lung cancer: An analysis of three prospective cohort studies [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A39.

Background: Given the inverse relationship described previously between telomere content and thyroid subsequent malignant neoplasm (thyroid SMN) in survivors of childhood cancer, we investigated the relationship between known genetic determinants of leukocyte telomere length (LTL) and thyroid SMN among survivors. Methods: Leveraging data from a large, genotyped survivor cohort, the Childhood Cancer Survivor Study, we used a well-described genetic risk score method to estimate the HR for thyroid SMN among 5,324 genotyped survivors. Results: We identified 118 survivors with thyroid SMN and 5,206 without thyroid SMN. No association between genetically estimated LTL and risk for thyroid SMN was identified. Conclusions: Our results suggest that variation in common SNPs influencing LTL is not strongly associated with risk for thyroid SMN in survivors of childhood cancer. Impact: The previously observed inverse relationship between LTL and thyroid SMN risk in survivors of childhood cancer may be related to alternative molecular mechanisms and warrants further study.

Telomere length (TL) comparisons from different methods are challenging due to differences in laboratory techniques and data configuration. This study aimed to assess the validity of converting the quantitative polymerase chain reaction (qPCR) telomere/single copy gene (T/S) ratio to TL in kilobases (kb). We developed a linear regression equation to predict TL from qPCR T/S using flow cytometry with fluorescence in situ hybridization (flow FISH) TL data from 181 healthy donors (age range = 19&ndash, 53) from the National Marrow Donor Program (NMDP) biorepository. TL measurements by qPCR and flow FISH were modestly correlated (R2 = 0.56, p &lt, 0.0001). In Bland-Altman analyses, individuals with the shortest (&le, 10th percentile) or longest (&ge, 90th) flow FISH TL had an over- or under-estimated qPCR TL (bias = 0.89 and &minus, 0.77 kb, respectively). Comparisons of calculated TL from the NMDP samples and 1810 age- and sex-matched individuals from the National Health and Nutrition Examination Survey showed significant differences (median = 7.1 versus 5.8 kb, respectively, p &lt, 0.0001). Differences in annual TL attrition were also noted (31 versus 13 bp/year, respectively, p = 0.02). Our results demonstrate that TL calculated in kb from qPCR T/S may yield biased estimates for individuals with the shortest or longest TL, those often of high clinical interest. We also showed that calculated TL in kb from qPCR data are not comparable across populations and therefore are not necessarily useful.

Recent studies suggest improved survival in patients with severe aplastic anemia receiving hematopoietic cell transplant (HCT) from unrelated donors with longer telomeres. Here, we tested whether this effect is generalizable to patients with acute leukemia. From the Center for International Blood and Marrow Transplant Research (CIBMTR®) database, we identified 1097 patients who received 8/8 HLA-matched unrelated HCT for acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) between 2004 and 2012 with myeloablative conditioning, and had pre-HCT blood sample from the donor in CIBMTR repository. The median age at HCT for recipients was 40 years (range ≤1-68), and 32 years for donors (range = 18-61). We used qPCR for relative telomere length (RTL) measurement, and Cox proportional hazard models for statistical analyses. In a discovery cohort of 300 patients, longer donor RTL (>25th percentile) was associated with reduced risks of relapse (HR = 0.62, p = 0.05) and acute graft-versus-host disease II-IV (HR = 0.68, p = 0.05), and possibly with a higher probability of neutrophil engraftment (HR = 1.3, p = 0.06). However, these results did not replicate in two validation cohorts of 297 and 488 recipients. There was one exception; a higher probability of neutrophil engraftment was observed in one validation cohort (HR = 1.24, p = 0.05). In a combined analysis of the three cohorts, no statistically significant associations (all p > 0.1) were found between donor RTL and any outcomes.

OBJECTIVES Gender-related factors can influence management decisions, treatment outcomes and the overall long-term wellbeing of people living with HIV (PLWH). The Women Against Viruses in Europe (WAVE) Working Group was established to promote the health and wellbeing of women living with HIV (WLWH). WAVE is part of the European AIDS Clinical Society (EACS) and organizes annual workshops to discuss different issues in the management of WLWH. METHODS In 2016, 34 WAVE members including community representatives, HIV clinicians and researchers met to discuss standards of care for WLWH and to review current guidelines. Participants focused on three different themes: (1) access to and engagement and retention in care; (2) monitoring of women on antiretroviral therapy and management of comorbidities; and (3) review of EACS treatment guidelines. RESULTS Five priority areas for optimizing the care of WLWH were identified: (1) psychosocial aspects of HIV diagnosis and care; (2) mental health and wellbeing; (3) pharmacokinetics, toxicity and tolerability of antiretroviral therapy; (4) coinfections and comorbidities; and (5) sexual and reproductive health. WAVE recommendations are provided for each of these areas, and gaps in knowledge and needs for changes in currently existing standards are discussed. CONCLUSIONS This position statement provides an overview of the key recommendations to optimize the care of WLWH that emerged during the 2016 WAVE workshop.

Several methods have been employed to measure telomere length (TL) in human studies. It has been difficult to directly compare the results from these studies because of differences in the laboratory techniques and output parameters. We compared TL measurements (TLMs) by the three most commonly used methods, quantitative polymerase chain reaction (qPCR), flow cytometry with fluorescence in situ hybridization (flow FISH) and Southern blot, in a cohort of patients with the telomere biology disorder dyskeratosis congenita (DC) and in their unaffected relatives (controls). We observed a strong correlation between the Southern blot average TL and the flow FISH total lymphocyte TL in both the DC patients and their unaffected relatives (R2 of 0.68 and 0.73, respectively). The correlation between the qPCR average TL and that of the Southern blot method was modest (R2 of 0.54 in DC patients and of 0.43 in unaffected relatives). Similar results were noted when comparing the qPCR average TL and the flow FISH total lymphocyte TL (R2 of 0.49 in DC patients and of 0.42 in unaffected relatives). In conclusion, the strengths of the correlations between the three widely used TL assays (qPCR, flow FISH, and Southern blot) were significantly different. Careful consideration is warranted when selecting the method of TL measurement for research and for clinical studies.

10028 Background: Radiotherapy for childhood cancer is associated with strikingly elevated risk for developing subsequent neoplasms (SNs). Whether mutations in DNA repair and radiation sensitivity genes modulate SN risks is largely unknown. Methods: We conducted whole-exome sequencing in 5105 long-term childhood cancer survivors of European descent (mean follow-up = 32.7 years). SnpEff and ClinVar identified potentially damaging rare variants in 476 DNA repair or radiation sensitivity genes. Conditional logistic regression assessed SN risk associated with these variants aggregated by gene or pathway (N = 155 with ≥5 carriers). Controls were matched on sex, childhood cancer type and diagnosis age, radiation dose to the SN site, and survival. Exact p-values were calculated by permutation. Analyses used all survivors or subsets stratified on radiation dose. Results: A total of 1108 (21.7%) survivors developed at least one SN type known to be related to ionizing radiation exposure (e.g., breast cancer, basal cell carcinoma, meningioma, thyroid cancer, sarcoma). Radiation-related SN risk was associated with homologous recombination (HR) gene variants for SN sites that received > 0- < 10 Gy (20.9% cases, 11.0% controls; odds ratio [OR] = 2.20, 95% confidence interval [CI] 1.52-3.18; P = 1.41x10-4), most notably for FANCM (3.1% cases, 0.5% controls; OR = 9.91, 95%CI 3.73-26.4; P = 2.85x10-4). For radiation-related SNs at sites with higher doses (≥10 Gy), associations were not observed for the HR pathway (14.4% cases, 12.4% controls, P = 0.17) but were observed for two individual genes implicated in double-strand DNA break repair, EXO1 (1.8% cases, 0.4% controls; OR = 6.50, 95%CI 3.49-12.1; P = 7.43x10-4) and NEIL3 (0% cases, 1.0% controls; P = 3.23x10-4). Conclusions: In this discovery study, we identified dose-specific novel associations between SN risk after radiotherapy for childhood cancer and potentially damaging rare variants in genes involved in double-strand DNA break repair, particularly HR. If replicated, these results could impact long-term screening of childhood cancer survivors and risk-benefit assessments of treatment approaches.

Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of abnormal telomere biology on survival after unrelated donor hematopoietic cell transplant (HCT) for acquired severe aplastic anemia (SAA). Patient pre-transplant blood samples, and clinical and outcome data were available at the Center for International Blood and Marrow Transplant Research. We used qPCR to measure relative telomere length (RTL) and whole exome sequencing to identify patients with pathogenic (P) or likely pathogenic (LP) variants in telomere biology disorder (TBD) related genes. Cox proportional hazard models were used for survival analysis. The study included 490 SAA patients who received HCT between 1990 and 2013 at a median age of 20 years. Eighty patients (16.3%) had pre-HCT RTL 0.10 for all other categories). A similar high mortality risk was found in patients with P/LP TBD-related variants (HR=2.0, 95% CI=1.28-3.15, p=0.003). A time-dependent effect for post-HCT mortality was only observed in relation to RTL (HR for RTL

Telomeres are tandem nucleotide repeats and a protein complex located at the end of the chromosomes maintaining genomic stability. Their potential as a predictive biomarker for outcomes after allogeneic hematopoietic cell transplant (HCT) in hematologic malignancies is still unclear. From the Center for International Blood and Marrow Transplant Research we randomly selected 536 acute leukemia patients from those who underwent myeloablative 8/8 HLA-matched unrelated donor HCT between 2005 and 2012 and who had an available pre-HCT blood sample in the repository. Relative telomere length (RTL) was measured by real-time quantitative PCR. We used Kaplan-Meier and competing risk estimators to calculate survival probability and cumulative incidence, respectively, across patient RTL tertiles. Cox proportional hazard regression was used for adjusted analyses. The study included 396 acute myeloid leukemia (AML) and 140 acute lymphoblastic leukemia (ALL) patients. Median age at HCT was 41 years (range, .5 to 66), and median follow-up for survivors was 5.1 years (range, .4 to 8.3). Significant inverse correlations between age and RTL were observed in patients with AML (r = -.44, P .0001) and ALL (r = -.48, P .0001). Patients with ALL had longer RTL than those with AML (.48 versus .43, respectively); the difference was not statistically significant after adjusting for patient age (P = .96). Pre-HCT RTL in acute leukemia patients was not statistically significantly associated with overall survival (HR for longest RTL compared with shortest, .91; 95% CI, .65 to 1.28), disease-free survival (HR, .90; 95% CI, .64 to 1.25), transplant-related mortality (HR, .97; 95% CI, .60 to 1.59), incidence of relapse (HR, .89; 95% CI, .56 to 1.40), neutrophil engraftment (HR, 1.06; 95% CI, .85 to 1.32), or grades II to IV acute graft-versus-host disease (HR, 1.11; 95% CI, .81 to 1.53), grades III-IV acute graft-versus-host disease (HR, .92; 95% CI, .54 to 1.59), and chronic graft-versus-host disease (HR, 1.10; 95% CI, .81 to 1.50). In this study, recipient pre-HCT RTL had no prognostic role in post-transplant outcomes in acute leukemia patients.

Background Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking. Methods We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided. Results Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8

We previously showed an association between donor leukocyte relative telomere length (RTL) and post-hematopoietic cell transplantation (HCT) survival in patients with severe aplastic anemia (SAA) who received bone marrow grafts at ages

Studies have suggested mosaic loss of chromosome Y (mLOY) in blood-derived DNA is common in older men. Cohort studies investigating mLOY and mortality have reported contradictory results. Previous work found that a 1.6 Mb deletion of the AZFc region on the Y chromosome (the 'gr/gr' deletion) is associated with both male infertility and increased risk of testicular germ cell tumors (TGCT). We investigated whether mosaic loss across the entire Y chromosome was associated with TGCT. We obtained blood- and buccal-derived DNA from two case-control studies: the NCI Familial Testicular Cancer Study (cases=172; controls=163) and the NCI US Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study (cases=506; controls=611). We used 15 quantitative polymerase chain reactions spanning the Y chromosome to assess mLOY. Multivariate logistic regression models adjusted for study batch effects detected no significant overall relationship between mean chromosome Y target-to-reference (T/R) ratio and TGCT (odds ratio=0.34, 95% confidence interval=0.10-1.17, P=0.09). When restricted to familial TGCT cases, a significantly lower T/R ratio was observed in cases compared with controls (0.993 vs 1.014, P-value=0.01). Our study suggests that mLOY, as measured by 15 probes spanning the Y chromosome, could be associated with familial TGCT, but larger studies are required to confirm this observation.