Rhabdoid tumors in patients conceived following ART: is there an association?
Karolina NemesMartin BeneschJulia KolarovaPascal D. JohannMartin HasselblattChristian ThomasSusanne BensSelina GlaserOle AmmerpohlOlga LiaugaudienėAlireza SadeghipourNicolas von der WeidIrene SchmidCorrie GiddingAnat Erdreich‐EpsteinClaudia KhuranaGeorg Ebetsberger‐DachsAndreas LemmerZiad KhatibCarmen Hernández MarqúesJane PearsFranz QuehenbergerUwe KordesChristian VokuhlJoachim GerßHeike SchwarzBrigitte BisonJaclyn A. BiegelReiner SiebertMichael C. Frühwald
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Abstract STUDY QUESTION In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART? SUMMARY ANSWER We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT_ART) as compared to other children with RT. WHAT IS KNOWN ALREADY Anecdotal evidence suggests an association of ART with RT. STUDY DESIGN, SIZE, DURATION This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0–120 months) for children with RT_ART and 18.5 months (range 0–153 months) for the EU-RHAB control cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS We analyzed 14 children with RT_ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age). MAIN RESULTS AND THE ROLE OF CHANCE The median age at diagnosis of 14 individuals with RT_ART was 9 months (range 0–66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0–253), P = 0.03). A significant female predominance was observed in the RT_ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT_ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT_ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT_ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT_ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT_ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT_ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205). LIMITATIONS, REASONS FOR CAUTION RTs are very rare malignancies and our results are based on a small number of children with RT_ART. WIDER IMPLICATIONS OF THE FINDINGS This cohort of patients with RT_ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT_ART patients is not yet understood and needs to be evaluated, ideally in larger international series. STUDY FUNDING/COMPETING INTEREST(S) M.C.F. is supported by the ‘Deutsche Kinderkrebsstiftung’ DKS 2020.10, by the ‘Deutsche Forschungsgemeinschaft’ DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the ‘Deutsche Kinderkrebsstiftung’ DKS 2020.05. We declare no competing interests. TRIAL REGISTRATION NUMBER N/A.Vitamin D deficiency is less common among HIV-infected African–American men than in a matched cohort
The aim of this study was to compare the prevalence of vitamin D sufficiency and deficiency in a HIV-infected cohort of African-American men with that of a general population. We found median vitamin D concentrations were significantly greater in the HIV-infected cohort, 18 ng/ml as compared to the National Health and Nutrition Examination Survey cohort, 14 ng/ml (P ≤ 0.0001). Thus, factors other than measured vitamin D are likely to be responsible for higher rates of bone disease in this population.
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OBJECTIVES: To examine the cancer risk of shoe manufacturing workers and evaluate whether the risk was associated with exposure to leather dust and solvents. METHODS: Data from two historical cohort studies of shoe workers were expanded and analysed in parallel. A total of 4215 shoemakers from England contributing 103 726 person-years at risk and 2008 shoemakers from Florence, Italy, contributing 54,395 person-years at risk were included in the analysis. Exposure to leather dusts and solvents from glues was evaluated on the basis of job title information. Standardised mortality ratios (SMR) were calculated as ratios of observed deaths (Obs) over expected derived from national mortalities. RESULTS: Overall mortality was lower than expected in both cohorts (English cohort: Obs 3314, SMR 81, 95% confidence interval (95% CI) 78-84; Florence cohort: Obs 333, SMR 87, 95% CI 78-97). An increased risk of nasal cancer was found (English cohort: Obs 12, SMR 741; Florence cohort: Obs 1, SMR 909). 10 of the 13 cases occurred among English workers employed in the manufacture of welted boots (SMR 926, 95% CI 444-1703), a sector of the industry thought to have had the highest exposure to leather dust. Mortality from leukaemia was not increased in the English cohort (Obs 16, SMR 89), but was increased in the Florence cohort (Obs 8, SMR 214, 95% CI 92-421); and the highest risk was found among shoe workers in Florence who were first exposed between 1950 and 1959 when exposure to benzene was substantial (Obs 3, SMR 536, 95% CI 111-1566). Some evidence for an excess risk of stomach, bladder, and kidney cancer, as well as multiple myeloma and non-Hodgkin's lymphoma was also found in the Florence cohort only among workers employed in jobs with the highest exposure to solvents. CONCLUSIONS: These findings confirm the associations between exposure to leather dust and nasal cancer and between exposure to benzene and leukaemia in the shoe manufacturing industry and suggest that the risk of other cancers may be increased among workers exposed to solvents or glues.
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Objectives
To investigate deaths recorded as lung cancer or COPD (as distinct from other non-malignant respiratory disease), in a cohort occupationally exposed to silica.Methods
Vital status and cause of death were ascertained for a cohort of 5115 pottery workers previously followed to 1992. SMRs were calculated for underlying cause of death 1985–2008 compared to reference data from Stoke on Trent. Analysis of ‘mentioned’ cause of death was restricted to 1993–2008. Information on duration of employment and smoking was available for the whole cohort but exposure data were restricted to those included in an earlier validation cohort and those who were still employed in 1981 or later.Results
Of 5115 in the original cohort, 27 were duplicates, 29 were not traced and 258 had died before 1985, leaving 4801, with 1904 deaths. Deaths from lung cancer (N=243) were raised SMR=1.15 (1.01–1.30) as were deaths from COPD (N=158) both as an underlying (SMR=1.46 (1.24–1.71)) and as a ‘mentioned’ (SMR=1.31 (1.14–1.50)) cause. In a survival analysis duration of exposure was not related to deaths recorded as lung cancer or COPD for the cohort as a whole. In those (N=1943) with exposure data, early deaths (before July 1992) from either lung cancer or COPD were related to mean exposure in smokers but this relation was not seen in those dying from these causes in more recent years.Conclusions
Silica exposure appears to have contributed to early, but not recent, deaths although an excess of COPD deaths continues to be recorded.Cite
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Background: The level of epigenetic DNA methylation is an important factor in the pathogenesis of various human diseases. Methods: As smoking may influence DNA methylation, we investigated the effect of smoking habits on global DNA methylation in 313 genomic DNA samples. Results: We did not find an effect of smoking on global DNA methylation. However, there was an association of the offspring's DNA methylation with paternal DNA methylation that was strongest if both had never smoked ((R2corr=0.408, Beta=0.683, P=0.020) and completely vanished if the offspring smoked or had ever smoked. Conclusion: These findings suggest that smoking influences global DNA methylation.
Epigenomics
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Introduction: Vitamin D deficiency has been documented across all age groups and both sexes from India. However, there is paucity of data on vitamin D deficiency in a particular cohort of population. Objectives: To assess the vitamin D status in a cohort of physicians and diabetologists in Kolkata. Material and Methods: An observational cross sectional study carried out in the month of December 2011 in a cohort of 40 physicians and diabetologists in Kolkata. Results: A total of 40 subjects were studied. Mean age of the cohort was 52.22 ± 10.91. Mean serum vitamin D level was 13.02 ± 4.77 ng/ml. Nearly 92.5% and 5.0% of subjects had vitamin D deficiency and insufficiency, respectively. Conclusions: Vitamin D deficiency is highly prevalent in physicians and diabetologists in Kolkata.
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BackgroundThe cross-sectional HIV care continuum is widely used to assess the success of HIV care programmes among populations of people with HIV and the potential for ongoing transmission. We aimed to investigate whether a longitudinal continuum, which incorporates loss to follow-up and mortality, might provide further insights about the performance of care programmes.MethodsIn this longitudinal cohort study, we included individuals who entered the UK Collaborative HIV Cohort (CHIC) study between Jan 1, 2000, and Dec 31, 2004, and were linked to the national HIV cohort database (HIV and AIDS Reporting System). For each month during a 10 year follow up period, we classified individuals into one of ten distinct categories according to engagement in care, antiretroviral therapy (ART) use, viral suppression, loss to cohort follow-up and loss to care, and mortality, and assessed the proportion of person-months of follow-up spent in each stage of the continuum. 5 year longitudinal continuums were also constructed for three separate cohorts (baseline years of entry 2000–03, 2004–07, and 2008–09) to compare changes over time.FindingsWe included 12 811 people contributing 1 537 320 person-months in our analysis. During 10 years of follow-up, individuals spent 811 057 (52·8%) of 1 537 320 person-months on ART. Of the 811 057 person-months spent on ART, individuals had a viral load of 200 copies per mL or less for 607 185 (74·9%) person-months. 10 years after cohort entry, 3612 (28·1%) of 12 811 individuals were lost to follow-up, 954 (26·4%) of whom had transferred to a non-CHIC UK clinic for care. By 10 years, 759 (5·9%) of 12 811 participants who entered the cohort had died. Loss to follow-up decreased and the proportion of person-months that individuals spent virally suppressed increased over calendar time.InterpretationLoss to follow-up in HIV care programmes was high and rates of viral suppression were lower than previously reported. Complementary information provided by a longitudinal continuum might highlight areas for intervention along the HIV care pathway, however, transfers outside the cohort must be accounted for.FundingMedical Research Council, UK.
Continuum of care
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The E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) cohort was initiated in 1990 to investigate therisk factors associated with cancer and other major non-communicable diseases in women. The participants were insured through a national health system that primarily covered teachers, and were enrolled from 1990 after returning baseline self-administered questionnaires and providing informed consent. The cohort comprised nearly 100,000 women with baseline ages ranging from 40 to 65 years. Follow-up questionnaires were sent approximately every 2-3 years after the baseline and addressed general and lifestyle characteristics together with medical events (cancer, cardiovascular diseases, diabetes, depression, fractures and asthma, among others). The follow-up questionnaire response rate remained stable at approximately 80%. A biological material bank was generated and included blood samples collected from 25,000 women and saliva samples from an additional 47,000 women. Ageing among the E3N cohort provided the opportunity to investigate factors related to age-related diseases and conditions as well as disease survival. The new E4N complementary cohort (Epidemiology 4 kNowledge), which comprises the children and grandchildren of the E3N cohort as well as the children's fathers, will allow researchers to investigate key life periods during which exposures to environmental factors most strongly influence the later disease risk. The E3N and E4N cohort data will be used to investigate diseases and risk factors through a transgenerational approach. Requests for collaborations are welcome, particularly those in conjunction with rare diseases.
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ABSTRACT Purpose The Mother and Child Covid-19 study is a cohort recruiting pregnant women and their children in Cantabria, North of Spain, during COVID-19 pandemic in order to ascertain Consequences of SARS-CoV-2 infection on pregnant women and their descendants. This article reports the cohort profile and preliminary results as recruitment is still open. Participants Three sub-cohorts can be identified at recruitment. Sub-cohort 1 includes women giving birth between 23 rd March and 25 th May 2020; they have been retrospectively recruited and could have been exposed to COVID-19 only in their third trimester of pregnancy. Sub-cohort 2 includes women giving birth from 26 th May 2020 on; they are being prospectively recruited and could have been exposed to COVID-19 in both their second and third trimesters of pregnancy. Sub-cohort 3 includes women in their 12 th week of pregnancy prospectively recruited from 26 th May 2020 on; they could have been exposed to COVID-19 anytime in their pregnancy. All women are being tested for SARS-CoV-2 infection using both RT-PCR for RNA detection and ELISA for anti-SARS-CoV-2 antibodies. All neonates are being tested for antibodies using immunochemoluminiscency tests; if the mother is tested positive for SARS-CoV-2 RNA, a naso-pharyngeal swab is also obtained from the child for RT-PCR analysis. Findings to date As of 22 nd October, 1167 women have been recruited (266, 354 and 547 for sub-cohorts 1, 2 and 3, respectively). Fourteen women tested positive to SARS-CoV-2 RNA by the day of delivery. All fourteen children born from these women tested negative for SARS-CoV-2 RNA. Future plans Children from women included in sub-cohort 3 are expected to be recruited by the end of 2020. Children will be followed-up for one year in order to ascertain the effect that COVID-19 on their development. ARTICLE SUMMARY Strengths and limitations Strengths This cohort would ascertain the effect of COVID-19 in both mother and children whatever the trimester of the infection. It would also compare health care provided to pregnant women during the COVID-19 pandemic with that provided in the same hospital before the emergence of COVID-19. The cohort is recruited in Spain, one of the developed countries earlier and more affected by COVID-19. Limitations The study could be underpowered according to the prevalence reported in a Spanish national study. Information regarding exposure to people infected by SARS-CoV-2 or risk activities is self-reported.
Pandemic
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Epidemiological research suggests that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals indicate that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero. Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genome-wide DNA methylation using the Illumina MethylationEPIC array in a cross-sectional study of matched human blood and sperm from lean (discovery n = 47; replication n = 21) and obese (n = 22) males to analyse tissue covariation of DNA methylation, and identify obesity-associated methylomic signatures. We found that DNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (~1%). At the majority of these sites, DNA methylation appears to be influenced by genetic variation. Obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity was not associated with altered covariation patterns or accelerated epigenetic ageing in the two tissues. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P = 8.95 × 10−8; 2% DNA methylation difference) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n = 5,917), spermatozoa displayed differential DNA methylation across pathways enriched in transcriptional regulation. Overall, human sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. We observed that obesity was only nominally associated with differential DNA methylation in sperm, and therefore suggest that spermatozoal DNA methylation is an unlikely mediator of intergenerational effects of metabolic traits.
CpG site
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In this manuscript, we update the profile of the 1982 Pelotas Birth Cohort Study.In 1982, 5914 live births whose families lived in the urban are of Pelotas were enrolled in the cohort. In 2012-13, we tried to locate the whole original cohort; 3701 participants were interviewed who, added to the 325 known deaths, represented a follow-up rate of 68.1%. In contrast to the previous home interviews, in this wave all participants were invited to visit the research clinic to be interviewed and examined. The visit was carried out at a mean age of 30.2 years and mainly focused on four categories of outcomes: (i) mental health; (ii) body composition; (iii) precursors of complex chronic diseases; and (iv) human capital. Requests for collaboration by outside researchers are welcome.
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