Pfeiffer, V. | Search bioRxiv

bioRxiv2019

Temporal trends in incidence of childhood cancer in Switzerland, 1985-2014

STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSIncidence of childhood cancer increased in most countries worldwide, but the reasons are unclear. This study investigates trends in childhood cancer incidence in Switzerland from 1985 to 2014.\n\nMethodsWe extracted data on all childhood cancer cases diagnosed at ages 0-14 years in Switzerland from the Swiss Childhood Cancer Registry. We included ICCC-3 main groups I-XII and calculated age-standardised, cumulative, and age-specific incidence for different diagnostic groups. We analysed trends in annual age-standardised incidence using JoinPoint regression models.\n\nResultsOver the study period from 1985-2014, 5104 of 5486 cancer diagnoses (93%) were microscopically verified. The proportion of children treated in paediatric cancer centres increased from 84% during 1985-1994 to 93% in 1995-2004 and 98% in 2005-2014 (p<0.001). Using the 2010 European standard population, age-standardised incidence was 143 in 1985-1994, 154 in 1995-2004, and 162 per million in 2005-2014. Over the period 1985-2014, incidence for all cancers increased by 0.7% (95% confidence interval [CI] 0.5-1.0) per year, 0.8% (95% CI 0.2%-1.4%) for leukaemias, 3.8% (95% CI 1.7%-6.0%) for epithelial neoplasms and melanomas, and 3.0% (95% CI 1.3%-4.6%) for CNS tumours for the period 1985-2002.\n\nConclusionTrends in incidence were driven mostly by increases among leukaemias and CNS tumours. For CNS tumours, observed trends may be explained at least partially by diagnostic changes and improved registration. For leukaemias, rising incidence may be real and at least partly due to changes in risk factors.\n\nHighlightsO_LIIn Switzerland, incidence of childhood cancer increased by 18% from 1985-2014.\nC_LIO_LIIncrease in incidence was mainly caused by brain tumours and leukaemias.\nC_LIO_LIImproved registration and diagnostics may have increased brain tumour incidence.\nC_LIO_LIIncreasing trend for leukaemias may be real, but reasons remain elusive.\nC_LI

epidemiology↗

bioRxiv2019

SMCHD1 Promotes ATM-dependent DNA Damage Signaling and Repair of Uncapped Telomeres

SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing protein 1) has been implicated in X-chromosome inactivation, imprinting and DNA damage repair. Mutations in SMCHD1 can also cause facioscapulohumoral muscular dystrophy. More recently, SMCHD1 has also been detected as component of telomeric chromatin. Here, we identify requirements of SMCHD1 for DNA damage signaling and non-homologous end joining (NHEJ) at unprotected telomeres. Co-depletion of SMCHD1 with TRF2 reduced the rate of 3 overhang removal in time course experiments and the number of telomere end fusions. In SMCHD1 deficient cells, the formation of ATM pS1981, {gamma}H2AX and 53BP1 containing telomere dysfunction induced foci (TIFs) were diminished indicating defects in checkpoint signaling. Strikingly, removal of TPP1 and subsequent activation of ATR signaling rescued telomere fusion events in TRF2-depleted SMCHD1 knockout cells. Together, these data indicate that SMCHD1 depletion reduces telomere fusions in TRF2-depleted cells due to defects in ATM-dependent DNA checkpoint signaling. SMCHD1 mediates DNA damage signaling activation upstream of ATM phosphorylation at uncapped telomeres.

molecular biology↗