Deaths due to differentiated thyroid cancer: A 46-year perspective

From 1940 to 1986, a total of 798 patients were treated for differentiated thyroid carcinoma. One hundred and seventy-two patients died during the follow-up period: 42 (24.4%) patients from thyroid cancer, 14 (8.1%) from other causes with extensive thyroid cancer present, 75 (43.6%) with no thyroid cancer, and 41 (23.8%) with an unknown status of thyroid cancer . Of the 42 patients dying due to thyroid cancer, 15 were male and 27, female. Mean age at diagnosis was 48.3±17.7 years with one-third of patients age 45 or younger at the time of the initial diagnosis. The primary tumors were large (>4 cm) and 59.5% of the patients had local invasion and/or cervical metastasis. Distant metastases were present in 9 (21.4%) patients at the time of diagnosis . Surgical therapy included total thyroidectomy (72.1%) and limited or radical neck dissection (69.4%). Radioactive iodine ( 131 I) was used to treat residual cancer and/or distant metastasis in 73.8% of the patients. External radiation therapy was used to treat locally advanced or recurrent disease in 52.3% of the patients. Distant metastases and local recurrence were identified earlier in patients with follicular thyroid cancer whose survival time and disease-free interval were significantly shorter ( p < 0.001) than that of patients with papillary neoplasms. However, the survival and disease-free intervals were often very long in both papillary and follicular thyroid cancer deaths . Onset of differentiated thyroid cancer before the age of 40 years does not preclude serious sequelae and death. Since no known histopathologic features can consistently predict outcome, we continue to advocate aggressive treatment of all patients with differentiated thyroid cancer . Entre 1940 et 1986, 798 patients au total ont été traités pour un cancer différencié de la thyroïde. Cent-soixant-douze patients sont morts par la suite: 42 (24.4%) de leur cancer, 14 (8.1%) d'une autre cause alors que des signes d'extension du cancer étaient présents, 75 (43.6%) d'une autre cause sans signe de cancer, et 41 (23.8%) sans qu'on ait pu connaître le stade du cancer. Des 42 patients morts de leur cancer, il y avait 15 hommes et 27 femmes. L'âge moyen au moment du diagnostic était de 48.3±17.7 ans: un tiers des patients avait 45 ans ou moins au moment du diagnostic. Les tumeurs primitives avaient plus de 4 cm et 59.5% des patients présentaient un envahissement local et/ou une métastase cervicale. Les métastases à distance ont été détectées chez 9 (21.4%) patients au moment du diagnostic. Une thyroïdectomie totale a été effectuée chez 72.1% des patients, associée à un curage cervical limité ou radical chez 69.4% des patients. Chez 73.8% des patients on a traité le tissu cancéreux résiduel et/ou des métastases à distance par de l'I 131. La radiothérapie a été utilisée pour traiter les patients présentant une extension importante ou une récidive chez 52.3% des patients. Des métastases à distance et des récidives ont été identifiées précocement chez les patients ayant un cancer folliculaire. Dans ce groupe de patients, la survie et l'intervalle de temps sans maladie étaient significativement plus courts ( p <0.001) que chez les patients ayant un cancer papillaire. Il faut cependant noter que la survie et l'intervalle de temps sans maladie étaient très longs dans les 2 groupes de patients. La découverte d'un cancer différencié de la thyroïde avant l'âge de 40 ans n'est pas un facteur pronostique particulier. Puisqu'il n'y pas de facteur histologique permettant de prévoir l'évolution, nous continuons de préconiser un traitement agressif chez tout patient présentant un cancer différencié de la thyroïde. En el período 1940–1986, un total de 798 pacientes recibieron tratamiento para carcinoma tiroideo; 172 murieron en el curso del seguimiento: 42 (24.4%) por cancer tiroideo, 14 (8.1%) por otras causas pero con presencia de extenso cáncer tiroideo, 75 (43.6%) libres de cáncer tiroideo, y 41 (23.8%) con estado desconocido en cuanto al cancer tiroideo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41283/1/268_2005_Article_BF01655866.pd

A de novo paradigm for male infertility

Funding Information: (DFG, CRU326) to C.F. and F.T. This project was also supported in part by funding from the Australian National Health and Medical Research Council (APP1120356) to M.K.O.B., by grants from the National Institutes of Health of the United States of America (R01HD078641 to D.F.C. and K.I.A., P50HD096723 to D.F.C.) and from the Biotechnology and Biological Sciences Research Council (BB/S008039/1) to D.J.E. Funding Information: We are grateful for the participation of all patients and their parents in this study. We thank Laurens van de Wiel (Radboudumc), Sebastian Judd-Mole (Monash University), Arron Scott and Bryan Hepworth (Newcastle University) for technical support, and Margot J Wyrwoll (University of Münster) for help with handling MERGE samples and data. This project was funded by The Netherlands Organization for Scientific Research (918-15-667) to J.A.V. as well as an Investigator Award in Science from the Wellcome Trust (209451) to J.A.V. a grant from the Catherine van Tussenbroek Foundation to M.S.O. a grant from MERCK to R.S. a UUKi Rutherford Fund Fellowship awarded to B.J.H. and the German Research Foundation Clinical Research Unit “Male Germ Cells” Publisher Copyright: © 2022, The Author(s).De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.publishersversionpublishe

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)