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1.
Stem Cell Res ; 51: 102185, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33524673

RESUMO

Autism is a complex neuropsychiatric disorder defined by significant challenges in communication skills and social behavior as well as repetitive conduct and interests. Recent advances in stem cell technologies allow in vitro modeling of the underlying molecular disease mechanisms. Using integration-free episomal plasmids, we have generated a novel iPS cell line (SDUKIi006-A) from a patient diagnosed with atypical autism ("FYNEN cohort" of Southern Denmark). Characterization of the established cell line validated its expression of pluripotency markers, differentiation into the three germ layers, and the absence of chromosomal abnormalities.

2.
Glia ; 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33241604

RESUMO

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system (CNS) most frequently mediated by serum autoantibodies against the water channel aquaporin 4, expressed on CNS astrocytes, resulting in primary astrocytopathy. There is no cure for NMO, and treatment with Type I interferon (IFNI)-IFNß is ineffective or even detrimental. We have previously shown that both NMO lesions and associated microglial activation were reduced in mice lacking the receptor for IFNß. However, the role of microglia in NMO is not well understood. In this study, we clarify the pathomechanism for IFNI dependence of and the role of microglia in experimental NMO. Transcriptome analysis showed a strong IFNI footprint in affected CNS tissue as well as in microglial subpopulations. Treatment with IFNß led to exacerbated pathology and further microglial activation as evidenced by expansion of a CD11c+ subset of microglia. Importantly, depletion of microglia led to suppression of pathology and decrease of IFNI signature genes. Our data show a pro-pathologic role for IFNI-activated microglia in NMO and open new perspectives for microglia-targeted therapies.

3.
Haematologica ; 105(9): 2262-2272, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33054051

RESUMO

We report the final 2-year end-of-study results from the first clinical trial investigating combination treatment with ruxolitinib and low-dose pegylated interferon-α2 (PEG-IFNα2). The study included 32 patients with polycythemia vera and 18 with primary or secondary myelofibrosis; 46 patients were previously intolerant of or refractory to PEGIFNα2. The primary outcome was efficacy, based on hematologic parameters, quality of life measurements, and JAK2 V617F allele burden. We used the 2013 European LeukemiaNet and International Working Group- Myeloproliferative Neoplasms Research and Treatment response criteria, including response in symptoms, splenomegaly, peripheral blood counts, and bone marrow. Of 32 patients with polycythemia vera, ten (31%) achieved a remission which was a complete remission in three (9%) cases. Of 18 patients with myelofibrosis, eight (44%) achieved a remission; five (28%) were complete remissions. The cumulative incidence of peripheral blood count remission was 0.85 and 0.75 for patients with polycythemia vera and myelofibrosis, respectively. The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score decreased from 22 [95% confidence interval (95% CI):, 16-29] at baseline to 15 (95% CI: 10-22) after 2 years. The median JAK2 V617F allele burden decreased from 47% (95% CI: 33-61%) to 12% (95% CI: 6-22%), and 41% of patients achieved a molecular response. The drop-out rate was 6% among patients with polycythemia vera and 32% among those with myelofibrosis. Of 36 patients previously intolerant of PEG-IFNα2, 31 (86%) completed the study, and 24 (67%) of these received PEG-IFNα2 throughout the study. In conclusion, combination treatment improved cell counts, reduced bone marrow cellularity and fibrosis, decreased JAK2 V617F burden, and reduced symptom burden with acceptable toxicity in several patients with polycythemia vera or myelofibrosis. #EudraCT2013-003295-12.

4.
Stem Cell Res ; 49: 102038, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33068890

RESUMO

Autism is a heterogeneous neurodevelopmental disorder defined by deficits in socialization, communication, and patterns of behavior. Using stem cells to model brain disordersmay yield new understanding about the underlying neuropathological processes and could prove essential for drug development. We present here a newhuman inducedpluripotentstem cell (iPSC) line (SDUKIi004-A) generated from skin fibroblasts derived from a 21-year old male patient diagnosed with Pervasive DevelopmentalDisorder-Not Otherwise Specified (PDD-NOS)("FYNEN-cohort"). Reprogramming of the fibroblasts was accomplished using integration-free episomal plasmids. Characterization validated the expression of pluripotency markers, differentiation into the three germ layers, and absence of chromosomal abnormalities.

5.
NPJ Breast Cancer ; 6: 44, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32964118

RESUMO

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 3.1 × 10-9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

6.
Netw Syst Med ; 3(1): 122-129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32954379

RESUMO

Introduction: Multiple sclerosis (MS) is a chronic disorder of the central nervous system with an untreatable late progressive phase. Molecular maps of different stages of brain lesion evolution in patients with progressive multiple sclerosis (PMS) are missing but critical for understanding disease development and to identify novel targets to halt progression. Materials and Methods: The MS Atlas database comprises comprehensive high-quality transcriptomic profiles of 98 white matter (WM) brain samples of different lesion types (normal-appearing WM [NAWM], active, chronic active, inactive, remyelinating) from ten progressive MS patients and 25 WM areas from five non-neurological diseased cases. Results: We introduce the first MS brain lesion atlas (msatlas.dk), developed to address the current challenges of understanding mechanisms driving the fate on a lesion basis. The MS Atlas gives means for testing research hypotheses, validating biomarkers and drug targets. It comes with a user-friendly web interface, and it fosters bioinformatic methods for de novo network enrichment to extract mechanistic markers for specific lesion types and pathway-based lesion type comparison. We describe examples of how the MS Atlas can be used to extract systems medicine signatures and demonstrate the interface of MS Atlas. Conclusion: This compendium of mechanistic PMS WM lesion profiles is an invaluable resource to fuel future MS research and a new basis for treatment development.

7.
Stem Cell Res ; 48: 101974, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32916638

RESUMO

Autism spectrum disorder is a heterogenous neurodevelopmental disorder. The patients experience challenges in social interaction and communication skills as well as restricted and/or repetitive behaviors. To understand the molecular mechanisms underlying developmental brain disorders, patient-derived cellular models represent a useful tool. We have generated a human induced pluripotent stem cell line (SDUKIi003-A) from skin fibroblasts derived from a 20-year old male patient diagnosed with Asperger syndrome ("FYNEN-cohort" of Southern Denmark). The reprogramming of the fibroblasts was accomplished using integration-free episomal plasmids. Characterization validated the expression of pluripotency markers, differentiation into the three germ layers, and absence of chromosomal abnormalities.

8.
Surg Oncol ; 35: 71-78, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32846268

RESUMO

Surgical stress is followed by oxidative stress, where reactive oxygene species may act as regulators of pathways related to cancer cell survival and metastatic ability. Furthermore, reactive oxygene species may cause DNA and RNA damage. The aim of this study was to examine whether laparoscopic colon cancer surgery causes oxidative stress and dysregulation of related pathways. METHODS: Patients undergoing elective laparoscopic surgery for colon cancer were included. Blood and urine samples were drawn on the day prior to surgery and on day 1 and 10 after surgery. RESULTS: Twenty-six patients were included. Out of 140 genes previously identified as sensitive to regulation by reactive oxygene species, 46 were significantly differentially expressed on day 1 after surgery (FDR < 0.05). Upregulated genes were related to cellular immune suppression, proliferation, migration and epithelial to mesenchymal transition. Downregulated genes were related to IFN pathways and cytotoxic immunological reactions. Genes related to DNA repair were primarily downregulated on day one after surgery, and urinary excretion of 8oxdG was decreased on day two after (p = 0.004), and increased on day 10 after surgery (p = 0.01). CONCLUSION: Laparoscopic colon cancer surgery causes oxidative stress, and impaired DNA repair. Gene expression profiling indicates that reactive oxygen species may act as regulators of pathways related to increased risk of metastasis and cellular immune suppression after surgery. Measures of intracellular oxidative stress, indicates impaired DNA repair on day two after surgery, and sustained oxidative stress on day 10 after surgery.

9.
Mol Genet Genomic Med ; 8(10): e1452, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32812400

RESUMO

BACKGROUND: Alport syndrome is a progressive hereditary kidney disease clinically presenting with haematuria, proteinuria, and early onset end-stage renal disease, and often accompanied by hearing loss and ocular abnormalities. The inheritance is X-linked in the majority of families and caused by sequence variants in the COL4A5 gene encoding the α5-chain of type-IV collagen. The proportion of de novo COL4A5 sequence variants in X-linked Alport syndrome has been reported between 12 and 15% in previous studies. METHODS: In the present study we have systematically investigated the mosaic status of asymptomatic parents of six patients with X-linked Alport syndrome using next-generation sequencing of DNA extracted from different tissues. The deleterious COL4A5 sequence variants in these patients were previously assumed to be de novo, based on Sanger sequencing of the parents. RESULTS: A low-grade (1%) parental mosaicism was detected in only one out of six families (17%). In addition, in one out of six families (17%), we found that the mutational event probably occurred postzygotic. CONCLUSION: These findings highlight the importance of testing for mosaicism in unaffected parents of patients with sequence variants considered to be de novo, as it may have implications for the recurrence risk and thereby for the genetic counseling of the family.

11.
Stem Cell Res ; 46: 101834, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32447258

RESUMO

Autism spectrum disorders are characterized by impaired social interaction and communication as well as restricted and repetitive interests and behavior. Increasing evidence points to an early-stage disruption of brain development. A human-induced pluripotent stem cell line (SDUKIi002-A) was created from skin fibroblasts from a 22-year old autistic male identified in the "FYNEN-cohort" of Southern Denmark. Reprogramming of the fibroblasts was performed using integration-free episomal plasmids. Further characterization confirmed the expression of pluripotency markers, differentiation into the three germ layers, absence of chromosomal abnormalities, and mycoplasma infection.

12.
Epilepsia ; 61(6): 1142-1155, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32452540

RESUMO

OBJECTIVE: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. METHODS: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. RESULTS: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. SIGNIFICANCE: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.


Assuntos
Variação Genética/genética , Hérnia Diafragmática/diagnóstico por imagem , Hérnia Diafragmática/genética , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/genética , Proteínas de Membrana/genética , Adulto , Sequência de Aminoácidos , Criança , Estudos de Coortes , Eletroencefalografia/métodos , Facies , Hérnia Diafragmática/fisiopatologia , Humanos , Recém-Nascido , Deformidades Congênitas dos Membros/fisiopatologia , Imagem por Ressonância Magnética/métodos , Masculino
13.
Exp Hematol ; 84: 7-18.e12, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32173361

RESUMO

Mantle cell lymphoma (MCL) is a tumor with a poor prognosis. A few studies have examined the molecular landscape by next-generation sequencing and provided valuable insights into recurrent lesions driving this heterogeneous cancer. However, none has attempted to cross-link the individual genomic and transcriptomic profiles in sorted MCL cells to perform individual molecular characterizations of the lymphomas. Such approaches are relevant as MCL is heterogenous by nature, and thorough molecular diagnostics may potentially benefit the patient with more focused treatment options. In the work described here, we used sorted lymphoma cells from four patients at diagnosis and relapse by intersecting the coding DNA and mRNA. Even though only a few patients were included, this method enabled us to pinpoint a specific set of expressed somatic mutations, to present an overall expression profile different from the normal B cell counterparts, and to track molecular aberrations from diagnosis to relapse. Changes in single-nucleotide coding variants, subtle clonal changes in large-copy-number alterations, subclonal involvement, and changes in expression levels in the clinical course provided detailed information on each of the individual malignancies. In addition to mutations in known genes (e.g., TP53, CCND1, NOTCH1, ATM), we identified others, not linked to MCL, such as a nonsense mutation in SPEN and an MYD88 missense mutation in one patient, which along with copy number alterations exhibited a molecular resemblance to splenic marginal zone lymphoma. The detailed exonic and transcriptomic portraits of the individual MCL patients obtained by the methodology presented here could help in diagnostics, surveillance, and potentially more precise usage of therapeutic drugs by efficient screening of biomarkers.


Assuntos
Linfócitos B , Citometria de Fluxo , Linfoma de Célula do Manto , Mutação , Proteínas de Neoplasias , Adulto , Linfócitos B/metabolismo , Linfócitos B/patologia , Análise Mutacional de DNA , Perfilação da Expressão Gênica , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética
14.
Acta Neuropathol Commun ; 8(1): 2, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915070

RESUMO

There is great interest in understanding how the central nervous system (CNS) communicates with the immune system for recruitment of protective responses. Infiltrating phagocytic monocytes and granulocytes are implicated in neuroinflammation in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). To investigate how CNS endogenous signals can be harnessed to promote anti-inflammatory programs, we have used a particulate Toll-like receptor 9 and nucleotide-oligomerization domain 2 bispecific innate ligand (MIS416), to address whether its phagocytosis within the CNS recruits protective myeloid cells. We find that MIS416 injected intrathecally into the cerebrospinal fluid via the cisterna magna induced a local chemokine response that recruited blood-derived monocytes and neutrophils to the CNS. These cells phagocytosed MIS416. The increase in EAE severity normally seen from time of onset did not occur in mice receiving MIS416. This suppression of disease symptoms was dependent on expression of the type I interferon receptor (IFNAR). Transfer of intrathecal MIS416-induced neutrophils suppressed EAE in recipient mice, while monocytes did not transfer protection. MIS416-induced neutrophils showed increased IL-10 expression that was IFNAR1-driven. In contrast to intrathecal administration, intravenous administration of MIS416 led to monocyte but not neutrophil infiltration to the CNS. We thus identify a CNS-intrinsic and -specific phagocytosis-induced recruitment of anti-inflammatory neutrophils that contribute to CNS homeostasis and may have therapeutic potential.

15.
Acta Neuropathol Commun ; 7(1): 205, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829262

RESUMO

To identify pathogenetic markers and potential drivers of different lesion types in the white matter (WM) of patients with progressive multiple sclerosis (PMS), we sequenced RNA from 73 different WM areas. Compared to 25 WM controls, 6713 out of 18,609 genes were significantly differentially expressed in MS tissues (FDR < 0.05). A computational systems medicine analysis was performed to describe the MS lesion endophenotypes. The cellular source of specific molecules was examined by RNAscope, immunohistochemistry, and immunofluorescence. To examine common lesion specific mechanisms, we performed de novo network enrichment based on shared differentially expressed genes (DEGs), and found TGFß-R2 as a central hub. RNAscope revealed astrocytes as the cellular source of TGFß-R2 in remyelinating lesions. Since lesion-specific unique DEGs were more common than shared signatures, we examined lesion-specific pathways and de novo networks enriched with unique DEGs. Such network analysis indicated classic inflammatory responses in active lesions; catabolic and heat shock protein responses in inactive lesions; neuronal/axonal specific processes in chronic active lesions. In remyelinating lesions, de novo analyses identified axonal transport responses and adaptive immune markers, which was also supported by the most heterogeneous immunoglobulin gene expression. The signature of the normal-appearing white matter (NAWM) was more similar to control WM than to lesions: only 465 DEGs differentiated NAWM from controls, and 16 were unique. The upregulated marker CD26/DPP4 was expressed by microglia in the NAWM but by mononuclear cells in active lesions, which may indicate a special subset of microglia before the lesion develops, but also emphasizes that omics related to MS lesions should be interpreted in the context of different lesions types. While chronic active lesions were the most distinct from control WM based on the highest number of unique DEGs (n = 2213), remyelinating lesions had the highest gene expression levels, and the most different molecular map from chronic active lesions. This may suggest that these two lesion types represent two ends of the spectrum of lesion evolution in PMS. The profound changes in chronic active lesions, the predominance of synaptic/neural/axonal signatures coupled with minor inflammation may indicate end-stage irreversible molecular events responsible for this less treatable phase.


Assuntos
Encéfalo/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Crônica Progressiva/patologia , Análise de Sequência de RNA/métodos , Substância Branca/patologia , Perfilação da Expressão Gênica/métodos , Humanos , Receptor do Fator de Crescimento Transformador beta Tipo II/genética
16.
Haematologica ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31879329

RESUMO

We report the final two-year end-of-study results from the first clinical trial investigating combination treatment with ruxolitinib and low-dose pegylated interferon-α2 (PEG-IFNα2). The study included 32 patients with polycythemia vera (PV) and 18 with primary- or secondary myelofibrosis (MF); 46 patients were previously intolerant or refractory to PEG-IFNα2. The primary outcome was efficacy, based on hematological parameters, quality of life measurements, and JAK2 V617F allele burden. We used the 2013 ELN and IWG-MRT response criteria, including response in symptoms, splenomegaly, peripheral blood counts, and bone marrow. Of 32 patients with PV, 10 (31%) achieved remission; 3 (9%) achieved complete remission. Of 18 patients with MF, 8 (44%) achieved remission; 5 (28%) achieved complete remission. The cumulative incidence of peripheral blood count remission was 0.85 and 0.75 for patients with PV and MF, respectively. MPN-SAF total symptom score decreased from 22 (95%CI, 16-29) at baseline to 15 (95%CI, 10-22) after two years. The median JAK2 V617F allele burden de-creased from 47% (95%CI, 33-61%) to 12% (95%CI, 6-22%), and 41% of patients achieved a molecular response. The drop-out was 6% for PV patients and 32% for MF patients. Of 36 patients previously in-tolerant to PEG-IFNα2, 31 (86%) completed the study, and 24 (67%) of these received PEG-IFNα2 throughout the study. In conclusion, combination treatment improved cell counts, reduced bone marrow cellularity and fibrosis, decreased JAK2 V617F burden, and reduced symptom burden with acceptable toxicity in several patients with polycythemia vera or myelofibrosis. #EudraCT2013-003295-12.

17.
Cell Death Dis ; 10(11): 841, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31695025

RESUMO

The senescence response to oncogenes is believed to be a barrier to oncogenic transformation in premalignant lesions, and describing the mechanisms by which tumor cells evade this response is important for early diagnosis and treatment. The male germ cell-associated protein SSX2 is ectopically expressed in many types of cancer and is functionally involved in regulating chromatin structure and supporting cell proliferation. Similar to many well-characterized oncogenes, SSX2 has the ability to induce senescence in cells. In this study, we performed a functional genetic screen to identify proteins implicated in SSX2-induced senescence and identified several subunits of the Mediator complex, which is central in regulating RNA polymerase-mediated transcription. Further experiments showed that reduced levels of MED1, MED4, and MED14 perturbed the development of senescence in SSX2-expressing cells. In contrast, knockdown of MED1 did not prevent development of B-Raf- and Epirubicin-induced senescence, suggesting that Mediator may be specifically linked to the cellular functions of SSX2 that may lead to development of senescence or be central in a SSX2-specific senescence response. Indeed, immunostaining of melanoma tumors, which often express SSX proteins, exhibited altered levels of MED1 compared to benign nevi. Similarly, RNA-seq analysis suggested that MED1, MED4, and MED14 were downregulated in some tumors, while upregulated in others. In conclusion, our study reveals the Mediator complex as essential for SSX2-induced senescence and suggests that changes in Mediator activity could be instrumental for tumorigenesis.


Assuntos
Senescência Celular/genética , Melanoma/genética , Proteínas de Neoplasias/genética , Proteínas Repressoras/genética , Linhagem Celular Tumoral , Núcleo Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/genética , Melanoma/patologia , Proteínas Quinases/genética , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Fatores de Transcrição/genética , Transcrição Genética , Ativação Transcricional/genética
18.
Neurobiol Aging ; 84: 141-147, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31585296

RESUMO

Only few studies have investigated the genomewide transcriptome of normative cognitive aging. We therefore aimed at investigating blood gene expression patterns associated with cognitive aging using a population-based sample of 235 middle-aged monozygotic twin pairs with longitudinal data on cognitive function. This unique setup enabled examination of gene expression differences associated with individual and intrapair differences in cognitive level and change while controlling for underlying genetic variation and shared early environment. Overall, increased expression of several gene sets was found to strongly correlate with a lower cognitive level and cognitive decline. The most significantly correlated gene sets were related to protein metabolism, translation, RNA metabolism, infectious disease, and the immune system, which are all processes previously linked to transcription signatures of pathological and normal brain aging, and aging in blood. The results of our study thus suggest that gene expression patterns of cognitive level and decline in our sample mirror those seen in cognitively impaired individuals, which could point toward a more generic response to cognitive aging and aging in general.


Assuntos
Cognição , Envelhecimento Cognitivo , Disfunção Cognitiva/genética , Expressão Gênica , Gêmeos Monozigóticos/genética , Humanos , Pessoa de Meia-Idade
19.
Acta Neuropathol Commun ; 7(1): 136, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434573

RESUMO

The authors have retracted this article [1] because a line was omitted from the data sheet; this was due to a bug in the analysis scripts.

20.
Fam Cancer ; 18(4): 381-388, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31435815

RESUMO

The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) calculates the probability that a woman carries a pathogenic variant in BRCA1 or BRCA2 based on her pedigree and the population frequencies of pathogenic alleles of BRCA1 (0.0006394) and BRCA2 (0.00102) in the United Kingdom (UK). BOADICEA allows the clinician to define the population frequencies of pathogenic alleles of BRCA1 and BRCA2 for other populations but only includes preset values for the Ashkenazy Jewish and Icelandic populations. Among 173 early-onset breast cancer pedigrees in Denmark, BOADICEA discriminated well between carriers and non-carriers of pathogenic variants (area under the receiver operating characteristics curve: 0.81; 95% CI 0.74-0.86) but underestimated the frequency of carriers of pathogenic variants in BRCA1 or BRCA2 as measured by the observed-to-expected ratio (O/E 1.83; 95% CI 1.18-2.84). This reflects findings from older studies of BOADICEA in UK, German, Italian, and Chinese populations, all accounting for the different calibration for different carrier probabilities. To improve the performance of BOADICEA for non-UK populations, we developed a method to derive population frequencies of pathogenic alleles of BRCA1 and BRCA2. Compared to the UK population frequencies, we estimated the Danish population frequencies of pathogenic alleles to be higher for BRCA1 (0.0015; 95% CI 0.00064-0.0034) and lower for BRCA2 (0.00052; 95% CI 0.00018-0.0017) after adjusting for the different calibration of BOADICEA for different carrier probabilities. Incorporating additional population frequencies into BOADICEA could improve its performance for non-UK populations.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Frequência do Gene , Modelos Genéticos , Adulto , Idade de Início , Algoritmos , Neoplasias da Mama/epidemiologia , Calibragem , Dinamarca , Feminino , Heterozigoto , Humanos , Incidência , Linhagem , Reino Unido/epidemiologia
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