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1.
Nature ; 589(7841): 246-250, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33442040

RESUMO

Autism spectrum disorder (ASD) is an early-onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviours1,2. Family studies demonstrate that ASD has a substantial genetic basis with contributions both from inherited and de novo variants3,4. It has been estimated that de novo mutations may contribute to 30% of all simplex cases, in which only a single child is affected per family5. Tandem repeats (TRs), defined here as sequences of 1 to 20 base pairs in size repeated consecutively, comprise one of the major sources of de novo mutations in humans6. TR expansions are implicated in dozens of neurological and psychiatric disorders7. Yet, de novo TR mutations have not been characterized on a genome-wide scale, and their contribution to ASD remains unexplored. Here we develop new bioinformatics methods for identifying and prioritizing de novo TR mutations from sequencing data and perform a genome-wide characterization of de novo TR mutations in ASD-affected probands and unaffected siblings. We infer specific mutation events and their precise changes in repeat number, and primarily focus on more prevalent stepwise copy number changes rather than large expansions. Our results demonstrate a significant genome-wide excess of TR mutations in ASD probands. Mutations in probands tend to be larger, enriched in fetal brain regulatory regions, and are predicted to be more evolutionarily deleterious. Overall, our results highlight the importance of considering repeat variants in future studies of de novo mutations.


Assuntos
Transtorno do Espectro Autista/genética , Expansão das Repetições de DNA/genética , Predisposição Genética para Doença , Adolescente , Adulto , Transtorno do Espectro Autista/patologia , Encéfalo/metabolismo , Criança , Variações do Número de Cópias de DNA/genética , Feminino , Feto/metabolismo , Mutação em Linhagem Germinativa/genética , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Idade Paterna , Adulto Jovem
2.
Nat Rev Cancer ; 21(2): 122-137, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33328584

RESUMO

Although much work has focused on the elucidation of somatic alterations that drive the development of acute leukaemias and other haematopoietic diseases, it has become increasingly recognized that germline mutations are common in many of these neoplasms. In this Review, we highlight the different genetic pathways impacted by germline mutations that can ultimately lead to the development of familial and sporadic haematological malignancies, including acute lymphoblastic leukaemia, acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Many of the genes disrupted by somatic mutations in these diseases (for example, TP53, RUNX1, IKZF1 and ETV6) are the same as those that harbour germline mutations in children and adolescents who develop these malignancies. Moreover, the presumption that familial leukaemias only present in childhood is no longer true, in large part due to the numerous studies demonstrating germline DDX41 mutations in adults with MDS and AML. Lastly, we highlight how different cooperating events can influence the ultimate phenotype in these different familial leukaemia syndromes.


Assuntos
Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Progressão da Doença , Humanos , Fenótipo
3.
Proc Natl Acad Sci U S A ; 117(52): 33466-33473, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318203

RESUMO

Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM +/-) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM +/- mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM +/- mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM +/- mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm +/- mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm +/- mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1ß, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm +/- mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM +/- mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.


Assuntos
Asbestose/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Mesotelioma/genética , RecQ Helicases/genética , Adulto , Idoso , Animais , Asbesto Crocidolita , Família , Feminino , Instabilidade Genômica , Heterozigoto , Humanos , Incidência , Inflamação/patologia , Masculino , Camundongos , Pessoa de Meia-Idade
4.
Dig. liver dis ; 55(11): 1282-1293, Nov. 01, 2020.
Artigo em Inglês | BIGG - guias GRADE | ID: biblio-1128257

RESUMO

Cholangiocarcinoma (CCA) is the second most common primary liver cancer, characterized by a poor prognosis and resistance to chemotherapeutics. The progressive increase in CCA incidence and mortality registered worldwide in the last two decades and the need to clarify various aspects of clinical management have prompted the Italian Association for the Study of the Liver (AISF) to commission the drafting of dedicated guidelines in collaboration with a group of Italian scientific societies. These guidelines have been formulated in accordance with the Italian National Institute of Health indications and developed by following the GRADE method and related advancements.


Assuntos
Humanos , Colangiocarcinoma/classificação , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/prevenção & controle , Preparações Farmacêuticas , Mutação em Linhagem Germinativa/genética
5.
Eur J Endocrinol ; 183(6): K7-K12, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33105102

RESUMO

A monoallelic germline alteration of ARMC5 causes primary bilateral macronodular adrenal hyperplasia (PBMAH) with Cushing's syndrome via its subsequent somatic alteration on the other allele as the second hit. PBMAH is sometimes complicated with meningioma. Dependency of such a multi-organ disease on the second hit mechanism was reported before, but this finding has not been confirmed yet. We describe a case of a 65-year-old female with PBMAH, carrying a heterozygous germline alteration of ARMC5, p.R267*, complicated with meningioma associated with somatic loss of heterozygosity (LOH) of the unaffected allele. Pathogenic alterations of ARMC5 may also contribute to the development of meningioma by the two-hit mechanism.


Assuntos
Proteínas do Domínio Armadillo/genética , Síndrome de Cushing/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Idoso , Alelos , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Perda de Heterozigosidade/genética
6.
Ginebra; European Society for Medical Oncology; 2020; Sept. 28, 2020. 17 p.
Monografia em Inglês | BIGG - guias GRADE | ID: biblio-1127783

RESUMO

The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group identified that there is currently uncertainty within the oncology community surrounding the different methods for HRD testing in HGSC. To address this, a collaborative project was launched with a number of clinicians and scientists with expertise in the fields of PARPi clinical trials, cancer genomics and DNA repair. The group defined three main aims for the project: (i) Define the term 'HRD test' and recommend how an HRD test's clinical validity is currently best assessed in the context of HGSC, (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests, and (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC.


Assuntos
Humanos , Feminino , Biomarcadores , Neoplasias dos Genitais Femininos/diagnóstico , Mutação em Linhagem Germinativa/genética , Recombinação Homóloga/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
7.
Lancet Oncol ; 21(9): 1155-1164, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32771088

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. METHODS: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004. FINDINGS: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3-90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks. INTERPRETATION: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Adulto Jovem
8.
Tumori ; 106(5): 346-355, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32811340

RESUMO

Hereditary diffuse gastric cancer (HDGC), comprising 1%-3% of gastric malignances, has been associated with CDH1 variants. Accumulating evidence has demonstrated more than 100 germline CDH1 variant types. E-cadherin encoded by the CDH1 gene serves as a tumor suppressor protein. CDH1 promoter hypermethylation and other molecular mechanisms resulting in E-cadherin dysfunction are involved in the tumorigenesis of HDGC. Histopathology exhibits characteristic signet ring cells, and immunohistochemical staining may show negativity for E-cadherin and other signaling proteins. Early HDGC is difficult to detect by endoscopy due to the development of lesions beneath the mucosa. Prophylactic gastrectomy is the most recommended treatment for pathogenic CDH1 variant carriers. Recent studies have promoted the progression of promising molecular-targeted therapies and management strategies. This review summarizes recent advances in CDH1 variant types, tumorigenesis mechanisms, diagnosis, and therapy, as well as clinical implications for future gene therapies.


Assuntos
Antígenos CD/genética , Caderinas/genética , Carcinogênese/genética , Predisposição Genética para Doença , Neoplasias Gástricas/genética , Gastrectomia , Mutação em Linhagem Germinativa/genética , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/terapia
9.
Anticancer Res ; 40(8): 4567-4570, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727787

RESUMO

BACKGROUND/AIM: Historically, breast cancer has been treated according to an evaluation of biomarkers, such as the estrogen receptor and HER2 status. Recently, molecular profiling has been used to detect driver mutations and select anti-cancer treatment strategies. In addition to detecting pathogenic mutations, the total mutation count (tumor mutation burden) has been considered as another biomarker. MATERIALS AND METHODS: We performed molecular profiling of 143 breast cancer tissues obtained from resected tissues via surgical operation. RESULTS: Suspected germline mutations were detected in 10% of the patients with a higher somatic mutation ratio. CONCLUSION: As hypermutated breast cancers are more likely to benefit from certain anti-cancer treatment strategies, molecular profiling can be used as a biomarker.


Assuntos
Neoplasias da Mama/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptores Estrogênicos/genética
11.
Sci Rep ; 10(1): 12223, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699327

RESUMO

Whether telomere attrition reducing proliferative reserve in blood-cell progenitors is causal has important public-health implications. Mendelian randomization (MR) is an analytic technique using germline genetic variants as instrumental variables. If certain assumptions are met, estimates from MR should be free from most environmental sources of confounding and reverse causation. Here, two-sample MR is performed to test whether longer telomeres cause changes to hematological traits. Summary statistics for genetic variants strongly associated with telomere length were extracted from a genome-wide association (GWA) study for telomere length in individuals of European ancestry (n = 9190) and from GWA studies of blood-cell traits, also in those of European ancestry (n ~ 173,000 participants). A standard deviation increase in genetically influenced telomere length increased red blood cell and white blood cell counts, decreased mean corpuscular hemoglobinand mean cell volume, and had no observable impact on mean corpuscular hemoglobin concentration, red cell distribution width, hematocrit, or hemoglobin. Sensitivity tests for pleiotropic distortion were mostly inconsistent with glaring violations to the MR assumptions. Similar to germline mutations in telomere biology genes leading to bone-marrow failure, these data provide evidence that genetically influenced common variation in telomere length impacts hematologic traits in the population.


Assuntos
Células Sanguíneas/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Telômero/genética , Telômero/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla/métodos , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Homeostase do Telômero/genética , Adulto Jovem
12.
BMC Bioinformatics ; 21(1): 227, 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32498674

RESUMO

BACKGROUND: Mutations arise in the human genome in two major settings: the germline and the soma. These settings involve different inheritance patterns, time scales, chromatin structures, and environmental exposures, all of which impact the resulting distribution of substitutions. Nonetheless, many of the same single nucleotide variants (SNVs) are shared between germline and somatic mutation databases, such as between the gnomAD database of 120,000 germline exomes and the TCGA database of 10,000 somatic exomes. Here, we sought to explain this overlap. RESULTS: After strict filtering to exclude common germline polymorphisms and sites with poor coverage or mappability, we found 336,987 variants shared between the somatic and germline databases. A uniform statistical model explains 34% of these shared variants; a model that incorporates the varying mutation rates of the basic mutation types explains another 50% of shared variants; and a model that includes extended nucleotide contexts (e.g. surrounding 3 bases on either side) explains an additional 4% of shared variants. Analysis of read depth finds mixed evidence that up to 4% of the shared variants may represent germline variants leaked into somatic call sets. 9% of the shared variants are not explained by any model. Sequencing errors and convergent evolution did not account for these. We surveyed other factors as well: Cancers driven by endogenous mutational processes share a greater fraction of variants with the germline, and recently derived germline variants were more likely to be somatically shared than were ancient germline ones. CONCLUSIONS: Overall, we find that shared variants largely represent bona fide biological occurrences of the same variant in the germline and somatic setting and arise primarily because DNA has some of the same basic chemical vulnerabilities in either setting. Moreover, we find mixed evidence that somatic call-sets leak appreciable numbers of germline variants, which is relevant to genomic privacy regulations. In future studies, the similar chemical vulnerability of DNA between the somatic and germline settings might be used to help identify disease-related genes by guiding the development of background-mutation models that are informed by both somatic and germline patterns of variation.


Assuntos
Bases de Dados Genéticas , Mutação em Linhagem Germinativa/genética , Alelos , Evolução Biológica , Epigênese Genética , Frequência do Gene/genética , Humanos , Taxa de Mutação , Neoplasias/genética , Nucleotídeos/genética , Filogenia , Análise de Sequência de DNA
13.
Nat Commun ; 11(1): 3096, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555180

RESUMO

Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Variações do Número de Cópias de DNA/genética , Epigenômica , Mutação em Linhagem Germinativa/genética , Humanos , Filogenia
14.
Leukemia ; 34(10): 2673-2687, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32555368

RESUMO

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.


Assuntos
Deficiência de GATA2/genética , Fator de Transcrição GATA2/deficiência , Fator de Transcrição GATA2/genética , RNA/genética , Mutação Silenciosa/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Síndromes Mielodisplásicas/genética , Fenótipo , Adulto Jovem
15.
Jpn J Clin Oncol ; 50(10): 1214-1217, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32577752

RESUMO

Germline mutations of TP53 are responsible for Li-Fraumeni syndrome in its 60-80%. We found a novel germline mutation, TP53: c.997del:p.R333Vfs*12 (NM_000546.6, GRCh, 17:7670713..7670713). The proband is a 40-year-old female, who was suffered from osteosarcoma in her right forearm at her age of 11. She was also suffered from lung adenocarcinoma in her right upper lobe and bone metastasis in her right scapula at her age of 37. She was treated with gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) because of EGFR mutation (L747-S752 del). Her bone metastasis became resistant after 1-year treatment. Bone metastasis had an additional EGFR mutation (T790M). The secondary treatment with osimertinib, an another EGFR-TKI, can successfully control the tumors for over 2 years. This TP53 mutation (R333Vfs*12) was first found in lung adenocarcinomas. The therapeutic effect of osimertinib for this triple mutant lung adenocarcinoma is better than the previous report.


Assuntos
Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/genética , Mutação em Linhagem Germinativa/genética , Síndrome de Li-Fraumeni/complicações , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/genética , Proteína Supressora de Tumor p53/genética , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Adulto , Compostos de Anilina/uso terapêutico , Neoplasias Ósseas/secundário , Feminino , Gefitinibe/uso terapêutico , Humanos , Síndrome de Li-Fraumeni/tratamento farmacológico , Síndrome de Li-Fraumeni/genética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Linhagem , Inibidores de Proteínas Quinases/uso terapêutico
16.
Nat Commun ; 11(1): 2438, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415133

RESUMO

Cancers harbor many somatic mutations and germline variants, we hypothesized that the combined effect of germline variants that alter the structure, expression, or function of protein-coding regions of cancer-biology related genes (gHFI) determines which and how many somatic mutations (sM) must occur for malignant transformation. We show that gHFI and sM affect overlapping genes and the average number of gHFI in cancer hallmark genes is higher in patients who develop cancer at a younger age (r = -0.77, P = 0.0051), while the average number of sM increases in increasing age groups (r = 0.92, P = 0.000073). A strong negative correlation exists between average gHFI and average sM burden in increasing age groups (r = -0.70, P = 0.017). In early-onset cancers, the larger gHFI burden in cancer genes suggests a greater contribution of germline alterations to the transformation process while late-onset cancers are more driven by somatic mutations.


Assuntos
Mutação em Linhagem Germinativa/genética , Neoplasias/diagnóstico , Neoplasias/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Fases de Leitura Aberta/genética , Transdução de Sinais/genética
17.
Cytogenet Genome Res ; 160(4): 167-176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32396893

RESUMO

During gametogenesis, the human genome can acquire various de novo rearrangements. Most constitutional genomic rearrangements are created through 1 of the 4 well-known mechanisms, i.e., nonallelic homologous recombination, erroneous repair after double-strand DNA breaks, replication errors, and retrotransposition. However, recent studies have identified 2 types of extremely complex rearrangements that cannot be simply explained by these mechanisms. The first type consists of chaotic structural changes in 1 or a few chromosomes that result from "chromoanagenesis (an umbrella term that covers chromothripsis, chromoanasynthesis, and chromoplexy)." The other type is large independent rearrangements in multiple chromosomes indicative of "transient multifocal genomic crisis." Germline chromoanagenesis (chromothripsis) likely occurs predominantly during spermatogenesis or postzygotic embryogenesis, while multifocal genomic crisis appears to be limited to a specific time window during oogenesis and early embryogenesis or during spermatogenesis. This review article introduces the current understanding of the molecular basis of de novo rearrangements in the germline.


Assuntos
Cromotripsia , Mutação em Linhagem Germinativa/genética , Recombinação Genética , Desenvolvimento Embrionário/genética , Humanos , Oogênese/genética , Espermatogênese/genética
18.
BMC Med Genet ; 21(1): 92, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375678

RESUMO

BACKGROUND: Pediatric high-grade gliomas (pHGGs) are incurable malignant brain cancers. Clear somatic genetic drivers are difficult to identify in the majority of cases. We hypothesized that this may be due to the existence of germline variants that influence tumor etiology and/or progression and are filtered out using traditional pipelines for somatic mutation calling. METHODS: In this study, we analyzed whole-genome sequencing (WGS) datasets of matched germlines and tumor tissues to identify recurrent germline variants in pHGG patients. RESULTS: We identified two structural variants that were highly recurrent in a discovery cohort of 8 pHGG patients. One was a ~ 40 kb deletion immediately upstream of the NEGR1 locus and predicted to remove the promoter region of this gene. This copy number variant (CNV) was present in all patients in our discovery cohort (n = 8) and in 86.3% of patients in our validation cohort (n = 73 cases). We also identified a second recurrent deletion 55.7 kb in size affecting the BTNL3 and BTNL8 loci. This BTNL3-8 deletion was observed in 62.5% patients in our discovery cohort, and in 17.8% of the patients in the validation cohort. Our single-cell RNA sequencing (scRNA-seq) data showed that both deletions result in disruption of transcription of the affected genes. However, analysis of genomic information from multiple non-cancer cohorts showed that both the NEGR1 promoter deletion and the BTNL3-8 deletion were CNVs occurring at high frequencies in the general population. Intriguingly, the upstream NEGR1 CNV deletion was homozygous in ~ 40% of individuals in the non-cancer population. This finding was immediately relevant because the affected genes have important physiological functions, and our analyses showed that NEGR1 expression levels have prognostic value for pHGG patient survival. We also found that these deletions occurred at different frequencies among different ethnic groups. CONCLUSIONS: Our study highlights the need to integrate cancer genomic analyses and genomic data from large control populations. Failure to do so may lead to spurious association of genes with cancer etiology. Importantly, our results showcase the need for careful evaluation of differences in the frequency of genetic variants among different ethnic groups.


Assuntos
Butirofilinas/genética , Moléculas de Adesão Celular Neuronais/genética , Predisposição Genética para Doença , Glioma/genética , Variações do Número de Cópias de DNA/genética , Bases de Dados Genéticas , Intervalo Livre de Doença , Feminino , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa/genética , Glioma/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pediatria , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
19.
Nat Med ; 26(7): 1048-1053, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32451497

RESUMO

Common germline variants of the APOE gene are major risk modifiers of neurodegenerative and atherosclerotic diseases1-3, but their effect on cancer outcome is poorly defined. Here we report that, in a reversal of their effect on Alzheimer's disease, the APOE4 and APOE2 variants confer favorable and poor outcomes in melanoma, respectively. Mice expressing the human APOE4 allele exhibited reduced melanoma progression and metastasis relative to APOE2 mice. APOE4 mice exhibited enhanced anti-tumor immune activation relative to APOE2 mice, and T cell depletion experiments showed that the effect of APOE genotype on melanoma progression was mediated by altered anti-tumor immunity. Consistently, patients with melanoma carrying the APOE4 variant experienced improved survival in comparison to carriers of APOE2. Notably, APOE4 mice also showed improved outcomes under PD1 immune checkpoint blockade relative to APOE2 mice, and patients carrying APOE4 experienced improved anti-PD1 immunotherapy survival after progression on frontline regimens. Finally, enhancing APOE expression via pharmacologic activation of liver X receptors, previously shown to boost anti-tumor immunity4, exhibited therapeutic efficacy in APOE4 mice but not in APOE2 mice. These findings demonstrate that pre-existing hereditary genetics can impact progression and survival outcomes of a future malignancy and warrant prospective investigation of APOE genotype as a biomarker for melanoma outcome and therapeutic response.


Assuntos
Apolipoproteína E2/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Melanoma/genética , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Genótipo , Mutação em Linhagem Germinativa/genética , Mutação em Linhagem Germinativa/imunologia , Humanos , Melanoma/imunologia , Melanoma/patologia , Camundongos , Camundongos Transgênicos/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
20.
Neurology ; 94(24): e2521-e2531, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32345730

RESUMO

OBJECTIVE: To investigate the genotype-phenotype correlation between neurofibromatosis 1 (NF1) germline mutations and imaging features of neurofibromas on whole-body MRI (WBMRI) by using radiomics image analysis techniques. MATERIALS AND METHODS: Twenty-nine patients with NF1 who had known germline mutations determined by targeted next-generation sequencing were selected from a previous WBMRI study using coronal short tau inversion recovery sequence. Each tumor was segmented in WBMRI and a set of 59 imaging features was calculated using our in-house volumetric image analysis platform, 3DQI. A radiomics heatmap of 59 imaging features was analyzed to investigate the per-tumor and per-patient associations between the imaging features and mutation domains and mutation types. Linear mixed-effect models and one-way analysis of variance tests were performed to assess the similarity of tumor imaging features within mutation groups, between mutation groups, and between randomly selected groups. RESULTS: A total of 218 neurofibromas (97 discrete neurofibromas and 121 plexiform neurofibromas) were identified in 19 of the 29 patients. The unsupervised hierarchical clustering in heatmap analysis revealed 6 major image feature patterns that were significantly correlated with gene mutation domains and types with strong to very strong associations of genotype-phenotype correlations in both per-tumor and per-patient studies (p < 0.05, Cramer V > 0.5), whereas tumor size and locations showed no correlations with imaging features (p = 0.79 and p = 0.42, respectively). The statistical analyses revealed that the number of significantly different features (SDFs) within mutation groups were significantly lower than those between mutation groups (mutation domains: 10.9 ± 9.5% vs 31.9 ± 23.8% and mutation types: 31.8 ± 30.7% vs 52.6 ± 29.3%). The first and second quartile p values of within-patient groups were more than 2 times higher than those between-patient groups. However, the numbers of SDFs between randomly selected groups were much lower (approximately 5.2%). CONCLUSION: This preliminary study identified the NF1 radiogenomics linkage between NF1 causative mutations and MRI radiomic features, i.e., the correlation between NF1 genotype and imaging phenotype on WBMRI.


Assuntos
Imagem por Ressonância Magnética , Neurofibromatose 1/diagnóstico por imagem , Neurofibromatose 1/genética , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Mutação em Linhagem Germinativa/genética , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Neurofibroma/diagnóstico por imagem , Fenótipo , Imagem Corporal Total
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