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1.
Proc Natl Acad Sci U S A ; 116(35): 17231-17238, 2019 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-31405970

RESUMEN

Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.


Asunto(s)
ADN Antiguo , ADN Mitocondrial/genética , Domesticación , Flujo Génico , Filogenia , Porcinos/genética , Animales , Europa (Continente) , Historia Antigua , Medio Oriente , Pigmentación de la Piel/genética
2.
Int J Cancer ; 141(5): 877-886, 2017 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-28597939

RESUMEN

Precision oncology implies the ability to predict which patients will likely respond to specific cancer therapies based on increasingly accurate, high-resolution molecular diagnostics as well as the functional and mechanistic understanding of individual tumors. While molecular stratification of patients can be achieved through different means, a promising approach is next-generation sequencing of tumor DNA and RNA, which can reveal genomic alterations that have immediate clinical implications. Furthermore, certain genetic alterations are shared across multiple histologic entities, raising the fundamental question of whether tumors should be treated by molecular profile and not tissue of origin. We here describe MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a clinically applicable platform for prospective, biology-driven stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors. We illustrate how a standardized workflow for selection and consenting of patients, sample processing, whole-exome/genome and RNA sequencing, bioinformatic analysis, rigorous validation of potentially actionable findings, and data evaluation by a dedicated molecular tumor board enables categorization of patients into different intervention baskets and formulation of evidence-based recommendations for clinical management. Critical next steps will be to increase the number of patients that can be offered comprehensive molecular analysis through collaborations and partnering, to explore ways in which additional technologies can aid in patient stratification and individualization of treatment, to stimulate clinically guided exploratory research projects, and to gradually move away from assessing the therapeutic activity of targeted interventions on a case-by-case basis toward controlled clinical trials of genomics-guided treatments.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Oncología Médica/métodos , Neoplasias/genética , Medicina de Precisión/métodos , Humanos , Neoplasias/clasificación
3.
Mol Syst Biol ; 12(3): 861, 2016 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-27013061

RESUMEN

Epigenetic mechanisms have emerged as links between prenatal environmental exposure and disease risk later in life. Here, we studied epigenetic changes associated with maternal smoking at base pair resolution by mapping DNA methylation, histone modifications, and transcription in expectant mothers and their newborn children. We found extensive global differential methylation and carefully evaluated these changes to separate environment associated from genotype-related DNA methylation changes. Differential methylation is enriched in enhancer elements and targets in particular "commuting" enhancers having multiple, regulatory interactions with distal genes. Longitudinal whole-genome bisulfite sequencing revealed that DNA methylation changes associated with maternal smoking persist over years of life. Particularly in children prenatal environmental exposure leads to chromatin transitions into a hyperactive state. Combined DNA methylation, histone modification, and gene expression analyses indicate that differential methylation in enhancer regions is more often functionally translated than methylation changes in promoters or non-regulatory elements. Finally, we show that epigenetic deregulation of a commuting enhancer targeting c-Jun N-terminal kinase 2 (JNK2) is linked to impaired lung function in early childhood.


Asunto(s)
Epigénesis Genética , Secuencias Reguladoras de Ácidos Nucleicos , Fumar/genética , Niño , Cromatina/metabolismo , Estudios de Cohortes , Metilación de ADN , Femenino , Histonas/metabolismo , Humanos , Masculino , Proteína Quinasa 9 Activada por Mitógenos/genética , Madres , Fenotipo , Polimorfismo de Nucleótido Simple , Transcripción Genética
4.
Mol Biol Evol ; 30(4): 824-32, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23180578

RESUMEN

Zooarcheological evidence suggests that pigs were domesticated in Southwest Asia ~8,500 BC. They then spread across the Middle and Near East and westward into Europe alongside early agriculturalists. European pigs were either domesticated independently or more likely appeared so as a result of admixture between introduced pigs and European wild boar. As a result, European wild boar mtDNA lineages replaced Near Eastern/Anatolian mtDNA signatures in Europe and subsequently replaced indigenous domestic pig lineages in Anatolia. The specific details of these processes, however, remain unknown. To address questions related to early pig domestication, dispersal, and turnover in the Near East, we analyzed ancient mitochondrial DNA and dental geometric morphometric variation in 393 ancient pig specimens representing 48 archeological sites (from the Pre-Pottery Neolithic to the Medieval period) from Armenia, Cyprus, Georgia, Iran, Syria, and Turkey. Our results reveal the first genetic signatures of early domestic pigs in the Near Eastern Neolithic core zone. We also demonstrate that these early pigs differed genetically from those in western Anatolia that were introduced to Europe during the Neolithic expansion. In addition, we present a significantly more refined chronology for the introduction of European domestic pigs into Asia Minor that took place during the Bronze Age, at least 900 years earlier than previously detected. By the 5th century AD, European signatures completely replaced the endemic lineages possibly coinciding with the widespread demographic and societal changes that occurred during the Anatolian Bronze and Iron Ages.


Asunto(s)
ADN Mitocondrial/genética , Diente Molar/anatomía & histología , Sus scrofa/genética , Distribución Animal , Animales , Animales Domésticos/genética , Asia , Europa (Continente) , Humanos , Filogeografía , Análisis de Secuencia de ADN , Porcinos/genética
5.
Cancer Discov ; 11(11): 2780-2795, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34112699

RESUMEN

The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. SIGNIFICANCE: Rare cancers are difficult to treat; in particular, molecular pathogenesis-oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659.


Asunto(s)
Neoplasias , Transcriptoma , Adulto , Perfilación de la Expresión Génica , Genómica , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Secuenciación del Exoma
6.
Cold Spring Harb Mol Case Stud ; 2(6): a001180, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27900363

RESUMEN

Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision-making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multiagent chemotherapy. Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplified KRAS G12S mutation, compound-heterozygous TP53 mutation/deletion, high mutational load, and focal high-level amplification of Chromosomes 9p (including PDL1 [CD274] and JAK2) and 10p (including GATA3). Integrated analysis of molecular data and histopathology provided a rationale for immune checkpoint inhibitor (ICI) therapy with pembrolizumab, which resulted in rapid clinical improvement and a lasting partial remission. Histopathological analyses ruled out sarcoma and established the diagnosis of a poorly differentiated adenocarcinoma. Although neither histopathology nor molecular data were able to pinpoint the tissue of origin, our analyses established several differential diagnoses including triple-negative breast cancer (TNBC). We analyzed 157 TNBC samples from The Cancer Genome Atlas, revealing PDL1 copy number gains coinciding with excessive PDL1 mRNA expression in 24% of cases. Collectively, these results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype, show the predictive potential of PDL1 amplification for immune checkpoint inhibitors (ICIs), and suggest a targeted therapeutic strategy in Chromosome 9p24.1/PDL1-amplified cancers.


Asunto(s)
Antígeno B7-H1/genética , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/genética , Adulto , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/análisis , Toma de Decisiones Clínicas/métodos , Femenino , Factor de Transcripción GATA3/genética , Perfilación de la Expresión Génica/métodos , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Janus Quinasa 2/genética , Mutación , Estadificación de Neoplasias/métodos , Neoplasias Primarias Desconocidas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias de la Mama Triple Negativas/genética
7.
Cancer Cell ; 29(3): 379-393, 2016 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-26923874

RESUMEN

Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.


Asunto(s)
Epigénesis Genética/genética , Tumor Rabdoide/genética , Teratoma/genética , Neoplasias Encefálicas/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Humanos , Mutación/genética , Proteína SMARCB1 , Factores de Transcripción/genética
8.
Cancer Cell ; 27(2): 298-311, 2015 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-25670083

RESUMEN

Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.


Asunto(s)
Proteínas de Homeodominio/genética , Proteínas del Tejido Nervioso/genética , Proteínas de Unión al ARN/genética , Ribonucleasa III/genética , Tumor de Wilms/genética , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/biosíntesis , Mutación , Proteínas de Neoplasias/biosíntesis , Transcriptoma , Tumor de Wilms/patología
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