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1.
Genome Res ; 27(6): 902-912, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28465312

RESUMEN

The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.


Asunto(s)
Adenocarcinoma/genética , Antineoplásicos/uso terapéutico , Neoplasias Esofágicas/genética , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Tasa de Mutación , Proteínas de Neoplasias/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Biología Computacional , Variaciones en el Número de Copia de ADN , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Esófago/metabolismo , Esófago/patología , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Proteínas de Neoplasias/metabolismo , Mutación Puntual , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Factores de Tiempo
3.
JMIR Res Protoc ; 11(2): e31885, 2022 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-35142634

RESUMEN

BACKGROUND: Although the burden of premature myocardial infarction (MI) is high in Malaysia, direct evidence on the determinants of MI in this multi-ethnic population remains sparse. OBJECTIVE: The Malaysian Acute Vascular Events Risk (MAVERIK) study is a retrospective case-control study established to investigate the genomic, lipid-related, and other determinants of acute MI in Malaysia. In this paper, we report the study protocol and early results. METHODS: By June 2019, we had enrolled approximately 2500 patients with their first MI and 2500 controls without cardiovascular disease, who were frequency-matched by age, sex, and ethnicity, from 17 hospitals in Malaysia. For each participant, serum and whole blood have been collected and stored. Clinical, demographic, and behavioral information has been obtained using a 200-item questionnaire. RESULTS: Tobacco consumption, a history of diabetes, hypertension, markers of visceral adiposity, indicators of lower socioeconomic status, and a family history of coronary disease were more prevalent in cases than in controls. Adjusted (age and sex) logistic regression models for traditional risk factors indicated that current smoking (odds ratio [OR] 4.11, 95% CI 3.56-4.75; P<.001), previous smoking (OR 1.34, 95% CI 1.12-1.60; P=.001), a history of high blood pressure (OR 2.13, 95% CI 1.86-2.44; P<.001), a history of diabetes mellitus (OR 2.72, 95% CI 2.34-3.17; P<.001), a family history of coronary heart disease (OR 1.28, 95% CI 1.07-1.55; P=.009), and obesity (BMI >30 kg/m2; OR 1.19, 95% CI 1.05-1.34; P=.009) were associated with MI in age- and sex-adjusted models. CONCLUSIONS: The MAVERIK study can serve as a useful platform to investigate genetic and other risk factors for MI in an understudied Southeast Asian population. It should help to hasten the discovery of disease-causing pathways and inform regionally appropriate strategies that optimize public health action. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/31885.

4.
Nat Genet ; 52(1): 74-83, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31907488

RESUMEN

The poor outcomes in esophageal adenocarcinoma (EAC) prompted us to interrogate the pattern and timing of metastatic spread. Whole-genome sequencing and phylogenetic analysis of 388 samples across 18 individuals with EAC showed, in 90% of patients, that multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases, including lymph nodes and distant tissues-a mode of dissemination that we term 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points. These findings have implications for our understanding and clinical evaluation of EAC.


Asunto(s)
Adenocarcinoma/secundario , Evolución Clonal , Neoplasias Esofágicas/patología , Genómica/métodos , Modelos Estadísticos , Adenocarcinoma/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/secundario , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Secuenciación Completa del Genoma , Adulto Joven
5.
Nat Genet ; 48(10): 1131-41, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27595477

RESUMEN

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.


Asunto(s)
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Mutación , Adenocarcinoma/clasificación , Adenocarcinoma/inmunología , Adenocarcinoma/terapia , Anciano , Antineoplásicos/uso terapéutico , Antígenos CD8/inmunología , Línea Celular Tumoral , Estudios de Cohortes , Daño del ADN , ADN de Neoplasias , Neoplasias Esofágicas/clasificación , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/terapia , Femenino , Heterogeneidad Genética , Genoma Humano , Humanos , Masculino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo , Análisis de Secuencia de ADN
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