Nature genetics, 2019-03, Vol.51 (3), p.506-516
2019
Details
- Autor(en) / Beteiligte
- Titel
- The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic
- Ist Teil von
- Nature genetics, 2019-03, Vol.51 (3), p.506-516
- Ort / Verlag
- United States: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements. We identified a mean of 4.4 driver events per tumor, which were derived more commonly from mutations than copy number alterations, and compared the prevelence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS). We observed mutual exclusivity or co-occurrence of events within and between several dysregulated EAC pathways, a result suggestive of strong functional relationships. Indicators of poor prognosis (SMAD4 and GATA4) were verified in independent cohorts with significant predictive value. Over 50% of EACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated with clinically relevant sensitivity in a panel of EAC cell lines and organoids.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1061-4036, 1546-1718eISSN: 1546-1718DOI: 10.1038/s41588-018-0331-5Titel-ID: cdi_swepub_primary_oai_prod_swepub_kib_ki_se_140421638
- Format
- –
- Schlagworte
- Adenocarcinoma, Adenocarcinoma - genetics, Bioindicators, Biological markers, Biomarkers, Biomarkers, Tumor - genetics, Breast cancer, Cancer genetics, Care and treatment, Cohort Studies, Copy number, Cyclin-dependent kinase 4, Cyclin-dependent kinases, Development and progression, DNA Copy Number Variations - genetics, Esophageal cancer, Esophageal Neoplasms - genetics, Esophagus, Exome - genetics, Female, Gene expression, Gene Expression Profiling - methods, Gene Expression Regulation, Neoplastic - genetics, Gene mutation, Gene mutations, Gene sequencing, Genes, Genetic aspects, Genetic research, Genomes, Genomics, Genomics - methods, Humans, Kinases, Male, Medical prognosis, Medicin och hälsovetenskap, Mutation, Mutation - genetics, Organoids, Prognosis, Ribonucleic acid, RNA, RNA sequencing, Sensitizing, Smad4 protein, Therapeutics, Tumors