Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine
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| Title: | Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine |
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| Authors: | Christoph Röcken, Anu Amallraja, Christine Halske, Luka Opasic, Arne Traulsen, Hans-Michael Behrens, Sandra Krüger, Anne Liu, Jochen Haag, Jan-Hendrik Egberts, Philip Rosenstiel, Tobias Meissner |
| Source: | Genome Med Genome Medicine, Vol 13, Iss 1, Pp 1-19 (2021) Genome Medicine |
| Publisher Information: | Springer Science and Business Media LLC, 2020. |
| Publication Year: | 2020 |
| Subject Terms: | DNA Copy Number Variations, Evolution, Intratumoral heterogeneity, QH426-470, Adenocarcinoma, Aged, 80 and over [MeSH], Aged [MeSH], B7-H1 Antigen [MeSH], Evolution, Molecular [MeSH], TP53, Cohort Studies [MeSH], Lymphatic Metastasis [MeSH], SMAD4, Exome [MeSH], Sequence Analysis, DNA [MeSH], Gastric cancer, Stomach Neoplasms/genetics [MeSH], Clonal Evolution [MeSH], Mutation [MeSH], Humans [MeSH], Genetic Heterogeneity [MeSH], Precision Medicine/methods [MeSH], Whole Exome Sequencing [MeSH], Middle Aged [MeSH], Smad4 Protein/genetics [MeSH], Phylogeny [MeSH], Tumor Suppressor Protein p53/genetics [MeSH], DNA Copy Number Variations [MeSH], Targeting cancer evolution in the clinic, Research, Adenocarcinoma/genetics [MeSH], B7-H1 Antigen, Clonal Evolution, Cohort Studies, Evolution, Molecular, Genetic Heterogeneity, Stomach Neoplasms, Genetics, Humans, Exome, Precision Medicine, Phylogeny, Aged, Smad4 Protein, Aged, 80 and over, Sequence Analysis, DNA, Middle Aged, 3. Good health, Lymphatic Metastasis, Mutation, Medicine, Tumor Suppressor Protein p53 |
| Description: | Purpose: Cancer is a somatic evolutionary disease. Using multiregional whole exome sequencing, we tested the effect of somatic evolution on intratumoral heterogeneity and its putative clinical and biological implications in adenocarcinomas of the stomach and gastroesophageal junction (GC). Patients and Methods: The study comprised a prospective discovery cohort of 9 and a validation cohort of 463 GCs. Multiregional whole-exome sequencing was done using 48 tumor samples (range: 3-10 tumor samples/patient) of the discovery cohort.Results: In total, the discovery cohort harbored 16,537 non-synonymous mutations (mutations/sample: median n=159; mutations/patient: median n=369). Intratumoral heterogeneity of somatic mutations and copy number variants were present in all tumors of the discovery cohort. 53-91% of the non-synonymous mutations were not present in each patient’s sample; 399 genes harbored 2-4 different non-synonymous mutations in the same patient; 175 genes showed copy number variations, the majority being heterogeneous, including CD274 (PD-L1). Multi-sample tree-based analyses provided evidence for branched evolution being most complex in a microsatellite instable GC. The analysis of the mode of evolution showed a high degree of heterogeneity in deviation from neutrality within each tumor. Studies on the validation cohort showed that the subclonal loss of SMAD4 is an independent predictor for poor patient outcome in Caucasian patients.Conclusions: Neutral and non-neutral somatic evolution shape the mutational landscape in GC. It leads to complex spatial intratumoral heterogeneity and may have profound effects on patient management. It provides crucial information for an individualized understanding of clinical prognosis and therapeutic options in GC patients. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf |
| ISSN: | 1756-994X |
| DOI: | 10.21203/rs.3.rs-62554/v2 |
| DOI: | 10.1186/s13073-021-00975-y |
| DOI: | 10.21203/rs.3.rs-62554/v1 |
| Access URL: | https://europepmc.org/articles/pmc8576943?pdf=render https://genomemedicine.biomedcentral.com/track/pdf/10.1186/s13073-021-00975-y https://pubmed.ncbi.nlm.nih.gov/34749812 https://doaj.org/article/fd8df01746ac4a9f8e7885c8e7424eff https://www.researchsquare.com/article/rs-62554/v2.pdf?c=1631870597000 https://www.researchsquare.com/article/rs-62554/v1 https://pure.mpg.de/pubman/item/item_3275431_2/component/file_3275432/29970ea0-8bb7-4035-a078-9c4de5e6f16d.pdf http://hdl.handle.net/21.11116/0000-000A-1585-8 http://hdl.handle.net/21.11116/0000-000A-1587-6 https://repository.publisso.de/resource/frl:6465946 |
| Rights: | CC BY |
| Accession Number: | edsair.doi.dedup.....f79abf22f9d520fbd9bc38a7b27a7e60 |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Purpose: Cancer is a somatic evolutionary disease. Using multiregional whole exome sequencing, we tested the effect of somatic evolution on intratumoral heterogeneity and its putative clinical and biological implications in adenocarcinomas of the stomach and gastroesophageal junction (GC). Patients and Methods: The study comprised a prospective discovery cohort of 9 and a validation cohort of 463 GCs. Multiregional whole-exome sequencing was done using 48 tumor samples (range: 3-10 tumor samples/patient) of the discovery cohort.Results: In total, the discovery cohort harbored 16,537 non-synonymous mutations (mutations/sample: median n=159; mutations/patient: median n=369). Intratumoral heterogeneity of somatic mutations and copy number variants were present in all tumors of the discovery cohort. 53-91% of the non-synonymous mutations were not present in each patient’s sample; 399 genes harbored 2-4 different non-synonymous mutations in the same patient; 175 genes showed copy number variations, the majority being heterogeneous, including CD274 (PD-L1). Multi-sample tree-based analyses provided evidence for branched evolution being most complex in a microsatellite instable GC. The analysis of the mode of evolution showed a high degree of heterogeneity in deviation from neutrality within each tumor. Studies on the validation cohort showed that the subclonal loss of SMAD4 is an independent predictor for poor patient outcome in Caucasian patients.Conclusions: Neutral and non-neutral somatic evolution shape the mutational landscape in GC. It leads to complex spatial intratumoral heterogeneity and may have profound effects on patient management. It provides crucial information for an individualized understanding of clinical prognosis and therapeutic options in GC patients. |
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| ISSN: | 1756994X |
| DOI: | 10.21203/rs.3.rs-62554/v2 |