Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine
Saved in:
| Title: | Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine |
|---|---|
| Authors: | Röcken, Christoph, Amallraja, Anu, Halske, Christine, Opasic, Luka, Traulsen, Arne, Behrens, Hans-Michael, Krüger, Sandra, Liu, Anne, Haag, Jochen, Egberts, Jan-Hendrik, Rosenstiel, Philip, Meißner, Tobias |
| Source: | http://lobid.org/resources/99370670445306441#!, 13(1):177. |
| Publication Year: | 2021 |
| Collection: | Publisso (ZB MED-Publikationsportal Lebenswissenschaften) |
| Subject Terms: | Aged, 80 and over [MeSH], Aged [MeSH], B7-H1 Antigen [MeSH], Evolution, Molecular [MeSH], Intratumoral heterogeneity, 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] |
| Description: | Background!#!Cancer is a somatic evolutionary disease and adenocarcinomas of the stomach and gastroesophageal junction (GC) may serve as a two-dimensional model of cancer expansion, in which tumor subclones are not evenly mixed during tumor progression but rather spatially separated and diversified. We hypothesize that precision medicine efforts are compromised when clinical decisions are based on a single-sample analysis, which ignores the mechanisms of cancer evolution and resulting intratumoral heterogeneity. Using multiregional whole-exome sequencing, we investigated the effect of somatic evolution on intratumoral heterogeneity aiming to shed light on the evolutionary biology of GC.!##!Methods!#!The study comprised a prospective discovery cohort of 9 and a validation cohort of 463 GCs. Multiregional whole-exome sequencing was performed using samples form 45 primary tumors and 3 lymph node metastases (range 3-10 tumor samples/patient) of the discovery cohort.!##!Results!#!In total, the discovery cohort harbored 16,537 non-synonymous mutations. Intratumoral heterogeneity of somatic mutations and copy number variants were present in all tumors of the discovery cohort. Of the non-synonymous mutations, 53-91% 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. We found evidence of parallel evolution and evolutionary trajectories: different mutations of SMAD4 aligned with different subclones and were found only in TP53 mutant GCs.!##!Conclusions!#!Neutral and non-neutral somatic evolution shape the mutational landscape in GC along its lateral expansions. It leads to complex spatial intratumoral ... |
| Document Type: | article in journal/newspaper |
| Language: | English |
| Relation: | https://repository.publisso.de/resource/frl:6465946; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576943/ |
| DOI: | 10.1186/s13073-021-00975-y |
| Availability: | https://repository.publisso.de/resource/frl:6465946 https://doi.org/10.1186/s13073-021-00975-y https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576943/ |
| Rights: | https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: | edsbas.8181BBCD |
| Database: | BASE |
Nájsť tento článok vo Web of Science | Abstract: | Background!#!Cancer is a somatic evolutionary disease and adenocarcinomas of the stomach and gastroesophageal junction (GC) may serve as a two-dimensional model of cancer expansion, in which tumor subclones are not evenly mixed during tumor progression but rather spatially separated and diversified. We hypothesize that precision medicine efforts are compromised when clinical decisions are based on a single-sample analysis, which ignores the mechanisms of cancer evolution and resulting intratumoral heterogeneity. Using multiregional whole-exome sequencing, we investigated the effect of somatic evolution on intratumoral heterogeneity aiming to shed light on the evolutionary biology of GC.!##!Methods!#!The study comprised a prospective discovery cohort of 9 and a validation cohort of 463 GCs. Multiregional whole-exome sequencing was performed using samples form 45 primary tumors and 3 lymph node metastases (range 3-10 tumor samples/patient) of the discovery cohort.!##!Results!#!In total, the discovery cohort harbored 16,537 non-synonymous mutations. Intratumoral heterogeneity of somatic mutations and copy number variants were present in all tumors of the discovery cohort. Of the non-synonymous mutations, 53-91% 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. We found evidence of parallel evolution and evolutionary trajectories: different mutations of SMAD4 aligned with different subclones and were found only in TP53 mutant GCs.!##!Conclusions!#!Neutral and non-neutral somatic evolution shape the mutational landscape in GC along its lateral expansions. It leads to complex spatial intratumoral ... |
|---|---|
| DOI: | 10.1186/s13073-021-00975-y |