アイテム詳細

登録内容を編集

このアイテムは取り下げられました。リリース履歴を表示詳細要約

取り下げ

成果報告書

Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacleto precision medicine

MPS-Authors

/persons/resource/persons200288

Opašić, Luka
Department Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Max Planck Society;

/persons/resource/persons56973

Traulsen, Arne
Department Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Max Planck Society;

External Resource

There are no locators available

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

フルテキスト (公開)

(アクセスなし)

付随資料 (公開)

There is no public supplementary material available

引用

Röcken, C., Amallraja, A., Halske, C., Opašić, L., Traulsen, A., Behrens, H.-M., Krüger, S., Liu, A., Haag, J., Egberts, J.-H., Rosenstiel, P., & Meissner, T. (2020). Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacleto precision medicine. Research Square. doi:10.21203/rs.3.rs-62554/v2.

要旨

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.