English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
 
 
DownloadE-Mail
  Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacleto precision medicine

Röcken, C., Amallraja, A., Halske, C., Opašić, L., Traulsen, A., Behrens, H.-M., et al. (2020). Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacleto precision medicine. Research Square. doi:10.21203/rs.3.rs-62554/v2.

Item is

Files

show Files
hide Files
:
29970ea0-8bb7-4035-a078-9c4de5e6f16d.pdf (Preprint), 28MB
Name:
29970ea0-8bb7-4035-a078-9c4de5e6f16d.pdf
Description:
-
OA-Status:
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-

Locators

show

Creators

show
hide
 Creators:
Röcken, Christoph, Author
Amallraja, Anu, Author
Halske, Christine, Author
Opašić, Luka1, Author           
Traulsen, Arne1, Author           
Behrens, Hans-Michael, Author
Krüger, Sandra, Author
Liu, Anne, Author
Haag, Jochen, Author
Egberts, Jan-Hendrik, Author
Rosenstiel, Philip, Author
Meissner, Tobias, Author
Affiliations:
1Department Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445641              

Content

show
hide
Free keywords: Gastric cancer, intratumoral heterogeneity, evolution, SMAD4, TP53, oncology
 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.

Details

show
hide
Language(s): eng - English
 Dates: 2020-09-212020-09-21
 Publication Status: Published online
 Pages: 18
 Publishing info: -
 Table of Contents: -
 Rev. Type: No review
 Identifiers: DOI: 10.21203/rs.3.rs-62554/v2
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Research Square
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: -