Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine

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 diver...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Gastric cancer Intratumoral heterogeneity Evolution SMAD4 TP53 Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/fd8df01746ac4a9f8e7885c8e7424eff
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spelling	oai:doaj.org-article:fd8df01746ac4a9f8e7885c8e7424eff2021-11-14T12:27:42ZMultiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine10.1186/s13073-021-00975-y1756-994Xhttps://doaj.org/article/fd8df01746ac4a9f8e7885c8e7424eff2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13073-021-00975-yhttps://doaj.org/toc/1756-994XAbstract 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 heterogeneity, where lymph node metastases may stem from different areas of the primary tumor, synchronously. Our findings may have profound effects on future patient management. They illustrate the risk of mis-interpreting tumor genetics based on single-sample analysis and open new avenues for an evolutionary classification of GC, i.e., the discovery of distinct evolutionary trajectories which can be utilized for precision medicine.Christoph RöckenAnu AmallrajaChristine HalskeLuka OpasicArne TraulsenHans-Michael BehrensSandra KrügerAnne LiuJochen HaagJan-Hendrik EgbertsPhilip RosenstielTobias MeißnerBMCarticleGastric cancerIntratumoral heterogeneityEvolutionSMAD4TP53MedicineRGeneticsQH426-470ENGenome Medicine, Vol 13, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Gastric cancer Intratumoral heterogeneity Evolution SMAD4 TP53 Medicine R Genetics QH426-470
spellingShingle	Gastric cancer Intratumoral heterogeneity Evolution SMAD4 TP53 Medicine R Genetics QH426-470 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 Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine
description	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 heterogeneity, where lymph node metastases may stem from different areas of the primary tumor, synchronously. Our findings may have profound effects on future patient management. They illustrate the risk of mis-interpreting tumor genetics based on single-sample analysis and open new avenues for an evolutionary classification of GC, i.e., the discovery of distinct evolutionary trajectories which can be utilized for precision medicine.
format	article
author	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
author_facet	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
author_sort	Christoph Röcken
title	Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine
title_short	Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine
title_full	Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine
title_fullStr	Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine
title_full_unstemmed	Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine
title_sort	multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine
publisher	BMC
publishDate	2021
url	https://doaj.org/article/fd8df01746ac4a9f8e7885c8e7424eff
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Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine

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