Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

Abstract

Mismatch repair deficient (dMMR) gastro-oesophageal adenocarcinomas (GOAs) show better outcomes than their MMR-proficient counterparts and high immunotherapy sensitivity. The hypermutator-phenotype of dMMR tumours theoretically enables high evolvability but their evolution has not been investigated. Here we apply multi-region exome sequencing (MSeq) to four treatment-naive dMMR GOAs. This reveals extreme intratumour heterogeneity (ITH), exceeding ITH in other cancer types >20-fold, but also long phylogenetic trunks which may explain the exquisite immunotherapy sensitivity of dMMR tumours. Subclonal driver mutations are common and parallel evolution occurs in RAS, PIK3CA, SWI/SNFcomplex genes and in immune evasion regulators. MSeq data and evolution analysis of single region-data from 64 MSI GOAs show that chromosome 8 gains are early genetic events and that the hypermutator-phenotype remains active during progression. MSeq may be necessary for biomarker development in these heterogeneous cancers. Comparison with other MSeqanalysed tumour types reveals mutation rates and their timing to determine phylogenetic tree morphologies.

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

“…Next, we generated multiregional trees based on driver SNVs and CNVs. As shown in Figure 1 all tumors of our cohort provided evidence of branched somatic evolution, with the most complex being the MSI GC, con rming data published recently by von Loga et al 7 In addition, we inferred maximum parsimony trees in accordance with Lee et al 5 (Suppl. Figure 4).…”

“…4 However, various validation studies conducted by ourselves and other research groups lead to the identi cation of a marked intratumoral heterogeneity, which stands to compromise the development and usage of targeted therapies in GC. 5,6,7 We found evidence of intratumoral heterogeneity for e.g. HER2 status, 8 MSI status 9 and PIK3CA genotype.…”

“…Among alterations in receptor tyrosine kinases, 9 of 12 cases (75%) were discordant across all matched samples. 6 Von Loga et al 7 recently studied four MSI GCs by multiregional sequencing and found an extreme intratumoral heterogeneity as well as evidence of parallel evolution in this special subtype of GC. Likewise, in our cohort of nine GCs, the vast majority of non-synonymous mutations was distributed "heterogeneously" and not present in each patient sample.…”

“…22 Multiregional sequencing studies provide evidence of somatic evolution shaping the genetic landscape of GC leading to a substantial intraprimary and intermetastatic heterogeneity. 5,6,7 However, while heterogeneity may shed some light on the subclonal architecture of the tumor, homogeneity does not necessarily represent clonality.…”

Mismatch Repair System Genomic Scars in Gastroesophageal Cancers: Biology and Clinical Testing

“…Of note, MSI-H and PD-L1 POS phenotype are major prognostic factors as well as predictive biomarkers for ICI efficacy in GEC [21][22][23]. Multiregion exome sequencing revealed > 20-fold levels of intratumor heterogeneity in dMMR GEC compared to other cancer types, and also long phylogenetic trunks [24].…”