The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution

Alejandro Hernandez‐Sanchez ,Julia Krzykalla,Maartje Nielsen,Sanne W. Ten Broeke ,Matthias Kloor,Johannes Gebert,Florian Seidler,Johannes Witt,Angelika B. Riemer ,Elisabeth Pfaffendorf,Damian Stichel,Michael Jendrusch,Daniel Heid,Hendrik Bläker,Axel Benner,Pauline L. Pfuderer,Sarah Schott,Vincent Heuveline,Jukka‐Pekka Mecklin ,Aysel Ahadova,Saskia Haupt,Magnus von Knebel Doeberitz,Markus Draxlbauer,Moritz J. Przybilla ,Alexej Ballhausen,Sonja Krausert,Martin Simon Kalteis,Toni T. Seppälä ,Maria Bonsack,Katharina Urban

doi:10.1038/s41467-020-18514-5

Abstract

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers.

Highlights

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens
mismatch repair (MMR)-deficient tumors, due to their well-defined mechanism of genomic instability, represent an ideal tumor type to study the evolution of solid cancer development and the role of the immune system during this process
By analyzing a broad spectrum of coding microsatellites (cMS)-encompassing genes that are susceptible to mutation in MMR-deficient cells, we were able to identify recurrent mutations and frameshift peptides and to provide first evidence suggesting immunoediting during MSI cancer development

Summary

Introduction

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MSI tumors can develop sporadically or in the context of Lynch syndrome, the most common inherited cancer predisposition syndrome Due to this very specific process of genomic instability, the pathogenesis of MSI cancers can be precisely dissected[4]: indel mutations of coding microsatellites (cMSs), which almost exclusively affect coding mononucleotide repeats[5,6,7], in genomic regions encoding tumor-suppressor genes are considered major drivers of MSI tumorigenesis.

Methods

Results

Conclusion