Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Kondelin, Johanna; Gylfe, Alexandra E.; Lundgren, Sofie; Tanskanen, Tomas; Hamberg, Jiri; Aavikko, Mervi; Palin, Kimmo; Ristolainen, Heikki; Katainen, Riku; Kaasinen, Eevi; Taipale, Minna; Taipale, Jussi; Renkonen–Sinisalo, Laura; Järvinen, Heikki; Böhm, Jan; Mecklin∥, Jukka–Pekka; Vahteristo, Pia; Tuupanen, Sari; Aaltonen, Lauri A.; Pitkänen, Esa

doi:10.1158/0008-5472.can-17-0682

Cited by 20 publications

(30 citation statements)

References 39 publications

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“…Additionally, we investigated mutation profiles in a cohort of MSI endometrial cancers (MSI ECs; n=14). In agreement with previous reports (23,27), our results show that the load of indels at cMS in MSI CRC and EC is high and that multiple concomitant indels at several cMS in the same tumor are very common. Although most CRC and EC were distinguishable based on the cMS mutation patterns, a large set of cMS mutations were shared by the majority of MSI CRC and/or MSI EC (Fig.…”

Section: Cms Mutation Frequencies In Msi Crc and Ecsupporting

confidence: 93%

“…We ruled out a potential influence of cMS length, a well-known factor influencing the likelihood of indel mutations on the observed mutation frequency ( Fig. S54), (23,27,39) further supporting the concept of immunosurveillance-induced negative selection. Despite the statistically significant negative correlation between GELS and mutation frequency, we also observed some outliers ( Fig.…”

Section: Immunoselection During Msi Carcinogenesismentioning

confidence: 65%

“…TGFBR2, SLC35F5 or TFAM (Table S1). Importantly cMS repeats of increased length which are most susceptible to mutations and therefore encompass the most important mutational targets during MMR-deficient tumorigenesis, are missed by NGS technology that is in common use today (3,5,19,(22)(23)(24)(25)(26). To fill this gap and precisely quantify cMS mutation patterns and their resulting neoantigen frames in MMR-deficient cancers, we developed a novel algorithm based on fragment length analysis as the current gold standard for the detection of MSI.…”

Section: Cms Mutation Frequencies In Msi Crc and Ecmentioning

confidence: 99%

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The sharedneoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

Ballhausen

Przybilla

Jendrusch

et al. 2019

Preprint

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Glossary TermMeaning ELS Epitope likelihood score GELS General epitope likelihood score IRS Immune relevance score, based on the mutation frequency (ReFrame) and the GELS M1Reading frame resulting from the deletion of one nucleotide or insertions of two nucleotides M2Reading frame resulting from the deletions of two nucleotides or insertion of one nucleotide m1, m2, m3, etc.Minus one, two, three base pair deletions p1, p2, p3, etc.Plus one, two, three base pair insertions ReFrameREgression-based FRAMEshift quantification Abbreviations B2M Beta2-microglobulin cMS Coding microsatellites CRC Colorectal cancer MMR Mismatch repair EC Endometrium cancer FSP neoantigens Frameshift peptide neoantigens HLA Human leukocyte antigen ICB Immune checkpoint blockade MSI Microsatellite instability, microsatelliteunstable NGSNext generation sequencing Abstract:The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are particularly 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. The abundance of mutational neoantigens renders MSI cancers sensitive to immune checkpoint blockade. However, the neoantigen landscape of MMR-deficient cancers has not yet been systematically mapped. In the present study, we used a novel tool to monitor neoantigen-inducing indel mutations in MSI colorectal and endometrial cancer. Our results show that MSI cancers share several highly immunogenic neoantigens that result from specific, recurrent indel mutation events.Notably, the frequency of such indel mutations was negatively correlated to the predicted immunogenicity of the resulting neoantigens. These observations suggest continuous immunoediting of emerging MMR-deficient cells during tumor evolution. Main text:DNA MMR deficiency is a major mechanism causing genomic instability in human cancer. MMR-deficient cancers accumulate an exceptionally high number of somatic mutations. These mutations encompass certain types of single nucleotide alterations, but mostly insertion/deletion (indel) mutations at repetitive sequence stretches termed microsatellites (microsatellite instability, MSI) (1, 2). About 15% of colorectal cancers (CRC), up to 30% of endometrial cancers (EC) and multiple other tumors display the MSI phenotype (3). 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 affecting coding microsatellites (cMS), predominantly coding mononucleotide repeats, in genomic regions encoding tumor suppressor genes are considered major drivers of MSI tumorigenesis (5-7). Importantly, the same indels that inactivate tumor suppressor genes simultaneously cause translational frameshi...

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Section: Cms Mutation Frequencies In Msi Crc and Ecsupporting

confidence: 93%

Section: Immunoselection During Msi Carcinogenesismentioning

confidence: 65%

Section: Cms Mutation Frequencies In Msi Crc and Ecmentioning

confidence: 99%

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The sharedneoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

Ballhausen

Przybilla

Jendrusch

et al. 2019

Preprint

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“…Although many of the recurrently mutated coding microsatellites have been reported by whole genome or exome sequencing studies ( Supplementary Table 7) (13,14,20,27), our analysis identified new genes with recurrently mutated microsatellites.…”

Section: Recurrently Mutated Microsatellites In the Coding Regionmentioning

confidence: 75%

Comprehensive Analysis of Indels in Whole-genome Microsatellite Regions and Microsatellite Instability across 21 Cancer Types

Fujimoto

Fujita

Hasegawa

et al. 2018

Preprint

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20Microsatellites are repeats of 1-6bp units and ~10 million microsatellites have been 21 identified across the human genome. Microsatellites are vulnerable to DNA mismatch 22 germline variation of the microsatellites suggested that the amount of germline variations 34 and somatic mutation rates were correlated. Lastly, analysis of mutations in mismatch 35 repair genes showed that somatic SNVs and short indels had larger functional impact than 36 germline mutations and structural variations. Our analysis provides a comprehensive 37 picture of mutations in the microsatellite regions, and reveals possible causes of mutations, 38as well as provides a useful marker set for MSI detection. 39 40Introduction 41Recent large-scale whole genome sequencing studies have revealed the complexity of the 42 mutational landscape of the cancer genome (1-4). In cancer genomes, various types of 43 mutations, such as SNVs (single nucleotide variants), short indels (insertions and 44 deletions), genomic rearrangements, copy number alterations, insertion of 45 retrotransposons, and virus genome integrations, have been identified, and their 46 oncogenic roles have been characterized (1-5). Additionally, genome sequencing studies 47 have revealed the molecular basis of somatic mutations (6-9). However, somatic 48 mutations in microsatellites or repeat sequences have not been well-characterized in a 49 large whole genome sequencing cohort due to difficulties in accurately detecting 50 mutations using presently available short-read sequencing technologies. 51A microsatellite is defined as a tract of repetitive DNA motif composed of short 52 repeating units (10). The mutation rate of microsatellites has been known to be higher 53 than other genomic regions due to DNA polymerase slippage during DNA replication and 54 repair (10). Due to their fragility, microsatellites are used as markers of genomic 55 instability in cancer (11). In cancer genetics studies, microsatellite instability (MSI) has 56 been used for molecular diagnosis of Lynch syndrome and cancers with mismatch repair 57 deficiency (11). Furthermore, MSI-positive tumors are generally burdened with higher 58 numbers of somatic mutations and present many mutation-associated neo-antigens, which 59 might be recognized by the immune system. Presently, MSI can also be used as a marker 60 to predict the effect of immune therapy (12). The MSI phenotype is most common in 61 colorectal cancers, stomach cancers and uterine endometrial cancers (10-15%), although 62 it has also been observed across many tumor types at a few % (11). The MSI phenotype 63 is defined by the presence of somatic indels of the 2-5 microsatellite makers, whereby 64 BAT25/26 mononucleotide microsatellites are widely used to establish MSI status (11). 65Irrespective of the clinical importance of microsatellite, large-scale analysis of 66 somatic changes in microsatellites across various type of cancers is limited for whole 67 genome sequencing (WGS) data (13, 14). In the current study, we analyzed indels in 68 microsat...

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“…MSI results from biallelic inactivation of one of the MMR genes [13]. MSI, as one of immunogenic subtype in Colorectal cancer, has been exploded in research paper [14,15].…”

Section: Dendritic Cells Mast Cells Natural Killer (Nk) Cells Naivmentioning

confidence: 99%

Exploration of immunogene in colon cancer recurrence

Sun¹,

Yao²,

Yuan³

et al. 2018

Oncotarget

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Colon adenocarcinoma is the third most common cancer with high risk of recurrence and deteriorative consequences. Given the importance of immune genes in tumor regulation and cancer immunotherapy, there is a need to comprehensively profile the immunoregulatory genes from multiple types of colon cancer patient genomic data for discovering important associations and potential therapeutic targets of colon cancer recurrence. We used publicly available colon tumor tissue genomic data from The Cancer Genome Atlas database and immune genes data from innateDB database in this study. We derived the immune genes profiles by exploring multiple genomic profiles (gene expression, clinical and somatic mutation) in colon cancer. Some of the synthetic lethal genes we identified, such as CASP14, MS4A6E, KIR2DL1, KIR3DL1, KIR2DL3, CCL1, IL36B, FOXO3, POU2F1, SMAD3, HOXA9, PACS1, PROM1, DIDO1, SRC, CBFA2T2, NCOA6, PGAM1 and PROC, have been suggested to be potential targets correlated with immune genes for colon cancer recurrence treatment. Moreover, TLR2 could be promisingly new early stage indicator for colon adenocarcinoma recurrence. This is a systematic study that combines three different types of genomic data to molecularly characterize colon cancer and aims to identify potential targets for colon adenocarcinoma therapy. Meanwhile, the integrative analysis of immune genes for colon cancer could assist in identifying potential new symbols for colon adenocarcinoma recurrence.

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Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Cited by 20 publications

References 39 publications

The sharedneoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

The sharedneoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

Comprehensive Analysis of Indels in Whole-genome Microsatellite Regions and Microsatellite Instability across 21 Cancer Types

Exploration of immunogene in colon cancer recurrence

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