Integrated analysis of the immunological and genetic status in and across cancer types: impact of mutational signatures beyond tumor mutational burden

Budczies, Jan; Seidel, Anja; Christopoulos, Petros; Endris, Volker; Kloor, Matthias; Győrffy, Balázs; Seliger, Barbara; Schirmacher, Peter; Stenzinger, Albrecht; Denkert, Carsten

doi:10.1080/2162402x.2018.1526613

Cited by 68 publications

(60 citation statements)

References 47 publications

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“…Our results show that these tumors can be directly identified by a panel‐based one‐stop shop sequencing approach. Moreover, our data indicate that – in principle‐focused NGS‐based TMB assays can also infer mutational signatures, which appear to influence the immunological microenvironment, i.e. the effector cells upon which checkpoint blockers act, of these tumors.…”

Section: Discussionmentioning

confidence: 85%

Measurement of tumor mutational burden (TMB) in routine molecular diagnostics: in silico and real‐life analysis of three larger gene panels

Endris

Buchhalter

Allgäuer

et al. 2019

Intl Journal of Cancer

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107

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Assessment of Tumor Mutational Burden (TMB) for response stratification of cancer patients treated with immune checkpoint inhibitors is emerging as a new biomarker. Commonly defined as the total number of exonic somatic mutations, TMB approximates the amount of neoantigens that potentially are recognized by the immune system. While whole exome sequencing (WES) is an unbiased approach to quantify TMB, implementation in diagnostics is hampered by tissue availability as well as time and cost constrains. Conversely, panel-based targeted sequencing is nowadays widely used in routine molecular diagnostics, but only very limited data are available on its performance for TMB estimation. Here, we evaluated three commercially available larger gene panels with covered genomic regions of 0.39 Megabase pairs (Mbp), 0.53 Mbp and 1.7 Mbp using i) in silico analysis of TCGA (The Cancer Genome Atlas) data and ii) wet-lab sequencing of a total of 92 formalin-fixed and paraffin-embedded (FFPE) cancer samples grouped in three independent cohorts (non-small cell lung cancer, NSCLC; colorectal cancer, CRC; and mixed cancer types) for which matching WES data were available. We observed a strong correlation of the panel data with WES mutation counts especially for the gene panel >1Mbp. Sensitivity and specificity related to TMB cutpoints for checkpoint inhibitor response in NSCLC determined by wet-lab experiments well reflected the in silico data. Additionally, we highlight potential pitfalls in bioinformatics pipelines and provide recommendations for variant filtering. In summary, our study is a valuable data source for researchers working in the field of immuno-oncology as well as for diagnostic laboratories planning TMB testing. What's new?Tumor mutational burden (TMB) is an emerging biomarker to predict response to immune checkpoint inhibitors. While TMB can be measured by whole exome sequencing (WES), costs, turn-around time, and tissue availability currently favor a panel sequencing approach using FFPE tissue for routine diagnostics. However, performance remains to be clarified. Our study is the first worldwide that analyses three major commercial gene panels by comparing TMB approximation across panels as well as against the technical reference standard WES. The data suggest that TMB approximation using gene panel sequencing of FFPE tumor tissue is feasible and can be implemented in routine diagnostics.

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Section: Discussionmentioning

confidence: 85%

Measurement of tumor mutational burden (TMB) in routine molecular diagnostics: in silico and real‐life analysis of three larger gene panels

Endris

Buchhalter

Allgäuer

et al. 2019

Intl Journal of Cancer

Self Cite

107

View full text Add to dashboard Cite

show abstract

“…Indeed, older patients with breast cancer harbored a less active immune environment than younger patients with breast cancer. 7 Recent studies also noted a cancer type-specific (BRCA, PRAD) negative correlation of immune cell infiltration and mutational signature 1, 33 and further investigation is required to understand how signature 1-related mutated clones escaped from immune recognition.…”

Section: Discussionmentioning

confidence: 99%

Age-related mutational signature negatively associated with immune activity and survival outcome in triple-negative breast cancer

et al. 2020

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Triple-negative breast cancer (TNBC) is characterized by broad genomic and transcriptional heterogeneity and results in a worse prognosis than other breast cancer types. Here, we integrated genomic and transcriptomic data combined with clinicopathologic information from 538 patients with TNBC and identified four novel significantly mutated genes (SMGs), namely, KDM6A, CD86, RBM47, and IFNGR1. A mutational signature (known as age-related signature 1) featured by enrichment of C > T mutations at NpCpG trinucleotides was associated with worse survival in TNBC (HR, 1.76 [95% CI, 1.07-2.90]; P = .025). We also analyzed gene transcriptomic profiles of TNBC samples and identified immune regulation-related gene pathways (e.g., antigen processing presentation and interferon signaling), and the cell cycle was significantly altered in samples with different signature 1 activity groups. The analysis further revealed that signature 1 was associated with decreased tumor immunogenicity and immunocyte infiltration in TNBC. This negative correlation was also observed in lung adenocarcinoma and prostate cancer samples. Furthermore, we found that patients with mutational signature 1 were markedly associated with decreased tumor mutation burden, even after controlling for age, grade, histological type, lymph node status, mutations in BRCA1/2 and ATR, and APOBEC and homologous recombination repair deficiency signatures (OR, 0.19 [95% CI, 0.11-0.32]; P < .001). Overall, this study identified previously unreported SMGs and re-annotated that age-related signature 1 was associated with a weakened immune microenvironment and predictive of poor survival in TNBC, offering opportunities to stratify patients into optimal treatment plans based on genomic subtyping.

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“…This observation has led to the hypothesis that immune checkpoint inhibitors may be efficacious in POLE ultramutated tumors (Howitt et al 2015). Our results question a direct relationship between mutation burden, tumor immune response and PD-L1 expression, also raised in a larger study across 5722 cases from 21 cancer types in TCGA (Budczies et al 2018). While we observed a concordance between the computational and histological assessments of the immune infiltrate, the immune score in tumors with E/Q/Z mutations depended on MSI status.…”

Section: Discussionmentioning

confidence: 61%

Mutant POLQ and POLZ/REV3L DNA polymerases may contribute to favorable survival of tumors with POLE mutations outside the exonuclease domain

Knudsen¹,

Huang²,

Tanaka³

et al. 2020

Preprint

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Purpose: Tumors with mutations in the exonuclease domain of POLE are associated with ultrahigh mutation rates. POLE mutant tumors are best characterized in intestinal and uterine cancers and are associated with a prominent immune infiltrate and favorable prognosis. To determine whether mutations in other DNA polymerases cooperate with POLE mutations to generate the ultramutator phenotype, we analyzed exome sequence data from 15 cancer types with POLE mutations in The Cancer Genome Atlas (TCGA).Results: 36% of POLE mutant tumors, predominantly colorectal, stomach and endometrial cancers carried mutations in POLQ (E/Q) and/or POLZ/REV3L (E/Z). Mutation burden, microsatellite instability (MSI) status, tumor stage, disease free survival and immune scores were evaluated in these tumors. Compared to the POLE-only mutant tumors, tumors with E/Q, E/Z, and E/Q/Z mutations possessed significantly higher overall mutation frequencies (p < 0.001) and increased frequencies of mutations within the POLE exonuclease domain (p = 0.013). E/Q, E/Z, and E/Q/Z mutant colorectal, stomach and endometrial tumors within the TCGA cohort demonstrated 100% disease-free survival, even if mutations occurred outside the POLE exonuclease domain (p = 0.003). However, immune scores were related to microsatellite instability (MSI) and not POLE mutation status, suggesting that mechanisms in addition to host immune response may contribute to the prolonged disease-free survival.Conclusion: Our results demonstrate that POLE mutant tumors can be further substratified for outcomes prediction based on additional mutations in POLQ and ERV3L.

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Integrated analysis of the immunological and genetic status in and across cancer types: impact of mutational signatures beyond tumor mutational burden

Cited by 68 publications

References 47 publications

Measurement of tumor mutational burden (TMB) in routine molecular diagnostics: in silico and real‐life analysis of three larger gene panels

Measurement of tumor mutational burden (TMB) in routine molecular diagnostics: in silico and real‐life analysis of three larger gene panels

Age-related mutational signature negatively associated with immune activity and survival outcome in triple-negative breast cancer

Mutant POLQ and POLZ/REV3L DNA polymerases may contribute to favorable survival of tumors with POLE mutations outside the exonuclease domain

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