Mutational Signatures Driven by Epigenetic Determinants Enable the Stratification of Patients with Gastric Cancer for Therapeutic Intervention
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Mutational Signatures
2.2. dMMR Signatures and Prognostic Features
2.3. Clinical and Molecular Features in the S4 dMMR Groups
2.4. S4 is Associated with Epigenetic Changes and Mutational Background in MMR Genes
2.5. Somatic Changes Associated with S4
2.6. Tumor Microenvironment in S4 Groups
3. Discussion
4. Materials and Methods
4.1. Clinical and Genomic Data from Public Cohorts
4.2. Clinical and Genomic Data from the Validation Cohort
4.3. Statistical Analyses
4.4. Mutational Signatures in Cell Lines
4.5. Mutational Signature Estimation
4.6. Molecular Features
4.7. Identification of Significantly Mutated Genes
4.8. Evaluation of Tumor Microenvironment Composition and Immunological Aspects
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CIN | chromosomal instability |
dMMR | DNA mismatch repair deficiency |
HRR | homologous recombination repair |
GS | genomically stable |
GSEA | gene set enrichment analysis |
MSI | microsatellite instability |
MSI-H | microsatellite instability high |
MSI-L | microsatellite instability low |
NER | nucleotide excision repair |
OS | overall survival |
SNV | single-nucleotide variation |
TCGA | The Cancer Genome Atlas |
TMB | tumor mutational burden |
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Variable | All (n = 787) | S4low (n = 590) | S4high (n = 197) | p Value | |||
---|---|---|---|---|---|---|---|
N | % | N | % | N | % | ||
Age (mean ± SD) | 64.17 ± 11.73 | 64.17 ± 11.73 | 66.25 ± 10.68 | 0.0024 | |||
Gender | 767 | 97 | 571 | 91 | 196 | 99 | |
Female | 274 | 0.36 | 192 | 0.34 | 82 | 0.42 | 0.0473 |
Male | 493 | 0.64 | 379 | 0.66 | 114 | 0.58 | |
Race | 726 | 92 | 546 | 93 | 180 | 91 | |
White | 275 | 0.38 | 203 | 0.37 | 72 | 0.40 | 0.7427 |
Black | 13 | 0.02 | 11 | 0.02 | 2 | 0.01 | |
Asian | 437 | 0.60 | 331 | 0.61 | 106 | 0.59 | |
Other | 1 | 0.00 | 1 | 0.00 | 0 | 0.00 | |
Anatomic Site | 627 | 80 | 495 | 84 | 132 | 67 | |
Cardia/Proximal | 168 | 0.27 | 148 | 0.30 | 20 | 0.15 | 0.0015 |
Fundus/Body | 212 | 0.34 | 166 | 0.34 | 46 | 0.35 | |
Antrum/Distal | 242 | 0.39 | 178 | 0.36 | 64 | 0.48 | |
Other | 5 | 0.01 | 3 | 0.01 | 2 | 0.02 | |
Histology Lauren | 467 | 59 | 383 | 65 | 84 | 43 | |
Diffuse | 150 | 0.32 | 132 | 0.34 | 18 | 0.21 | 0.0041 |
Intestinal | 301 | 0.64 | 235 | 0.61 | 66 | 0.79 | |
Mixed | 16 | 0.03 | 16 | 0.04 | 0 | 0.00 | |
Stage T | 712 | 90 | 526 | 89 | 186 | 94 | |
T1-T2 | 181 | 0.25 | 132 | 0.25 | 49 | 0.26 | 0.8116 |
T3-T4 | 531 | 0.75 | 394 | 0.75 | 137 | 0.74 | |
Stage N | 712 | 90 | 526 | 59 | 186 | 94 | |
N0 | 173 | 0.24 | 115 | 0.22 | 58 | 0.31 | 0.0144 |
N+ | 539 | 0.76 | 411 | 0.78 | 128 | 0.69 | |
Stage M | 707 | 90 | 524 | 89 | 183 | 93 | |
M0 | 623 | 0.88 | 461 | 0.88 | 162 | 0.89 | 0.9422 |
M1 | 62 | 0.01 | 47 | 0.09 | 15 | 0.08 | |
MX | 22 | 0.03 | 16 | 0.03 | 6 | 0.03 | |
Pathological Stage | 715 | 91 | 546 | 93 | 169 | 86 | |
I | 85 | 0.12 | 58 | 0.11 | 27 | 0.16 | 0.0386 |
II | 220 | 0.31 | 160 | 0.29 | 60 | 0.36 | |
III | 289 | 0.40 | 228 | 0.42 | 61 | 0.36 | |
IV | 121 | 0.15 | 100 | 0.18 | 21 | 0.12 | |
Molecular Subtype | 403 | 51 | 289 | 49 | 114 | 58 | |
CIN | 223 | 0.55 | 206 | 0.71 | 17 | 0.15 | <0.0001 |
GS | 50 | 0.12 | 47 | 0.16 | 3 | 0.03 | |
EBV | 38 | 0.09 | 33 | 0.11 | 5 | 0.04 | |
MSI | 85 | 0.21 | 0 | 0.00 | 85 | 0.75 | |
POLE | 7 | 0.02 | 3 | 0.01 | 4 | 0.04 | |
MSIseq Status | 787 | 100 | 590 | 100 | 197 | 100 | |
MSI-H | 160 | 0.20 | 41 | 0.07 | 119 | 0.60 | <0.0001 |
Non MSI-H | 627 | 0.80 | 549 | 0.93 | 78 | 0.40 | |
Immune Subtypes | 388 | 49 | 285 | 48 | 103 | 52 | |
C1 | 128 | 0.33 | 101 | 0.35 | 27 | 0.26 | <0.0001 |
C2 | 209 | 0.54 | 135 | 0.47 | 74 | 0.72 | |
C3 | 35 | 0.09 | 34 | 0.12 | 1 | 0.01 | |
C4 | 9 | 0.02 | 8 | 0.03 | 1 | 0.01 | |
C6 | 7 | 0.02 | 7 | 0.02 | 0 | 0.00 |
Variable | Coefficient | Standard Error | CI (95%) for Coefficient | p-Value | OR | CI (95%) for Coefficient | ||
---|---|---|---|---|---|---|---|---|
Lower | Upper | Lower | Upper | |||||
Simple logistic regression model | ||||||||
ExpS2 | 4.772 | 0.5226 | 3.748 | 5.796 | <0.0001 | 118.155 | 42.424 | 329.078 |
ExpS4 | 3.2424 | 0.3469 | 2.562 | 3.922 | <0.0001 | 25.595 | 12.968 | 50.518 |
ExpS5 | 0.2725 | 0.1674 | −0.056 | 0.601 | 0.104 | 1.313 | 0.946 | 1.823 |
Multiple logistic regression model | ||||||||
Intercept | −2.640 | 0.300 | −3.227 | −2.052 | <0.0001 | |||
ExpS2 | 1.304 | 0.730 | −0.126 | 2.733 | 0.074 | 3.682 | 0.881 | 15.386 |
ExpS4 | 3.1162 | 0.5348 | 2.068 | 4.164 | <0.0001 | 22.561 | 7.909 | 64.353 |
ExpS5 | −2.231 | 0.4067 | −3.028 | −1.434 | <0.0001 | 0.107 | 0.048 | 0.238 |
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Buttura, J.R.; Provisor Santos, M.N.; Valieris, R.; Drummond, R.D.; Defelicibus, A.; Lima, J.P.; Calsavara, V.F.; Freitas, H.C.; Cordeiro de Lima, V.C.; Fernanda Bartelli, T.; et al. Mutational Signatures Driven by Epigenetic Determinants Enable the Stratification of Patients with Gastric Cancer for Therapeutic Intervention. Cancers 2021, 13, 490. https://doi.org/10.3390/cancers13030490
Buttura JR, Provisor Santos MN, Valieris R, Drummond RD, Defelicibus A, Lima JP, Calsavara VF, Freitas HC, Cordeiro de Lima VC, Fernanda Bartelli T, et al. Mutational Signatures Driven by Epigenetic Determinants Enable the Stratification of Patients with Gastric Cancer for Therapeutic Intervention. Cancers. 2021; 13(3):490. https://doi.org/10.3390/cancers13030490
Chicago/Turabian StyleButtura, Jaqueline Ramalho, Monize Nakamoto Provisor Santos, Renan Valieris, Rodrigo Duarte Drummond, Alexandre Defelicibus, João Paulo Lima, Vinicius Fernando Calsavara, Helano Carioca Freitas, Vladmir C. Cordeiro de Lima, Thais Fernanda Bartelli, and et al. 2021. "Mutational Signatures Driven by Epigenetic Determinants Enable the Stratification of Patients with Gastric Cancer for Therapeutic Intervention" Cancers 13, no. 3: 490. https://doi.org/10.3390/cancers13030490