Molecular features and prognostic factors of locally advanced microsatellite instability-high gastric cancer.
Gastric cancer
Locally advanced
Microsatellite instability-high
Molecular features
Prognostic factor
Journal
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association
ISSN: 1436-3305
Titre abrégé: Gastric Cancer
Pays: Japan
ID NLM: 100886238
Informations de publication
Date de publication:
14 May 2024
14 May 2024
Historique:
received:
03
12
2023
accepted:
03
05
2024
medline:
15
5
2024
pubmed:
15
5
2024
entrez:
14
5
2024
Statut:
aheadofprint
Résumé
Microsatellite instability-high (MSI-H) tumors are distinct molecular subtypes in gastric cancer. However, a few studies have comprehensively reported the molecular features of MSI-H tumors and their prognostic factors in locally advanced gastric cancer. This study aimed to clarify the molecular features and prognostic factors of locally advanced MSI-H gastric cancer. This study included 499 patients with locally advanced gastric cancer who underwent radical gastrectomy. We evaluated the MSI status and compared with previously published whole-exome sequencing, panel sequencing, and gene expression profiling data. Clinicopathological characteristics and molecular profiles were compared between patients with MSI-H and microsatellite stable (MSS) gastric cancer. A subgroup analysis of survival was performed in patients with MSI-H gastric cancer. MSI-H tumors were detected in 79 of 499 patients (15.8%). MSI-H tumors were associated with an increased tumor mutational burden, MLH1 downregulation, CD274 (PD-L1) upregulation, and enrichment of cell cycle pathways. Among patients with MSI-H gastric cancer, the disease-specific survival (DSS) tended to be better in the surgery plus tegafur, gimeracil, and oteracil potassium (S-1) adjuvant chemotherapy group than in the surgery alone group, especially for stage III patients. Furthermore, DSS was better in the T cell-inflamed gene expression signature-high group, and it tended to be worse in the non-solid type poorly differentiated adenocarcinoma group. The molecular features and prognostic factors of locally advanced MSI-H gastric cancer were clarified. S-1 adjuvant chemotherapy appears to be beneficial, and the T cell-inflamed gene expression signature and histopathological type are prognostic factors in MSI-H tumors.
Sections du résumé
BACKGROUND
BACKGROUND
Microsatellite instability-high (MSI-H) tumors are distinct molecular subtypes in gastric cancer. However, a few studies have comprehensively reported the molecular features of MSI-H tumors and their prognostic factors in locally advanced gastric cancer. This study aimed to clarify the molecular features and prognostic factors of locally advanced MSI-H gastric cancer.
METHODS
METHODS
This study included 499 patients with locally advanced gastric cancer who underwent radical gastrectomy. We evaluated the MSI status and compared with previously published whole-exome sequencing, panel sequencing, and gene expression profiling data. Clinicopathological characteristics and molecular profiles were compared between patients with MSI-H and microsatellite stable (MSS) gastric cancer. A subgroup analysis of survival was performed in patients with MSI-H gastric cancer.
RESULTS
RESULTS
MSI-H tumors were detected in 79 of 499 patients (15.8%). MSI-H tumors were associated with an increased tumor mutational burden, MLH1 downregulation, CD274 (PD-L1) upregulation, and enrichment of cell cycle pathways. Among patients with MSI-H gastric cancer, the disease-specific survival (DSS) tended to be better in the surgery plus tegafur, gimeracil, and oteracil potassium (S-1) adjuvant chemotherapy group than in the surgery alone group, especially for stage III patients. Furthermore, DSS was better in the T cell-inflamed gene expression signature-high group, and it tended to be worse in the non-solid type poorly differentiated adenocarcinoma group.
CONCLUSIONS
CONCLUSIONS
The molecular features and prognostic factors of locally advanced MSI-H gastric cancer were clarified. S-1 adjuvant chemotherapy appears to be beneficial, and the T cell-inflamed gene expression signature and histopathological type are prognostic factors in MSI-H tumors.
Identifiants
pubmed: 38744779
doi: 10.1007/s10120-024-01506-5
pii: 10.1007/s10120-024-01506-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.
Références
World Health Organization. Cancer Today. https://gco.iarc.fr/today/home . Accessed 3 Dec 2023
Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010;11:439–49.
doi: 10.1016/S1470-2045(10)70070-X
pubmed: 20409751
Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357:1810–20.
doi: 10.1056/NEJMoa072252
pubmed: 17978289
Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, et al. Addition of docetaxel to oral fluoropyrimidine improves efficacy in patients with stage III gastric cancer: interim analysis of JACCRO GC-07, a randomized controlled trial. J Clin Oncol. 2019;37:1296–304.
doi: 10.1200/JCO.18.01138
pubmed: 30925125
pmcid: 6524985
The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.
doi: 10.1038/nature13480
Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–56.
doi: 10.1038/nm.3850
pubmed: 25894828
Polom K, Marano L, Marrelli D, De Luca R, Roviello G, Savelli V, et al. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br J Surg. 2018;105:159–67.
doi: 10.1002/bjs.10663
pubmed: 29091259
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.
doi: 10.1126/science.aan6733
pubmed: 28596308
pmcid: 5576142
Furukawa K, Hatakeyama K, Terashima M, Nagashima T, Urakami K, Ohshima K, et al. Molecular classification of gastric cancer predicts survival in patients undergoing radical gastrectomy based on project HOPE. Gastric Cancer. 2022;25:138–48.
doi: 10.1007/s10120-021-01242-0
pubmed: 34476642
Yamaguchi K, Urakami K, Ohshima K, Mochizuki T, Akiyama Y, Uesaka K, et al. Implementation of individualized medicine for cancer patients by multiomics-based analyses-the Project HOPE. Biomed Res. 2014;35:407–12.
doi: 10.2220/biomedres.35.407
pubmed: 25743347
Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14:101–12.
doi: 10.1007/s10120-011-0041-5
Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2021. Gastric Cancer. 2023;26:1–25.
doi: 10.1007/s10120-022-01331-8
Nagashima T, Yamaguchi K, Urakami K, Shimoda Y, Ohnami S, Ohshima K, et al. Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients. Cancer Sci. 2020;111:687–99.
doi: 10.1111/cas.14290
pubmed: 31863614
pmcid: 7004528
Shen R, Seshan VE. FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res. 2016;44:e131.
doi: 10.1093/nar/gkw520
pubmed: 27270079
pmcid: 5027494
Favero F, Joshi T, Marquard AM, Birkbak NJ, Krzystanek M, Li Q, et al. Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data. Ann Oncol. 2015;26:64–70.
doi: 10.1093/annonc/mdu479
pubmed: 25319062
Donehower LA, Soussi T, Korkut A, Liu Y, Schultz A, Cardenas M, et al. Integrated analysis of TP53 gene and pathway alterations in the cancer genome atlas. Cell Rep. 2019;28:1370-84.e5.
doi: 10.1016/j.celrep.2019.07.001
pubmed: 31365877
pmcid: 7546539
Hatakeyama K, Nagashima T, Ohshima K, Ohnami S, Ohnami S, Shimoda Y, et al. Characterization of tumors with ultralow tumor mutational burden in Japanese cancer patients. Cancer Sci. 2020;111:3893–901.
doi: 10.1111/cas.14572
pubmed: 32662546
pmcid: 7540986
Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127:2930–40.
doi: 10.1172/JCI91190
pubmed: 28650338
pmcid: 5531419
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.
doi: 10.1073/pnas.0506580102
pubmed: 16199517
pmcid: 1239896
Choi YY, Kim H, Shin SJ, Kim HY, Lee J, Yang HK, et al. Microsatellite instability and programmed cell death-ligand 1 expression in stage II/III gastric cancer: post hoc analysis of the CLASSIC randomized controlled study. Ann Surg. 2019;270:309–16.
doi: 10.1097/SLA.0000000000002803
pubmed: 29727332
Smyth EC, Wotherspoon A, Peckitt C, Gonzalez D, Hulkki-Wilson S, Eltahir Z, et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3:1197–203.
doi: 10.1001/jamaoncol.2016.6762
pubmed: 28241187
Nie RC, Chen GM, Yuan SQ, Kim JW, Zhou J, Nie M, et al. Adjuvant chemotherapy for gastric cancer patients with mismatch repair deficiency or microsatellite instability: systematic review and meta-analysis. Ann Surg Oncol. 2022;29:2324–31.
doi: 10.1245/s10434-021-11050-6
pubmed: 34796431
Kang SY, Kim DG, Ahn S, Ha SY, Jang KT, Kim KM. Comparative analysis of microsatellite instability by next-generation sequencing, MSI PCR and MMR immunohistochemistry in 1942 solid cancers. Pathol Res Pract. 2022;233:153874.
doi: 10.1016/j.prp.2022.153874
pubmed: 35405622
Ratovomanana T, Cohen R, Svrcek M, Renaud F, Cervera P, Siret A, et al. Performance of next-generation sequencing for the detection of microsatellite instability in colorectal cancer with deficient DNA mismatch repair. Gastroenterology. 2021;161:814–26.
doi: 10.1053/j.gastro.2021.05.007
pubmed: 33992635
Lu X, Nguyen TA, Moon SH, Darlington Y, Sommer M, Donehower LA. The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer Metastas Rev. 2008;27:123–35.
doi: 10.1007/s10555-008-9127-x
Matheu A, Maraver A, Serrano M. The Arf/p53 pathway in cancer and aging. Cancer Res. 2008;68:6031–4.
doi: 10.1158/0008-5472.CAN-07-6851
pubmed: 18676821
Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.
doi: 10.1056/NEJMoa022289
pubmed: 12867608
pmcid: 3584639
Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219–26.
doi: 10.1200/JCO.2009.27.1825
pubmed: 20498393
pmcid: 2903323
André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015;33:4176–87.
doi: 10.1200/JCO.2015.63.4238
pubmed: 26527776
Akimoto E, Kuwata T, Shitara K, Kawazoe A, Sakamoto N, Ishii G, et al. Impact of programmed death-ligand 1 expression on mismatch repair deficiency and Epstein–Barr virus status on survival outcomes in patients with stage II/III gastric cancer after surgery. Ann Surg Oncol. 2023;30:5227–36.
doi: 10.1245/s10434-023-13266-0
pubmed: 36934377
Hyung J, Cho H, Kim HD, Park YS, Moon M, Ryu MH, et al. DNA mismatch repair deficiency and outcomes of patients with locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery plus postoperative S-1: a sub-analysis of the phase 3 PRODIGY trial. Gastric Cancer. 2024;27:110–7.
doi: 10.1007/s10120-023-01434-w
pubmed: 37889360
Kim JW, Cho SY, Chae J, Kim JW, Kim TY, Lee KW, et al. Adjuvant chemotherapy in microsatellite instability-high gastric cancer. Cancer Res Treat. 2020;52:1178–87.
pubmed: 32599979
pmcid: 7577821
Nakamura K, Hatakeyama K, Furukawa K, Fujiya K, Kamiya S, Hikage M, et al. Prediction of S-1 adjuvant chemotherapy benefit in stage II/III gastric cancer treatment based on comprehensive gene expression analysis. Gastric Cancer. 2020;23:648–58.
doi: 10.1007/s10120-020-01056-6
pubmed: 32185558
Yang Y, Shi Z, Bai R, Hu W. Heterogeneity of MSI-H gastric cancer identifies a subtype with worse survival. J Med Genet. 2021;58:12–9.
doi: 10.1136/jmedgenet-2019-106609
pubmed: 32170001
Hu W, Yang Y, Qi L, Chen J, Ge W, Zheng S. Subtyping of microsatellite instability-high colorectal cancer. Cell Commun Signal. 2019;17:79.
doi: 10.1186/s12964-019-0397-4
pubmed: 31331345
pmcid: 6647262
Ozer M, Vegivinti CTR, Syed M, Ferrell ME, Gonzalez Gomez C, Cheng S, et al. Neoadjuvant immunotherapy for patients with dMMR/MSI-high gastrointestinal cancers: a changing paradigm. Cancers. 2023;15:3833.
doi: 10.3390/cancers15153833
pubmed: 37568648
pmcid: 10417711
Mestrallet G, Brown M, Bozkus CC, Bhardwaj N. Immune escape and resistance to immunotherapy in mismatch repair deficient tumors. Front Immunol. 2023;14:1210164.
doi: 10.3389/fimmu.2023.1210164
pubmed: 37492581
pmcid: 10363668