Molecular evolution of intestinal-type early gastric cancer according to Correa cascade

Abstract

Early screening is crucial for the prevention of intestinal-type gastric cancer. The current study aimed to ascertain the molecular evolution of intestinal-type gastric cancer based on the Correa cascade for precise gastric cancer screening. We collected sequential lesions of the Correa cascade in the formalin-fixed and paraffin-embedded endoscopic submucosal dissection (ESD)-resected specimens from 14 Chinese patients by microdissection, and subsequently determined the profiles of somatic aberrations during gastric carcinogenesis using whole-exome sequencing, identifying multiple variants at different Correa stages. The results showed that TP53, PCLO, and PRKDC were the most frequently mutated genes in early gastric cancer (EGC). We found a high frequency of TP53 alterations in low-grade intraepithelial neoplasia (LGIN), which further increased in high-grade intraepithelial neoplasia (HGIN) and EGC. Intestinal metaplasia (IM) showed no significant correlation with EGC in terms of mutational spectra, whereas both LGIN and HGIN showed higher genomic similarities to EGC, compared with IM. Based on Jaccard similarity coefficients, we constructed three evolutionary models, with most patients showing linear progression from LGIN to HGIN, ultimately resulting in EGC. The extracellular matrix-receptor interaction pathway was revealed to be involved in the linear evolution. Additionally, the retrospective validation study of 39 patients diagnosed with LGIN indicated that PRKDC mutations, in addition to TP53 mutations, may drive LGIN progression to HGIN or EGC. In conclusion, the current study unveils the genomic evolution across the Correa cascade of intestinal-type gastric cancer, elucidates the underlying molecular mechanisms of gastric carcinogenesis, and provides evidence for potential personalized gastric cancer surveillance.

Keywords

intestinal-type gastric cancer / Correa cascade / gastric intestinal metaplasia / low-grade intraepithelial neoplasia / molecular evolution

Fundings

The current study was financially supported by the National Natural Science Foundation of China (Grant Nos. 81871959, 82373143, and 82003180).

Acknowledgments

The authors are grateful to Prof. Shoulin Wang (School of Public Health, Nanjing Medical University) for the constructive opinions and critical review, and Prof. Yifen Zhang (Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine) for the pathology support.

References

[1] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. doi: 10.3322/caac.21660

[2] ASGE Standards of Practice Committee, Evans JA, Chandrasekhara V, et al. The role of endoscopy in the management of premalignant and malignant conditions of the stomach[J]. Gastrointest Endosc, 2015, 82(1): 1-8. doi: 10.1016/j.gie.2015.03.1967

[3] Pimentel-Nunes P, Libânio D, Marcos-Pinto R, et al. Management of epithelial precancerous conditions and lesions in the stomach (MAPS Ⅱ): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019[J]. Endoscopy, 2019, 51(4): 365-388. doi: 10.1055/a-0859-1883

[4] Mabe K, Inoue K, Kamada T, et al. Endoscopic screening for gastric cancer in Japan: current status and future perspectives[J]. Dig Endosc, 2022, 34(3): 412-419. doi: 10.1111/den.14063

[5] Kim B, Cho SJ. Endoscopic screening and surveillance for gastric cancer[J]. Gastrointest Endosc Clin N Am, 2021, 31(3): 489-501. doi: 10.1016/j.giec.2021.03.004

[6] Tan P, Yeoh KG. Genetics and molecular pathogenesis of gastric adenocarcinoma[J]. Gastroenterology, 2015, 149(5): 1153-1162.e3.

[7] Sugai T, Eizuka M, Arakawa N, et al. Molecular profiling and comprehensive genome-wide analysis of somatic copy number alterations in gastric intramucosal neoplasias based on microsatellite status[J]. Gastric Cancer, 2018, 21(5): 765-775. doi: 10.1007/s10120-018-0810-5

[8] Deng N, Goh LK, Wang H, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets[J]. Gut, 2012, 61(5): 673-684. doi: 10.1136/gutjnl-2011-301839

[9] Verma R, Sharma PC. Next generation sequencing-based emerging trends in molecular biology of gastric cancer[J]. Am J Cancer Res, 2018, 8(2): 207-225. https://pubmed.ncbi.nlm.nih.gov/29511593/

[10] Fassan M, Simbolo M, Bria E, et al. High-throughput mutation profiling identifies novel molecular dysregulation in high-grade intraepithelial neoplasia and early gastric cancers[J]. Gastric Cancer, 2014, 17(3): 442-449. doi: 10.1007/s10120-013-0315-1

[11] Kakiuchi M, Nishizawa T, Ueda H, et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma[J]. Nat Genet, 2014, 46(6): 583-587. doi: 10.1038/ng.2984

[12] Correa P, Haenszel W, Cuello C, et al. A model for gastric cancer epidemiology[J]. Lancet, 1975, 2(7924): 58-60. doi: 10.1016/S0140-6736(75)90498-5

[13] Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2018 (5th edition)[J]. Gastric Cancer, 2021, 24(1): 1-21. doi: 10.1007/s10120-020-01042-y

[14] Yao K, Uedo N, Kamada T, et al. Guidelines for endoscopic diagnosis of early gastric cancer[J]. Dig Endosc, 2020, 32(5): 663-698. doi: 10.1111/den.13684

[15] Yoshida T, Yamaguchi T, Maekawa S, et al. Identification of early genetic changes in well-differentiated intramucosal gastric carcinoma by target deep sequencing[J]. Gastric Cancer, 2019, 22(4): 742-750. doi: 10.1007/s10120-019-00926-y

[16] Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data[J]. Bioinformatics, 2014, 30(15): 2114-2120. doi: 10.1093/bioinformatics/btu170

[17] Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform[J]. Bioinformatics, 2009, 25(14): 1754-1760. doi: 10.1093/bioinformatics/btp324

[18] Koboldt DC, Zhang Q, Larson DE, et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing[J]. Genome Res, 2012, 22(3): 568-576. doi: 10.1101/gr.129684.111

[19] Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic signaling pathways in the Cancer Genome Atlas[J]. Cell, 2018, 173(2): 321-337.e10. doi: 10.1016/j.cell.2018.03.035

[20] Reiter JG, Makohon-Moore AP, Gerold JM, et al. Reconstructing metastatic seeding patterns of human cancers[J]. Nat Commun, 2017, 8: 14114. doi: 10.1038/ncomms14114

[21] Puliga E, Corso S, Pietrantonio F, et al. Microsatellite instability in gastric cancer: between lights and shadows[J]. Cancer Treat Rev, 2021, 95: 102175. doi: 10.1016/j.ctrv.2021.102175

[22] Ooi CH, Ivanova T, Wu J, et al. Oncogenic pathway combinations predict clinical prognosis in gastric cancer[J]. PLoS Genet, 2009, 5(10): e1000676. doi: 10.1371/journal.pgen.1000676

[23] Chiurillo MA. Role of the Wnt/β-catenin pathway in gastric cancer: an in-depth literature review[J]. World J Exp Med, 2015, 5(2): 84-102. doi: 10.5493/wjem.v5.i2.84

[24] Yokozaki H, Yasui W, Tahara E. Genetic and epigenetic changes in stomach cancer[J]. Int Rev Cytol, 2001, 204: 49-95. https://pubmed.ncbi.nlm.nih.gov/11243597/

[25] Zhang X, Li M, Chen S, et al. Endoscopic screening in Asian countries is associated with reduced gastric cancer mortality: a meta-analysis and systematic review[J]. Gastroenterology, 2018, 155(2): 347-354.e9. doi: 10.1053/j.gastro.2018.04.026

[26] Huang KK, Ramnarayanan K, Zhu F, et al. Genomic and epigenomic profiling of high-risk intestinal metaplasia reveals molecular determinants of progression to gastric cancer[J]. Cancer Cell, 2018, 33(1): 137-150.e5. doi: 10.1016/j.ccell.2017.11.018

[27] Rokutan H, Abe H, Nakamura H, et al. Initial and crucial genetic events in intestinal-type gastric intramucosal neoplasia[J]. J Pathol, 2019, 247(4): 494-504. doi: 10.1002/path.5208

[28] Kim KW, Kim N, Choi Y, et al. Different effects of p53 protein overexpression on the survival of gastric cancer patients according to Lauren histologic classification: a retrospective study[J]. Gastric Cancer, 2021, 24(4): 844-857. doi: 10.1007/s10120-021-01163-y

[29] Zhang J, Liu F, Yang Y, et al. Integrated DNA and RNA sequencing reveals early drivers involved in metastasis of gastric cancer[J]. Cell Death Dis, 2022, 13(4): 392. doi: 10.1038/s41419-022-04838-1

[30] The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma[J]. Nature, 2014, 513(7517): 202-209. doi: 10.1038/nature13480

[31] Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes[J]. Nat Med, 2015, 21(5): 449-456. doi: 10.1038/nm.3850

[32] Wang H, Ding Y, Chen Y, et al. A novel genomic classification system of gastric cancer via integrating multidimensional genomic characteristics[J]. Gastric Cancer, 2021, 24(6): 1227-1241. doi: 10.1007/s10120-021-01201-9

[33] Shimizu T, Marusawa H, Matsumoto Y, et al. Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection[J]. Gastroenterology, 2014, 147(2): 407-417.e3.

[34] Sethi NS, Kikuchi O, Duronio GN, et al. Early TP53 alterations engage environmental exposures to promote gastric premalignancy in an integrative mouse model[J]. Nat Genet, 2020, 52(2): 219-230. doi: 10.1038/s41588-019-0574-9

[35] Li D, Bautista MC, Jiang SF, et al. Risks and predictors of gastric adenocarcinoma in patients with gastric intestinal metaplasia and dysplasia: a population-based study[J]. Am J Gastroenterol, 2016, 111(8): 1104-1113. doi: 10.1038/ajg.2016.188

[36] Shao L, Li P, Ye J, et al. Risk of gastric cancer among patients with gastric intestinal metaplasia[J]. Int J Cancer, 2018, 143(7): 1671-1677. doi: 10.1002/ijc.31571

[37] Zhang R, Rabinovitch PS, Mattis AN, et al. Gastric intestinal metaplasia in mucosa adjacent to gastric cancers is rarely associated with the aneuploidy that is characteristic of gastric dysplasia or cancer[J]. Am J Surg Pathol, 2021, 45(10): 1374-1381. doi: 10.1097/PAS.0000000000001764

[38] Chen Y, Dang Y, Sang H, et al. Establishment and validation of a model to determine the progression risk of low grade intraepithelial neoplasia[J]. Surg Endosc, 2021, 35(4): 1551-1557. doi: 10.1007/s00464-020-07531-6