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. 2024 Dec 2;24(1):1482.
doi: 10.1186/s12885-024-13236-z.

Prognostic effect of immunohistochemically determined molecular subtypes in gastric cancer

Jefim Brodkin  1 , Tuomas Kaprio  2   3 , Jaana Hagström  2   4   5 , Alli Leppä  3 , Arto Kokkola  3 , Caj Haglund  2   3   4 , Camilla Böckelman  2   3
Affiliations

Prognostic effect of immunohistochemically determined molecular subtypes in gastric cancer

Jefim Brodkin et al. BMC Cancer. .

Abstract

Introduction: Gastric cancer is the fifth most common cancer worldwide and the fourth most common cause of cancer-related death. Two molecular subtyping classifications were recently introduced: The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) classifications.

Methods: We classified a cohort of 283 gastric cancer patients undergoing surgery at Helsinki University Hospital between 2000 and 2009. We constructed a tumour tissue microarray immunostained for the following markers: microsatellite instability (MSI) markers MSH2, MSH6, MLH1, and PMS2; p53; E-cadherin; and EBERISH.

Results: In the univariate survival analysis for disease-specific survival, the Epstein-Barr virus (EBV) -positive subtype exhibited the worst prognosis with a hazard ratio (HR) of 2.49 (95% confidence interval [CI] 1.19-5.25, p = 0.016) compared with the most benign subtype, chromosomal instability (CIN). Using TCGA's classification, the genetically stable (GS) and MSI subtypes exhibited a worse survival compared with CIN (HR 1.73 [95% CI 1.15-2.60], p = 0.009 and HR 1.74 [95% CI 1.06-2.84], p = 0.027, respectively). Using the ACRG classification, the p53 aberrant subtype exhibited the best prognosis, whereas wild-type p53, MSI, and the epithelial-mesenchymal transition (EMT) subtypes exhibited poorer prognoses (EMT: HR 1.90 [95% CI 1.30-2.77], p < 0.001) when compared with aberrant p53.

Conclusions: Immunohistochemical analysis can identify prognostically different molecular subtypes of gastric cancer. The method is inexpensive and fast, yet reveals significant information for clinical decision-making. However, our study did not find that either molecular subtyping performed better than the other classification. Thus, further development of the most optimal grouping of different molecular subtypes is still needed.

Keywords: Epstein–Barr virus; Gastric cancer; Immunohistochemistry; Survival.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Appropriate ethical permits were granted by the National Supervisory Authority of Health and Welfare (permit for research conducted with human samples: Valvira Dnro 1004/06.01.03.01/2012), the hospital district of Helsinki and Uusimaa (permit number HUS/23/2024), and the Ethics Committee of Medicine of the Helsinki University Central Hospital (permit number HUS/1223/2021). Patient information, samples, and data were handled and stored in accordance with the Declaration of Helsinki and other local regulations. The National Supervisory Authority of Health and Welfare granted permission to study the archived tissue samples without requiring individual informed consent (Valvira Dnro 1004/06.01.03.01/2012). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of immunohistochemical molecular subtypes. Flowchart presents the subtyping according to a) The Cancer Genome Atlas and b) Asian Cancer Research Group classifications. Abbreviations: EBERISH, Epstein–Barr virus encoding region in situ hybridisation; EBV, Epstein–Barr virus; MSI, microsatellite instability; MMRd/p, mismatch repair deficient/proficient; CIN, chromosomal instability; GS, genetically stable; EMT, epithelial–mesenchymal transition; p53aber, aberrant p53; p53wt, wild-type p53
Fig. 2
Fig. 2
Sankey diagram of connections between subtypes. Width of the connecting line indicates how many patients had different subtypes in the Cancer Genome Atlas and Asian Cancer Research Group–based classifications. Abbreviations: CIN, chromosomal instability; GS, genetically stable; MSI, microsatellite instability; EBV, Epstein–Barr virus; p53aber, aberrant p53; p53wt, wild-type p53; EMT, epithelial–mesenchymal transition
Fig. 3
Fig. 3
Disease-specific survival of patients according to subtypes. Disease-specific survival of a) subtypes based on the Cancer Genome Atlas classification and b) subtypes based on the Asian Cancer Research Group classification. Survival curves were drawn according to the Kaplan–Meier method and the p values were calculated using the log-rank test. Abbreviations: EBV, Epstein–Barr virus; MSI, microsatellite instability; CIN, chromosomal instability; GS, genetically stable; EMT, epithelial–mesenchymal transition; p53aber, aberrant p53; p53wt, wild-type p53
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References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. - PubMed
    1. Leja M, Grinberga-Derica I, Bilgilier C, Steininger C. Review: Epidemiology of Helicobacter pylori infection. Helicobacter. 2019;24(Suppl 1): e12635. - PubMed
    1. Wipfli H, Samet JM. One Hundred Years in the Making: The Global Tobacco Epidemic. Annu Rev Public Health. 2016;37:149–66. - PubMed
    1. Cancer statistics. Helsinki: Finnish Cancer Registry. 1953. Available from https://tilastot.syoparekisteri.fi/syovat. Cited 2023 Apr 10.
    1. Laurén P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49. - PubMed

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