Top

Gastric Cancer

Published in:

01-05-2020 | Gastric Cancer | Original Article

Combination of L1 methylation and tumor-infiltrating lymphocytes as prognostic marker in advanced gastric cancer

Authors: Younghoon Kim, Ye-Young Rhee, Xianyu Wen, Nam-Yun Cho, Jeong Mo Bae, Woo Ho Kim, Gyeong Hoon Kang

Published in: Gastric Cancer | Issue 3/2020

Abstract

Background

High density of tumor-infiltrating lymphocyte (TIL) is known to be associated with prolonged survival time, whereas tumoral-L1 hypomethylation has been associated with shortened survival time in patients with gastric cancer (GC). Since L1-methylation level is high in lymphocytes, higher density of TIL could lead to higher measurement of L1-methylation level in cancer tissues which contain cancer cells as well as non-neoplastic cells, including TIL. Putative interaction of TIL in the relationship between L1-methylation level and survival led us to explore combinatory statuses of tumoral-L1-methylation level and TIL density as a prognostic marker in GC.

Methods

TIL and tumoral-L1-methylation level were measured in advanced GC samples (n = 491), using CD3 immunohistochemistry and pyrosequencing-methylation analysis, respectively. TIL density was measured in tumor center and invasive front areas.

Results

TIL density correlated with tumoral-L1-methylation level but the relationship was weak. Combinatory statuses of L1-methylation level and CD3 TIL density were found to be statistically significant in survival analysis. Multivariate analysis revealed that the relationship between combinatory statuses and survival was independent. Prognostic value of the combinatory statuses at invasive front was significant in an independent set.

Conclusions

Our findings indicate that tumoral-L1-methylation level is correlated with TIL density and that combinatory statuses might help to find a subset of GCs with worse clinical outcome in GCs with low-L1-methylation status or a subset of GCs with better clinical outcome in GCs with high-L1-methylation status.

Available only for authorised users

Chalitchagorn K, Shuangshoti S, Hourpai N, Kongruttanachok N, Tangkijvanich P, Thong-ngam D, et al. Distinctive pattern of LINE-1 methylation level in normal tissues and the association with carcinogenesis. Oncogene. 2004;23(54):8841–6. https://doi.org/10.1038/sj.onc.1208137.CrossRefPubMed

Weisenberger DJ, Campan M, Long TI, Kim M, Woods C, Fiala E, et al. Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res. 2005;33(21):6823–36. https://doi.org/10.1093/nar/gki987.CrossRefPubMedPubMedCentral

Lisanti S, Omar WA, Tomaszewski B, De Prins S, Jacobs G, Koppen G, et al. Comparison of methods for quantification of global DNA methylation in human cells and tissues. PLoS O ne. 2013;8(11):e79044. https://doi.org/10.1371/journal.pone.0079044.CrossRef

Shigaki H, Baba Y, Watanabe M, Murata A, Iwagami S, Miyake K, et al. LINE-1 hypomethylation in gastric cancer, detected by bisulfite pyrosequencing, is associated with poor prognosis. Gastric Cancer. 2013;16(4):480–7. https://doi.org/10.1007/s10120-012-0209-7.CrossRefPubMed

Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Chan AT, Schernhammer ES, et al. A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J Natl Cancer Inst. 2008;100(23):1734–8. https://doi.org/10.1093/jnci/djn359.CrossRefPubMedPubMedCentral

Bae JM, Shin SH, Kwon HJ, Park SY, Kook MC, Kim YW, et al. ALU and LINE-1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications. Int J Cancer. 2012;131(6):1323–31. https://doi.org/10.1002/ijc.27369.CrossRefPubMed

Iwagami S, Baba Y, Watanabe M, Shigaki H, Miyake K, Ishimoto T, et al. LINE-1 hypomethylation is associated with a poor prognosis among patients with curatively resected esophageal squamous cell carcinoma. Ann Surg. 2013;257(3):449–55. https://doi.org/10.1097/SLA.0b013e31826d8602.CrossRefPubMed

Kim Y, Wen X, Jeong S, Cho NY, Kim WH, Kang GH. Combinatory low methylation statuses of SAT-alpha and L1 are associated with shortened survival time in patients with advanced gastric cancer. Gastric Cancer. 2018;22(1):37–47. https://doi.org/10.1007/s10120-018-0852-8.CrossRefPubMed

Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer. 2008;99(10):1704–11. https://doi.org/10.1038/sj.bjc.6604738.CrossRefPubMedPubMedCentral

10.

Zheng X, Song X, Shao Y, Xu B, Chen L, Zhou Q, et al. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis. Oncotarget. 2017;8(34):57386–98. https://doi.org/10.18632/oncotarget.18065.CrossRefPubMedPubMedCentral

11.

Estecio MR, Gharibyan V, Shen L, Ibrahim AE, Doshi K, He R, et al. LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability. PLoS O ne. 2007;2(5):e399. https://doi.org/10.1371/journal.pone.0000399.CrossRef

12.

Wen X, Jeong S, Kim Y, Bae JM, Cho NY, Kim JH, et al. Improved results of LINE-1 methylation analysis in formalin-fixed, paraffin-embedded tissues with the application of a heating step during the DNA extraction process. Clin Epigenetics. 2017;9:1. https://doi.org/10.1186/s13148-016-0308-0.CrossRefPubMedPubMedCentral

13.

Tellez CS, Shen L, Estecio MR, Jelinek J, Gershenwald JE, Issa JP. CpG island methylation profiling in human melanoma cell lines. Melanoma Res. 2009;19(3):146–55.CrossRef

14.

Kim Y, Wen X, Jeong S, Cho NY, Kim WH, Kang GH. Combinatory low methylation statuses of SAT-alpha and L1 are associated with shortened survival time in patients with advanced gastric cancer. Gastric Cancer. 2019;22(1):37–47. https://doi.org/10.1007/s10120-018-0852-8.CrossRefPubMed

15.

Bankhead P, Loughrey MB, Fernandez JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7(1):16878. https://doi.org/10.1038/s41598-017-17204-5.CrossRefPubMedPubMedCentral

16.

Kang GH, Lee S, Cho NY, Gandamihardja T, Long TI, Weisenberger DJ, et al. DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Investig. 2008;88(2):161–70. https://doi.org/10.1038/labinvest.3700707.CrossRefPubMed

17.

Song YS, Kim Y, Cho NY, Yang HK, Kim WH, Kang GH. Methylation status of long interspersed element-1 in advanced gastric cancer and its prognostic implication. Gastric Cancer. 2016;19(1):98–106. https://doi.org/10.1007/s10120-015-0463-6.CrossRefPubMed

18.

Furlan C, Polesel J, Barzan L, Franchin G, Sulfaro S, Romeo S, et al. Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma. Clin Epigenetics. 2017;9:58. https://doi.org/10.1186/s13148-017-0357-z.CrossRefPubMedPubMedCentral

19.

Baba Y, Watanabe M, Murata A, Shigaki H, Miyake K, Ishimoto T, et al. LINE-1 hypomethylation, DNA copy number alterations, and CDK6 amplification in esophageal squamous cell carcinoma. Clin Cancer Res. 2014;20(5):1114–24. https://doi.org/10.1158/1078-0432.CCR-13-1645.CrossRefPubMed

20.

Harada K, Baba Y, Ishimoto T, Chikamoto A, Kosumi K, Hayashi H, et al. LINE-1 methylation level and patient prognosis in a database of 208 hepatocellular carcinomas. Ann Surg Oncol. 2015;22(4):1280–7. https://doi.org/10.1245/s10434-014-4134-3.CrossRefPubMed

21.

Jeong S, Lee K, Wen X, Kim Y, Cho NY, Jang JJ, et al. Tumoral LINE-1 hypomethylation is associated with poor survival of patients with intrahepatic cholangiocarcinoma. BMC Cancer. 2017;17(1):588. https://doi.org/10.1186/s12885-017-3595-8.CrossRefPubMedPubMedCentral

22.

Imperatori A, Sahnane N, Rotolo N, Franzi F, Nardecchia E, Libera L, et al. LINE-1 hypomethylation is associated to specific clinico-pathological features in stage I non-small cell lung cancer. Lung Cancer. 2017;108:83–9. https://doi.org/10.1016/j.lungcan.2017.03.003.CrossRefPubMed

23.

Yamamura K, Kosumi K, Baba Y, Harada K, Gao F, Zhang X, et al. LINE-1 methylation level and prognosis in pancreas cancer: pyrosequencing technology and literature review. Surg Today. 2017;47(12):1450–9. https://doi.org/10.1007/s00595-017-1539-1.CrossRefPubMed

24.

Rhee YY, Lee TH, Song YS, Wen X, Kim H, Jheon S, et al. Prognostic significance of promoter CpG island hypermethylation and repetitive DNA hypomethylation in stage I lung adenocarcinoma. Virchows Arch. 2015. https://doi.org/10.1007/s00428-015-1749-0.CrossRefPubMed

25.

Ogino S, Kawasaki T, Nosho K, Ohnishi M, Suemoto Y, Kirkner GJ, et al. LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Int J Cancer. 2008;122(12):2767–73. https://doi.org/10.1002/ijc.23470.CrossRefPubMedPubMedCentral

26.

Mima K, Nowak JA, Qian ZR, Cao Y, Song M, Masugi Y, et al. Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival. Oncotarget. 2016;7(34):55098–109. https://doi.org/10.18632/oncotarget.10398.CrossRefPubMedPubMedCentral

27.

Jung H, Choi JK, Lee EA. Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers. Genome Res. 2018. https://doi.org/10.1101/gr.231837.117.CrossRefPubMedPubMedCentral

28.

Kim KJ, Wen XY, Yang HK, Kim WH, Kang GH. Prognostic implication of M2 macrophages are determined by the proportional balance of tumor associated macrophages and tumor infiltrating lymphocytes in microsatellite-unstable gastric carcinoma. PLoS O ne. 2015;10(12):e0144192. https://doi.org/10.1371/journal.pone.0144192.CrossRef

29.

Hur K, Niwa T, Toyoda T, Tsukamoto T, Tatematsu M, Yang HK, et al. Insufficient role of cell proliferation in aberrant DNA methylation induction and involvement of specific types of inflammation. Carcinogenesis. 2011;32(1):35–41. https://doi.org/10.1093/carcin/bgq219.CrossRefPubMed

30.

Wang HC, Chen CW, Yang CL, Tsai IM, Hou YC, Chen CJ, et al. Tumor-associated macrophages promote epigenetic silencing of gelsolin through DNA methyltransferase 1 in gastric cancer cells. Cancer Immunol Res. 2017;5(10):885–97. https://doi.org/10.1158/2326-6066.CrossRefPubMed

Title: Combination of L1 methylation and tumor-infiltrating lymphocytes as prognostic marker in advanced gastric cancer
Authors: Younghoon Kim
Ye-Young Rhee
Xianyu Wen
Nam-Yun Cho
Jeong Mo Bae
Woo Ho Kim
Gyeong Hoon Kang
Publication date: 01-05-2020
Publisher: Springer Singapore
Keywords: Gastric Cancer
Gastric Cancer
Published in: Gastric Cancer / Issue 3/2020
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI: https://doi.org/10.1007/s10120-019-01025-8

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Combination of L1 methylation and tumor-infiltrating lymphocytes as prognostic marker in advanced gastric cancer

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2020

Author’s reply: Stent-in-stent technique resolves late stent obstruction

Achieving sequential therapy in advanced gastric cancer: the importance of appropriate patient management for the elderly and/or those with ascites

Adherence with operative standards in the treatment of gastric cancer in the United States

Utility of the one-step nucleic acid amplification assay in sentinel node mapping for early gastric cancer patients

Claudin-6 is a single prognostic marker and functions as a tumor-promoting gene in a subgroup of intestinal type gastric cancer

LBX2-AS1/miR-219a-2-3p/FUS/LBX2 positive feedback loop contributes to the proliferation of gastric cancer

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page