Combination of L1 methylation and tumor-infiltrating lymphocytes as prognostic marker in advanced gastric cancer
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ORIGINAL ARTICLE
Combination of L1 methylation and tumor‑infiltrating lymphocytes as prognostic marker in advanced gastric cancer Younghoon Kim1,2 · Ye‑Young Rhee3 · Xianyu Wen4 · Nam‑Yun Cho2 · Jeong Mo Bae1,2 · Woo Ho Kim1 · Gyeong Hoon Kang1,2 Received: 4 August 2019 / Accepted: 18 October 2019 © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019
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. Keywords T lymphocyte · L1 element · Gastric cancer · Prognosis
Younghoon Kim and Ye-Young Rhee contributed equally to this article. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10120-019-01025-8) contains supplementary material, which is available to authorized users. * Gyeong Hoon Kang [email protected] 1
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
2
Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
3
Pathology Center, Seegene Medical Foundation, Seoul, Korea
4
Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Introduction 5-Methylcytosine constitutes approximately 0.9% of humangenomic DNA and a decrease in the DNA-methylation content is a common finding in human cancers with exceptions such as renal-cell carcinoma and thyroid cancer
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