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

  • Younghoon Kim
  • Ye-Young Rhee
  • Xianyu Wen
  • Nam-Yun Cho
  • Jeong Mo Bae
  • Woo Ho Kim
  • Gyeong Hoon KangEmail author
Original Article
  • 26 Downloads

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 

Notes

Funding

This work was funded by a Grant from the National Research Foundation (NRF) funded by the Korean Ministry of Science, ICT and Future Planning (2016M3A9B6026921), a Grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Korean Ministry of Health and Welfare (HI14C1277), and a Grant from SNUH Research Fund [0420180210 (2018-1212)], and Seegene Medical Foundation Scholarship fund (Grant no. 2019-001).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10120_2019_1025_MOESM1_ESM.tif (1.6 mb)
Fig. S1. Scatter plots correlating the L1 methylation level and the CD3 TIL density at the tumor center (a, c, e, & g) or the CD3 TIL density at the invasive front (b, d, f, & h). (a) & (b) overall gastric cancer cases, (c) & (d) gastric cancer of the intestinal type, (e) & (f) gastric cancers of the diffuse type, and (g) & (h) gastric cancers of the mixed type (TIFF 1611 kb)
10120_2019_1025_MOESM2_ESM.tif (576 kb)
Fig. S2. Kaplan-Meier survival curves for low and high CD3 TIL density subgroups of cancer-specific survival. (a) Survival curves for CD3 TIL density at the tumor center. (b) Survival curves for CD3 TIL density at the invasive front (TIFF 577 kb)
10120_2019_1025_MOESM3_ESM.tif (480 kb)
Fig. S3. Kaplan-Meier survival curves for L1 methylation status of (a) overall survival and (b) cancer-specific survival (TIFF 481 kb)
10120_2019_1025_MOESM4_ESM.tif (700 kb)
Fig. S4. Kaplan-Meier survival curves for four subgroups generated by a combination of L1 methylation levels and CD3 TIL densities of cancer-specific survival. (a) Survival curves for the combination of the L1 methylation level and the CD3 TIL density at the tumor center. (b) Survival curves for the combination of the L1 methylation level and the CD3 TIL density at the invasive front (TIFF 701 kb)
10120_2019_1025_MOESM5_ESM.tif (743 kb)
Fig. S5. Kaplan-Meier survival curves for four subgroups generated by a combination of L1 methylation levels and CD3 TIL densities of cancer-specific survival in the validation set. (a) Survival curves for the combination of the L1 methylation level and the CD3 TIL density at the tumor center. (b) Survival curves for the combination of the L1 methylation level and the CD3 TIL density at the invasive front (TIFF 744 kb)
10120_2019_1025_MOESM6_ESM.tif (423 kb)
Fig. S6. Kaplan-Meier survival curves for the combination of the L1 methylation level and the CD3 TIL density at the tumor center according to tumor purity. (a) Survival curve for the combination of the L1 methylation level and the CD3 TIL density at the tumor center in gastric cancers with ≥50% tumor purity. (b) Survival curve for the combination of the L1 methylation level and the CD3 TIL density at the invasive front in gastric cancers with ≥50% tumor purity. (c) Survival curve for the combination of the L1 methylation level and the CD3 TIL density at the tumor center in gastric cancers with <50% tumor purity. (d) Survival curve for the combination of the L1 methylation level and the CD3 TIL density at the invasive front in gastric cancers with <50% tumor purity (TIFF 424 kb)
10120_2019_1025_MOESM7_ESM.docx (19 kb)
Supplementary file7 (DOCX 18 kb)

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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

Authors and Affiliations

  • Younghoon Kim
    • 1
    • 2
  • Ye-Young Rhee
    • 3
  • Xianyu Wen
    • 4
  • Nam-Yun Cho
    • 2
  • Jeong Mo Bae
    • 1
    • 2
  • Woo Ho Kim
    • 1
  • Gyeong Hoon Kang
    • 1
    • 2
    Email author
  1. 1.Department of PathologySeoul National University College of MedicineSeoulKorea
  2. 2.Laboratory of Epigenetics, Cancer Research InstituteSeoul National University College of MedicineSeoulKorea
  3. 3.Pathology CenterSeegene Medical FoundationSeoulKorea
  4. 4.Guangdong Institute of Gastroenterology, The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouChina

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