Immunoprofiles and DNA methylation of inflammatory marker genes in ulcerative colitis-associated colorectal tumorigenesis

Satu Mäki-Nevala; Sanjeevi Ukwattage; Erkki Ville Wirta; Maarit Ahtiainen; Ari Ristimäki; Toni T. Seppälä; Anna Lepistö; Jukka Pekka Mecklin; Päivi Peltomäki

doi:10.3390/biom11101440

Immunoprofiles and DNA methylation of inflammatory marker genes in ulcerative colitis-associated colorectal tumorigenesis

Satu Mäki-Nevala^*
, Sanjeevi Ukwattage
, Erkki Ville Wirta
, Maarit Ahtiainen
, Ari Ristimäki
, Toni T. Seppälä
, Anna Lepistö
, Jukka Pekka Mecklin
, Päivi Peltomäki

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

9 Citations (Scopus)

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Abstract

Immunological and epigenetic changes are interconnected and contribute to tumorigenesis. We determined the immunoprofiles and promoter methylation of inflammationrelated genes for colitis-associated colorectal carcinomas (CA-CRC). The results were compared with Lynch syndrome (LS)-associated colorectal tumors, which are characterized by an active immune environment through inherited mismatch repair defects. CA-CRCs (n = 31) were immunohistochemically evaluated for immune cell scores (ICSs) and PDCD1 and CD274 expression. Seven inflammation-associated genes (CD274, NTSR1, PPARG, PTGS2, PYCARD, SOCS1, and SOCS2), the repair gene MGMT, and eight standard marker genes for the CpG Island Methylator Phenotype (CIMP) were investigated for promoter methylation in CA-CRCs, LS tumors (n = 29), and paired normal mucosae by multiplex ligation-dependent probe amplification. All but one CA-CRCs were microsatellite-stable and all LS tumors were microsatellite-unstable. Most CACRCs had a high ICS (55%) and a positive CD274 expression in immune cells (52%). NTSR1 revealed frequent tumor-specific hypermethylation in CA-CRC and LS. When compared to LS mucosae, normal mucosae from patients with CA-CRC showed significantly higher methylation of NTSR1 and most CIMP markers. In conclusion, CA-CRCs share a frequent ICShigh/CD274pos expression pattern with LS tumors. Elevated methylation in normal mucosa may indicate field cancerization as a feature of CA-CRC-associated tumorigenesis.

Original language	English
Article number	1440
Journal	Biomolecules
Volume	11
Issue number	10
DOIs	https://doi.org/10.3390/biom11101440
Publication status	Published - Oct 2021
Publication type	A1 Journal article-refereed

Funding

This study was funded by Jane and Aatos Erkko Foundation (to P.P., J.?P.M. and T.T.S.); the Academy of Finland (grant numbers 330606 to P.P. and 331284 to S.M.?N.); the Finnish Cancer Foundation (to P.P., J.?P.M., T.T.S. and A.R.); Finnish Medical Foundation (to T.T.S.); Emil Aaltonen Foundation (to T.T.S.); the Sigrid Juselius Foundation (to P.P., T.T.S. and A.R.) and the HiLIFE Fellows 2017?2020 (to P.P.). Funding: This study was funded by Jane and Aatos Erkko Foundation (to P.P., J.‐P.M. and T.T.S.); the Academy of Finland (grant numbers 330606 to P.P. and 331284 to S.M.‐N.); the Finnish Cancer Foundation (to P.P., J.‐P.M., T.T.S. and A.R.); Finnish Medical Foundation (to T.T.S.); Emil Aaltonen Foundation (to T.T.S.); the Sigrid Juselius Foundation (to P.P., T.T.S. and A.R.) and the HiLIFE Fel‐ lows 2017–2020 (to P.P.).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Colon cancer
DNA methylation
Immune cell score
Inflammation-associated genes
Lynch syndrome
Ulcerative colitis

Publication forum classification

Publication forum level 1

ASJC Scopus subject areas

Biochemistry
Molecular Biology

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10.3390/biom11101440Licence: CC BY

biomolecules-11-01440-v2Final published version, 4.24 MBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-202110277870Licence: CC BY

Cite this

@article{6a5c6afa12364f24bc8e382778d913e8,

title = "Immunoprofiles and DNA methylation of inflammatory marker genes in ulcerative colitis-associated colorectal tumorigenesis",

abstract = "Immunological and epigenetic changes are interconnected and contribute to tumorigenesis. We determined the immunoprofiles and promoter methylation of inflammationrelated genes for colitis-associated colorectal carcinomas (CA-CRC). The results were compared with Lynch syndrome (LS)-associated colorectal tumors, which are characterized by an active immune environment through inherited mismatch repair defects. CA-CRCs (n = 31) were immunohistochemically evaluated for immune cell scores (ICSs) and PDCD1 and CD274 expression. Seven inflammation-associated genes (CD274, NTSR1, PPARG, PTGS2, PYCARD, SOCS1, and SOCS2), the repair gene MGMT, and eight standard marker genes for the CpG Island Methylator Phenotype (CIMP) were investigated for promoter methylation in CA-CRCs, LS tumors (n = 29), and paired normal mucosae by multiplex ligation-dependent probe amplification. All but one CA-CRCs were microsatellite-stable and all LS tumors were microsatellite-unstable. Most CACRCs had a high ICS (55\%) and a positive CD274 expression in immune cells (52\%). NTSR1 revealed frequent tumor-specific hypermethylation in CA-CRC and LS. When compared to LS mucosae, normal mucosae from patients with CA-CRC showed significantly higher methylation of NTSR1 and most CIMP markers. In conclusion, CA-CRCs share a frequent ICShigh/CD274pos expression pattern with LS tumors. Elevated methylation in normal mucosa may indicate field cancerization as a feature of CA-CRC-associated tumorigenesis.",

keywords = "Colon cancer, DNA methylation, Immune cell score, Inflammation-associated genes, Lynch syndrome, Ulcerative colitis",

author = "Satu M{\"a}ki-Nevala and Sanjeevi Ukwattage and Wirta, \{Erkki Ville\} and Maarit Ahtiainen and Ari Ristim{\"a}ki and Sepp{\"a}l{\"a}, \{Toni T.\} and Anna Lepist{\"o} and Mecklin, \{Jukka Pekka\} and P{\"a}ivi Peltom{\"a}ki",

note = "Funding Information: This study was funded by Jane and Aatos Erkko Foundation (to P.P., J.?P.M. and T.T.S.); the Academy of Finland (grant numbers 330606 to P.P. and 331284 to S.M.?N.); the Finnish Cancer Foundation (to P.P., J.?P.M., T.T.S. and A.R.); Finnish Medical Foundation (to T.T.S.); Emil Aaltonen Foundation (to T.T.S.); the Sigrid Juselius Foundation (to P.P., T.T.S. and A.R.) and the HiLIFE Fellows 2017?2020 (to P.P.). Funding Information: Funding: This study was funded by Jane and Aatos Erkko Foundation (to P.P., J.‐P.M. and T.T.S.); the Academy of Finland (grant numbers 330606 to P.P. and 331284 to S.M.‐N.); the Finnish Cancer Foundation (to P.P., J.‐P.M., T.T.S. and A.R.); Finnish Medical Foundation (to T.T.S.); Emil Aaltonen Foundation (to T.T.S.); the Sigrid Juselius Foundation (to P.P., T.T.S. and A.R.) and the HiLIFE Fel‐ lows 2017–2020 (to P.P.). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = oct,

doi = "10.3390/biom11101440",

language = "English",

volume = "11",

journal = "Biomolecules",

issn = "2218-273X",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "10",

}

TY - JOUR

T1 - Immunoprofiles and DNA methylation of inflammatory marker genes in ulcerative colitis-associated colorectal tumorigenesis

AU - Mäki-Nevala, Satu

AU - Ukwattage, Sanjeevi

AU - Wirta, Erkki Ville

AU - Ahtiainen, Maarit

AU - Ristimäki, Ari

AU - Seppälä, Toni T.

AU - Lepistö, Anna

AU - Mecklin, Jukka Pekka

AU - Peltomäki, Päivi

N1 - Funding Information: This study was funded by Jane and Aatos Erkko Foundation (to P.P., J.?P.M. and T.T.S.); the Academy of Finland (grant numbers 330606 to P.P. and 331284 to S.M.?N.); the Finnish Cancer Foundation (to P.P., J.?P.M., T.T.S. and A.R.); Finnish Medical Foundation (to T.T.S.); Emil Aaltonen Foundation (to T.T.S.); the Sigrid Juselius Foundation (to P.P., T.T.S. and A.R.) and the HiLIFE Fellows 2017?2020 (to P.P.). Funding Information: Funding: This study was funded by Jane and Aatos Erkko Foundation (to P.P., J.‐P.M. and T.T.S.); the Academy of Finland (grant numbers 330606 to P.P. and 331284 to S.M.‐N.); the Finnish Cancer Foundation (to P.P., J.‐P.M., T.T.S. and A.R.); Finnish Medical Foundation (to T.T.S.); Emil Aaltonen Foundation (to T.T.S.); the Sigrid Juselius Foundation (to P.P., T.T.S. and A.R.) and the HiLIFE Fel‐ lows 2017–2020 (to P.P.). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/10

Y1 - 2021/10

N2 - Immunological and epigenetic changes are interconnected and contribute to tumorigenesis. We determined the immunoprofiles and promoter methylation of inflammationrelated genes for colitis-associated colorectal carcinomas (CA-CRC). The results were compared with Lynch syndrome (LS)-associated colorectal tumors, which are characterized by an active immune environment through inherited mismatch repair defects. CA-CRCs (n = 31) were immunohistochemically evaluated for immune cell scores (ICSs) and PDCD1 and CD274 expression. Seven inflammation-associated genes (CD274, NTSR1, PPARG, PTGS2, PYCARD, SOCS1, and SOCS2), the repair gene MGMT, and eight standard marker genes for the CpG Island Methylator Phenotype (CIMP) were investigated for promoter methylation in CA-CRCs, LS tumors (n = 29), and paired normal mucosae by multiplex ligation-dependent probe amplification. All but one CA-CRCs were microsatellite-stable and all LS tumors were microsatellite-unstable. Most CACRCs had a high ICS (55%) and a positive CD274 expression in immune cells (52%). NTSR1 revealed frequent tumor-specific hypermethylation in CA-CRC and LS. When compared to LS mucosae, normal mucosae from patients with CA-CRC showed significantly higher methylation of NTSR1 and most CIMP markers. In conclusion, CA-CRCs share a frequent ICShigh/CD274pos expression pattern with LS tumors. Elevated methylation in normal mucosa may indicate field cancerization as a feature of CA-CRC-associated tumorigenesis.

AB - Immunological and epigenetic changes are interconnected and contribute to tumorigenesis. We determined the immunoprofiles and promoter methylation of inflammationrelated genes for colitis-associated colorectal carcinomas (CA-CRC). The results were compared with Lynch syndrome (LS)-associated colorectal tumors, which are characterized by an active immune environment through inherited mismatch repair defects. CA-CRCs (n = 31) were immunohistochemically evaluated for immune cell scores (ICSs) and PDCD1 and CD274 expression. Seven inflammation-associated genes (CD274, NTSR1, PPARG, PTGS2, PYCARD, SOCS1, and SOCS2), the repair gene MGMT, and eight standard marker genes for the CpG Island Methylator Phenotype (CIMP) were investigated for promoter methylation in CA-CRCs, LS tumors (n = 29), and paired normal mucosae by multiplex ligation-dependent probe amplification. All but one CA-CRCs were microsatellite-stable and all LS tumors were microsatellite-unstable. Most CACRCs had a high ICS (55%) and a positive CD274 expression in immune cells (52%). NTSR1 revealed frequent tumor-specific hypermethylation in CA-CRC and LS. When compared to LS mucosae, normal mucosae from patients with CA-CRC showed significantly higher methylation of NTSR1 and most CIMP markers. In conclusion, CA-CRCs share a frequent ICShigh/CD274pos expression pattern with LS tumors. Elevated methylation in normal mucosa may indicate field cancerization as a feature of CA-CRC-associated tumorigenesis.

KW - Colon cancer

KW - DNA methylation

KW - Immune cell score

KW - Inflammation-associated genes

KW - Lynch syndrome

KW - Ulcerative colitis

U2 - 10.3390/biom11101440

DO - 10.3390/biom11101440

M3 - Article

AN - SCOPUS:85116694343

SN - 2218-273X

VL - 11

JO - Biomolecules

JF - Biomolecules

IS - 10

M1 - 1440

ER -

Immunoprofiles and DNA methylation of inflammatory marker genes in ulcerative colitis-associated colorectal tumorigenesis

Abstract

Funding

UN SDGs

Keywords

Publication forum classification

ASJC Scopus subject areas

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