Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix

Damian T. Rieke, Sebastian Ochsenreither, Konrad Klinghammer, Tanguy Lim Seiwert, Frederick Klauschen, Inge Tinhofer, Ulrich Keilholz

Research output: Contribution to journalArticle

Abstract

Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood. Since alterations in DNA repair genes have been connected to the efficacy of checkpoint inhibitors, we investigated associations between methylation of DNA repair genes and CTLA4 and CD274 (PDL1) expression. A list of DNA repair genes (179 genes) was selected from the literature, methylation status and expression of inflammation-associated genes (The Cancer Genome Atlas data) was correlated in head and neck squamous cell carcinoma (HNSCC), cervical and lung squamous cell carcinoma. A significant positive correlation of the methylation status of 15, 3 and 2 genes with checkpoint expression was identified, respectively. RAD51B methylation was identified in all cancer subtypes. In HNSCC and cervical cancer, there was significant enrichment for homologous recombination genes. Methylation of the candidate genes was also associated with expression of other checkpoints, ligands, MHC- and T-cell associated genes as well as an interferon-inflammatory immune gene signature, predictive for the efficacy of PD-1 inhibition in HNSCC. Homologous recombination deficiency might therefore be mediated by DNA repair gene hypermethylation and linked to an immune-evasive phenotype in SCC. The methylation status of these genes could represent a new predictive biomarker for immune checkpoint inhibition.

Original languageEnglish (US)
Pages (from-to)75379-75393
Number of pages15
JournalOncotarget
Volume7
Issue number46
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Homologous Recombination
Cervix Uteri
Methylation
Lung
Genes
DNA Repair
Carcinoma, squamous cell of head and neck
Squamous Cell Neoplasms
Atlases
Neoplasm Genes
Head and Neck Neoplasms
Uterine Cervical Neoplasms
Interferon-gamma
Squamous Cell Carcinoma
Biomarkers
Genome
Ligands
Inflammation
T-Lymphocytes
Phenotype

Keywords

  • DNA repair
  • HRD
  • Immune checkpoints
  • Immune therapy
  • Inflamed gene expression signature

ASJC Scopus subject areas

  • Oncology

Cite this

Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix. / Rieke, Damian T.; Ochsenreither, Sebastian; Klinghammer, Konrad; Lim Seiwert, Tanguy; Klauschen, Frederick; Tinhofer, Inge; Keilholz, Ulrich.

In: Oncotarget, Vol. 7, No. 46, 01.01.2016, p. 75379-75393.

Research output: Contribution to journalArticle

Rieke, Damian T. ; Ochsenreither, Sebastian ; Klinghammer, Konrad ; Lim Seiwert, Tanguy ; Klauschen, Frederick ; Tinhofer, Inge ; Keilholz, Ulrich. / Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix. In: Oncotarget. 2016 ; Vol. 7, No. 46. pp. 75379-75393.
@article{5371d320af1f4100b427e12046ce6c6d,
title = "Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix",
abstract = "Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood. Since alterations in DNA repair genes have been connected to the efficacy of checkpoint inhibitors, we investigated associations between methylation of DNA repair genes and CTLA4 and CD274 (PDL1) expression. A list of DNA repair genes (179 genes) was selected from the literature, methylation status and expression of inflammation-associated genes (The Cancer Genome Atlas data) was correlated in head and neck squamous cell carcinoma (HNSCC), cervical and lung squamous cell carcinoma. A significant positive correlation of the methylation status of 15, 3 and 2 genes with checkpoint expression was identified, respectively. RAD51B methylation was identified in all cancer subtypes. In HNSCC and cervical cancer, there was significant enrichment for homologous recombination genes. Methylation of the candidate genes was also associated with expression of other checkpoints, ligands, MHC- and T-cell associated genes as well as an interferon-inflammatory immune gene signature, predictive for the efficacy of PD-1 inhibition in HNSCC. Homologous recombination deficiency might therefore be mediated by DNA repair gene hypermethylation and linked to an immune-evasive phenotype in SCC. The methylation status of these genes could represent a new predictive biomarker for immune checkpoint inhibition.",
keywords = "DNA repair, HRD, Immune checkpoints, Immune therapy, Inflamed gene expression signature",
author = "Rieke, {Damian T.} and Sebastian Ochsenreither and Konrad Klinghammer and {Lim Seiwert}, Tanguy and Frederick Klauschen and Inge Tinhofer and Ulrich Keilholz",
year = "2016",
month = "1",
day = "1",
doi = "10.18632/oncotarget.12211",
language = "English (US)",
volume = "7",
pages = "75379--75393",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "46",

}

TY - JOUR

T1 - Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix

AU - Rieke, Damian T.

AU - Ochsenreither, Sebastian

AU - Klinghammer, Konrad

AU - Lim Seiwert, Tanguy

AU - Klauschen, Frederick

AU - Tinhofer, Inge

AU - Keilholz, Ulrich

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood. Since alterations in DNA repair genes have been connected to the efficacy of checkpoint inhibitors, we investigated associations between methylation of DNA repair genes and CTLA4 and CD274 (PDL1) expression. A list of DNA repair genes (179 genes) was selected from the literature, methylation status and expression of inflammation-associated genes (The Cancer Genome Atlas data) was correlated in head and neck squamous cell carcinoma (HNSCC), cervical and lung squamous cell carcinoma. A significant positive correlation of the methylation status of 15, 3 and 2 genes with checkpoint expression was identified, respectively. RAD51B methylation was identified in all cancer subtypes. In HNSCC and cervical cancer, there was significant enrichment for homologous recombination genes. Methylation of the candidate genes was also associated with expression of other checkpoints, ligands, MHC- and T-cell associated genes as well as an interferon-inflammatory immune gene signature, predictive for the efficacy of PD-1 inhibition in HNSCC. Homologous recombination deficiency might therefore be mediated by DNA repair gene hypermethylation and linked to an immune-evasive phenotype in SCC. The methylation status of these genes could represent a new predictive biomarker for immune checkpoint inhibition.

AB - Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood. Since alterations in DNA repair genes have been connected to the efficacy of checkpoint inhibitors, we investigated associations between methylation of DNA repair genes and CTLA4 and CD274 (PDL1) expression. A list of DNA repair genes (179 genes) was selected from the literature, methylation status and expression of inflammation-associated genes (The Cancer Genome Atlas data) was correlated in head and neck squamous cell carcinoma (HNSCC), cervical and lung squamous cell carcinoma. A significant positive correlation of the methylation status of 15, 3 and 2 genes with checkpoint expression was identified, respectively. RAD51B methylation was identified in all cancer subtypes. In HNSCC and cervical cancer, there was significant enrichment for homologous recombination genes. Methylation of the candidate genes was also associated with expression of other checkpoints, ligands, MHC- and T-cell associated genes as well as an interferon-inflammatory immune gene signature, predictive for the efficacy of PD-1 inhibition in HNSCC. Homologous recombination deficiency might therefore be mediated by DNA repair gene hypermethylation and linked to an immune-evasive phenotype in SCC. The methylation status of these genes could represent a new predictive biomarker for immune checkpoint inhibition.

KW - DNA repair

KW - HRD

KW - Immune checkpoints

KW - Immune therapy

KW - Inflamed gene expression signature

UR - http://www.scopus.com/inward/record.url?scp=84996836157&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84996836157&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.12211

DO - 10.18632/oncotarget.12211

M3 - Article

C2 - 27683114

AN - SCOPUS:84996836157

VL - 7

SP - 75379

EP - 75393

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 46

ER -