Cargando…

Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome

Despite major improvements in diagnostics and therapy in early as well as in locally advanced breast cancer (LABC), metastatic relapse occurs in about 20% of patients, often explained by early micro-metastatic spread into bone marrow by disseminated tumor cells (DTC). Although neoadjuvant chemothera...

Descripción completa

Detalles Bibliográficos
Autores principales: Rebmann, Vera, Schwich, Esther, Michita, Rafael Tomoya, Grüntkemeier, Lisa, Bittner, Ann-Kathrin, Rohn, Hana, Horn, Peter A., Hoffmann, Oliver, Kimmig, Rainer, Kasimir-Bauer, Sabine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8790528/
https://www.ncbi.nlm.nih.gov/pubmed/35095919
http://dx.doi.org/10.3389/fimmu.2021.817132
_version_ 1784640034019737600
author Rebmann, Vera
Schwich, Esther
Michita, Rafael Tomoya
Grüntkemeier, Lisa
Bittner, Ann-Kathrin
Rohn, Hana
Horn, Peter A.
Hoffmann, Oliver
Kimmig, Rainer
Kasimir-Bauer, Sabine
author_facet Rebmann, Vera
Schwich, Esther
Michita, Rafael Tomoya
Grüntkemeier, Lisa
Bittner, Ann-Kathrin
Rohn, Hana
Horn, Peter A.
Hoffmann, Oliver
Kimmig, Rainer
Kasimir-Bauer, Sabine
author_sort Rebmann, Vera
collection PubMed
description Despite major improvements in diagnostics and therapy in early as well as in locally advanced breast cancer (LABC), metastatic relapse occurs in about 20% of patients, often explained by early micro-metastatic spread into bone marrow by disseminated tumor cells (DTC). Although neoadjuvant chemotherapy (NACT) has been a successful tool to improve overall survival (OS), there is growing evidence that various environmental factors like the non-classical human leukocyte antigen-G (HLA-G) promotes cancer invasiveness and metastatic progression. HLA-G expression is associated with regulatory elements targeting certain single-nucleotide polymorphisms (SNP) in the HLA-G 3’ untranslated region (UTR), which arrange as haplotypes. Here, we systematically evaluated the impact of HLA-G 3’UTR polymorphisms on disease status, on the presence of DTC, on soluble HLA-G levels, and on therapy and disease outcome in non-metastatic LABC patients. Although haplotype frequencies were similar in patients (n = 142) and controls (n = 204), univariate analysis revealed that the UTR-7 haplotype was related to patients with low tumor burden, whereas UTR-4 was associated with tumor sizes >T1. Furthermore, UTR-4 was associated with the presence of DTC, but UTR-3 and UTR-7 were related to absence of DTC. Additionally, increased levels of soluble HLA-G molecules were found in patients carrying UTR-7. Regarding therapy and disease outcome, univariate and multivariate analysis highlighted UTR-1 or UTR-2 as a prognostic parameter indicative for a beneficial course of disease in terms of complete response towards NACT or progression-free survival (PFS). At variance, UTR-4 was an independent risk factor for a reduced OS besides already known parameters. Taken into account the most common HLA-G 3’UTR haplotypes (UTR-1–UTR-7, UTR-18), deduction of the UTR-1/2/4 haplotypes to specific SNPs revealed that the +3003C variant, unique for UTR-4, seemed to favor a detrimental disease outcome, while the +3187G and +3196G variants, unique for UTR-1 or UTR-2, were prognostic parameters for a beneficial course of disease. In conclusion, these data suggest that the HLA-G 3’UTR variants +3003C, +3187G, and +3196G are promising candidates for the prediction of therapy and disease outcome in LABC patients.
format Online
Article
Text
id pubmed-8790528
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-87905282022-01-27 Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome Rebmann, Vera Schwich, Esther Michita, Rafael Tomoya Grüntkemeier, Lisa Bittner, Ann-Kathrin Rohn, Hana Horn, Peter A. Hoffmann, Oliver Kimmig, Rainer Kasimir-Bauer, Sabine Front Immunol Immunology Despite major improvements in diagnostics and therapy in early as well as in locally advanced breast cancer (LABC), metastatic relapse occurs in about 20% of patients, often explained by early micro-metastatic spread into bone marrow by disseminated tumor cells (DTC). Although neoadjuvant chemotherapy (NACT) has been a successful tool to improve overall survival (OS), there is growing evidence that various environmental factors like the non-classical human leukocyte antigen-G (HLA-G) promotes cancer invasiveness and metastatic progression. HLA-G expression is associated with regulatory elements targeting certain single-nucleotide polymorphisms (SNP) in the HLA-G 3’ untranslated region (UTR), which arrange as haplotypes. Here, we systematically evaluated the impact of HLA-G 3’UTR polymorphisms on disease status, on the presence of DTC, on soluble HLA-G levels, and on therapy and disease outcome in non-metastatic LABC patients. Although haplotype frequencies were similar in patients (n = 142) and controls (n = 204), univariate analysis revealed that the UTR-7 haplotype was related to patients with low tumor burden, whereas UTR-4 was associated with tumor sizes >T1. Furthermore, UTR-4 was associated with the presence of DTC, but UTR-3 and UTR-7 were related to absence of DTC. Additionally, increased levels of soluble HLA-G molecules were found in patients carrying UTR-7. Regarding therapy and disease outcome, univariate and multivariate analysis highlighted UTR-1 or UTR-2 as a prognostic parameter indicative for a beneficial course of disease in terms of complete response towards NACT or progression-free survival (PFS). At variance, UTR-4 was an independent risk factor for a reduced OS besides already known parameters. Taken into account the most common HLA-G 3’UTR haplotypes (UTR-1–UTR-7, UTR-18), deduction of the UTR-1/2/4 haplotypes to specific SNPs revealed that the +3003C variant, unique for UTR-4, seemed to favor a detrimental disease outcome, while the +3187G and +3196G variants, unique for UTR-1 or UTR-2, were prognostic parameters for a beneficial course of disease. In conclusion, these data suggest that the HLA-G 3’UTR variants +3003C, +3187G, and +3196G are promising candidates for the prediction of therapy and disease outcome in LABC patients. Frontiers Media S.A. 2022-01-12 /pmc/articles/PMC8790528/ /pubmed/35095919 http://dx.doi.org/10.3389/fimmu.2021.817132 Text en Copyright © 2022 Rebmann, Schwich, Michita, Grüntkemeier, Bittner, Rohn, Horn, Hoffmann, Kimmig and Kasimir-Bauer https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Rebmann, Vera
Schwich, Esther
Michita, Rafael Tomoya
Grüntkemeier, Lisa
Bittner, Ann-Kathrin
Rohn, Hana
Horn, Peter A.
Hoffmann, Oliver
Kimmig, Rainer
Kasimir-Bauer, Sabine
Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome
title Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome
title_full Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome
title_fullStr Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome
title_full_unstemmed Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome
title_short Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome
title_sort systematic evaluation of hla-g 3’untranslated region variants in locally advanced, non-metastatic breast cancer patients: utr-1, 2 or utr-4 are predictors for therapy and disease outcome
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8790528/
https://www.ncbi.nlm.nih.gov/pubmed/35095919
http://dx.doi.org/10.3389/fimmu.2021.817132
work_keys_str_mv AT rebmannvera systematicevaluationofhlag3untranslatedregionvariantsinlocallyadvancednonmetastaticbreastcancerpatientsutr12orutr4arepredictorsfortherapyanddiseaseoutcome
AT schwichesther systematicevaluationofhlag3untranslatedregionvariantsinlocallyadvancednonmetastaticbreastcancerpatientsutr12orutr4arepredictorsfortherapyanddiseaseoutcome
AT michitarafaeltomoya systematicevaluationofhlag3untranslatedregionvariantsinlocallyadvancednonmetastaticbreastcancerpatientsutr12orutr4arepredictorsfortherapyanddiseaseoutcome
AT gruntkemeierlisa systematicevaluationofhlag3untranslatedregionvariantsinlocallyadvancednonmetastaticbreastcancerpatientsutr12orutr4arepredictorsfortherapyanddiseaseoutcome
AT bittnerannkathrin systematicevaluationofhlag3untranslatedregionvariantsinlocallyadvancednonmetastaticbreastcancerpatientsutr12orutr4arepredictorsfortherapyanddiseaseoutcome
AT rohnhana systematicevaluationofhlag3untranslatedregionvariantsinlocallyadvancednonmetastaticbreastcancerpatientsutr12orutr4arepredictorsfortherapyanddiseaseoutcome
AT hornpetera systematicevaluationofhlag3untranslatedregionvariantsinlocallyadvancednonmetastaticbreastcancerpatientsutr12orutr4arepredictorsfortherapyanddiseaseoutcome
AT hoffmannoliver systematicevaluationofhlag3untranslatedregionvariantsinlocallyadvancednonmetastaticbreastcancerpatientsutr12orutr4arepredictorsfortherapyanddiseaseoutcome
AT kimmigrainer systematicevaluationofhlag3untranslatedregionvariantsinlocallyadvancednonmetastaticbreastcancerpatientsutr12orutr4arepredictorsfortherapyanddiseaseoutcome
AT kasimirbauersabine systematicevaluationofhlag3untranslatedregionvariantsinlocallyadvancednonmetastaticbreastcancerpatientsutr12orutr4arepredictorsfortherapyanddiseaseoutcome