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.

Esther Schwich,Vera Rebmann,Peter A Horn,Oliver Hoffmann,Lisa Grüntkemeier,Sabine Kasimir-Bauer,Rainer Kimmig,Hana Rohn,Rafael Tomoya Michita,Ann-Kathrin Bittner

doi:10.3389/fimmu.2021.817132

Esther Schwich, Vera Rebmann + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2021.817132

Copy DOI

Abstract

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.

Highlights

Advanced breast cancer (LABC) is characterized by large tumor sizes, lymph node spread, and an unfavorable tumor biology in the absence of distant metastasis [1]
Concerning the clinical status of Locally advanced breast cancer (LABC) patients, presence of UTR-4 was positively associated with a tumor size >T1 (p = 0.03, relative risk [RR]: 2.48, 95% confidence interval [CI]: 1.11–5.9) as 33.7% (35/104) of patients having a tumor size >T1 carried UTR4, whereas only 13.9% (5/36) of patients with T1 were positive for UTR-4 (Figure 1A)
In contrast to UTR-4, presence of UTR-7 seemed to be associated with lower tumor stage (p = 0.03, RR: 0.45, 95% CI: 0.27–0.87): 22.2% (8/36) of the LABC patients with T1 carried UTR-7, while only 7.7% of patients with T > 1 were positive for this haplotype (Figure 1B)

Summary

Introduction

Advanced breast cancer (LABC) is characterized by large tumor sizes, lymph node spread, and an unfavorable tumor biology in the absence of distant metastasis [1]. There is growing evidence that the occurrence of cancer depends on various environmental factors as well as genetic susceptibilities In this regard, gene polymorphisms have been identified as a parameter in malignancies [6]. The HLA-G 3’UTR harbors several polymorphic sites (+3001C/T, +3003C/T, +3010C/G, +3027C/ A, +3032C/G, +3035C/T, 3052C/T, +3092G/T, +3111A/G, +3121C/T, +3142C/G, +33177G/T, +3183A/G, +3187A/G, +3196C/G, and +3227A/G) and a 14-bp insertion/deletion (IN/ DEL), which have been associated with differential HLA-G expression profiles or disease susceptibility [15,16,17]. The different mechanisms by which the various polymorphic sites influence HLA-G expression are still unknown, in silico studies revealed that several microRNAs target the HLA-G 3’UTR [18, 19]. For instance, binding of the key regulators depends on the presence of a Guanine at position +3142 [19], it is likely that polymorphisms in the HLA-G 3’UTR impact microRNA binding and HLA-G implications

Methods

Results

Conclusion