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Senologie - Zeitschrift für Mammadiagnostik und -therapie 2021; 18(04): 353-364
DOI: 10.1055/a-1678-0867
Wissenschaftliche Arbeit

Das Nicht-Pseudogen HLA‑J ist ein neuer prognostischer Marker für das Ansprechen auf Therapie und das Überleben bei Brustkrebs

HLA‑J, a Non-Pseudogene as a New Prognostic Marker for Therapy Response and Survival in Breast Cancer
Franziska M. Würfel
1   STRATIFYER Molecular Pathology GmbH, Cologne, Germany
6   Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany
,
Ralph M. Wirtz
1   STRATIFYER Molecular Pathology GmbH, Cologne, Germany
,
Christoph Winterhalter
2   Intellexon GmbH, Pöcking, Deutschland
,
Mario Taffurelli
3   General and Breast Surgery Unit University of Bologna S. Orsola Hospital Bologna, Bologna, Italy
,
Donatella Santini
4   Pathology Unit S. Orsola Hospital Bologna, Bologna, Italy
,
Anna Mandrioli
5   Addarii Breast and Gynaecological Medical Oncology S. Orsola Hospital Bologna, Bologna, Italy
,
Elke Veltrup
1   STRATIFYER Molecular Pathology GmbH, Cologne, Germany
,
Matthias Rübner
6   Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany
,
Peter A. Fasching
6   Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany
,
Wolfgang Würfel
2   Intellexon GmbH, Pöcking, Deutschland
,
Claudio Zamagni
5   Addarii Breast and Gynaecological Medical Oncology S. Orsola Hospital Bologna, Bologna, Italy
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Zusammenfassung

Humane Leukozyten-Antigene (HLA) sind Proteine auf der Zelloberfläche, die essenziell für die Immunzellinteraktion sind. HLA‑G ist für seine hohe immunosuppressive Wirkung sowie als potenzieller prädikativer Marker für Brustkrebs bekannt. Dagegen ist kaum etwas über HLA‑J und seine immunosuppressiven, prognostischen und prädiktiven Eigenschaften bekannt, da es basierend auf In-silico-Sequenzanalysen als „Pseudogen“ interpretiert wurde. Die Expression von HLA‑J, ESR1, ERBB2, KRT5 und KRT20 mRNA wurde in 29 frisch gefrorenen Brustkrebsbiopsien analysiert und mit den klinisch-pathologischen Daten von Patientinnen, welche mit neoadjuvanter Chemotherapie behandelt wurden, verglichen. Die mRNA-Expression wurde mit genspezifischen TaqMan-basierten Primer/Probe-Sets analysiert und auf Calmodulin 2 normalisiert. Alle Gewebeproben von Patientinnen mit Brustkrebs exprimierten HLA‑J, und der HLA‑J-mRNA-Spiegel war nach NACT oft erhöht. In den Brustkrebsstanzbiopsien war die HLA-J-mRNA-Expression signifikant mit der Überexpression von ESR1-mRNA (Spearmans ρ 0,5679; p = 0,0090) und KRT5-mRNA (Spearmans ρ 0,6121; p = 0,0041) assoziiert und dominierte im Luminal-B-Subtyp. Die Kaplan-Meier-Analyse zeigte, dass ein Anstieg der HLA-J-mRNA-Expression nach NACT mit einem schlechteren progressionsfreien Überleben einhergeht (p = 0,0096), womöglich als Gegenreaktion des Tumorgewebes, um eine Eliminierung durch tumorinfiltrierende Lymphozyten, welche durch eine NACT induziert wurden, zu verhindern. Diese Gegenreaktion ist mit einer schlechteren Prognose assoziiert. Soweit uns bekannt, handelt es sich hierbei um die erste Studie, die HLA-J als neuen prädiktiven Marker im Brustkrebs identifiziert hat und möglicherweise zur Immunevasion beiträgt.

Abstract

The human leukocyte antigen (HLA) genes are cell-surface proteins, essential for immune cell interaction. HLA‑G is known for their high immunosuppressive effect and its potential as predictive marker in breast cancer. However, nothing is known about the HLA‑J and its immunosuppressive, prognostic and predictive features, as it is assumed to be a “pseudogene” by in silico sequence interpretation. HLA‑J, ESR1, ERBB2, KRT5 and KRT20 mRNA expression were analysed in 29 fresh frozen breast cancer biopsies and their corresponding resectates obtained from patients treated with neoadjuvant chemotherapy (NACT). mRNA was analysed with gene specific TaqMan-based Primer/Probe sets and normalized to Calmodulin 2. All breast cancer samples did express HLA‑J and frequently increased HLA-J mRNA levels after NACT. HLA‑J mRNA was significantly associated with overexpression of the ESR1 mRNA status (Spearman ρ 0,5679; p = 0.0090) and KRT5 mRNA (Spearman ρ 0,6121; p = 0.0041) in breast cancer core biopsies and dominated in luminal B subtype. Kaplan Meier analysis revealed that an increase of HLA‑J mRNA expression after NACT had worse progression free survival (p = 0,0096), indicating a counterreaction of tumor tissues presumably to prevent elimination by enhanced immune infiltration induced by NACT. This counterreaction is associated with worse prognosis. To our knowledge this is the first study identifying HLA‑J as a new predictive marker in breast cancer being involved in immune evasion mechanisms.

Schlüsselwörter

MHC1 - HLA‑J - breast cancer subtypes - RT‑qPCR

Key words

MHC1 - HLA‑J - breast cancer subtypes - RT‑qPCR


Publikationsverlauf

Artikel online veröffentlicht:
14. Dezember 2021

© 2020. This article was originally published by Thieme as Franziska M. Würfel et al., HLA‑J, a Non-Pseudogene as a New Prognostic Marker for Therapy Response and Survival in Breast Cancer. Geburtsh Frauenheilk 2020; 80: 1123–1133 as an open access article under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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