Genomic Mapping Identifies Mutations in RYR2 and AHNAK as Associated with Favorable Outcome in Basal-Like Breast Tumors Expressing PD1/PD-L1.

Francisco J Cimas,Ádám Nagy,Balázs Győrffy,Elena García-Gil,Arancha Manzano,Pedro Pérez-Segura,Mariona Baliu-Piqué,Alberto Ocana,Atanasio Pandiella

doi:10.3390/cancers12082243

Abstract

Treatment with anti-PD-L1 antibodies has shown efficacy in basal-like breast cancer. In this context, identification of pre-activated immune tumors is a main goal. Here we explore mutations in PD1 and PD-L1 high-expressing tumors to identify genomic correlates associated with outcome. To do so, RNA-seq and mutation data from 971 breast cancer patients from the TCGA dataset were used to identify most prevalent mutations in patients with high levels of PD1 and PD-L1. Transcriptomic signatures associated with the selected mutations were identified and analyzed in terms of outcome and immune cell infiltration. We identified co-occurrent mutations in RYR2 and AHNAK in 8% and 5% of basal-like tumors respectively, which conferred good prognosis in patients with high expression of PD1 and PD-L1 genes. The transcriptomic signature associated with these mutations, composed of CXCL9, GBP5, C1QA, IL2RG, CSF2RB, IDO1 and LAG3 genes, also conferred good prognosis and correlated with immune infiltrations within the tumors. The joint signature classified patients with favorable relapse-free survival (HR: 0.28; CI: 0.2–0.38; p = 1.7 × 10−16) and overall survival (HR: 0.18; CI: 0.09–0.34; p = 6.8 × 10−9), showing a stronger prediction capacity than previous reported signatures. In conclusion, we describe two novel mutations and their transcriptomic signature, both associated with a favorable outcome and immune infiltrates in PD1 and PD-L1 high-expressing basal-like tumors.

Highlights

Immunotherapy has become a new promising therapeutic option to treat many solid tumors [1].Blocking inhibitory signals that reduce the activation of the immune response has gained momentum with the development of checkpoint inhibitors such as antibodies against the programmed cell death protein 1 and its ligand (PD1 and PD-L1) or cytotoxic T-lymphocyte antigen 4 (CTLA4) [1,2].Cancers 2020, 12, 2243; doi:10.3390/cancers12082243 www.mdpi.com/journal/cancers relevant clinical activity has been observed with this family of compounds, not all treated patients respond to checkpoint inhibitors [3]
We found that mutations in ryanodine receptor 2 (RYR2) and AHNAK predicted favorable prognosis in basal-like tumors with high expression of PD1 and PD-L1
We further identified a transcriptomic signature associated with these two mutations that predicted favorable outcome, even better than already described immunologic signatures, and that was associated with a high infiltration of immune cell populations within the tumors

Summary

Introduction

Relevant clinical activity has been observed with this family of compounds, not all treated patients respond to checkpoint inhibitors [3]. To get a clinical effect, the immune system must be in a pre-activated state with immune populations, as effector T cells, present within tumoral areas [4,5,6]. In this context, the presence of tumor-infiltrating lymphocytes (TIL) is associated with a favorable clinical outcome independently of the therapy administered, in correlation with a high number of effector immune cells [7,8]. Protein expression levels of the PD-L1 receptor quantified by immunohistochemistry (IHC) identify patients suitable for having a good clinical response [9,10,11,12]

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