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

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.

Association of RYR2 Mutation With Tumor Mutation Burden, Prognosis, and Antitumor Immunity in Patients With Esophageal Adenocarcinoma

“…RYR2 is a major component of the intracellular Ca 2+ release channels and is associated with the endoplasmic or sarcoplasmic reticulum of several cell types, especially in cardiomyocytes (Lanner et al, 2010;Van Petegem, 2015). Recent studies demonstrated that RYR2 was significantly mutated in multiple cancers, and RYR2 was reported to be a driver gene in cervical cancer, colon cancer, breast cancer, head and neck cancer, and lung adenocarcinoma (Wolff et al, 2018;Schmitt et al, 2019;Wang et al, 2019;Cimas et al, 2020;Wei et al, 2020). Femi (2018) demonstrated that mutation in RYR2 was a prognosis biomarker of cervical cancer and breast cancer.…”

Association of RYR2 Mutation with Tumor Mutation Burden, Prognosis and Antitumor Immunity in Patients with Esophageal Adenocarcinoma

“…RYR2 is a major component of the intracellular Ca 2+ release channels and is associated with the endoplasmic or sarcoplasmic reticulum of several cell types, especially in cardiomyocytes [20,21]. Recent studies demonstrated that RYR2 was signi cantly mutated in multiple cancers, and RYR2 was reported to be a driver gene in cervical cancer, colon cancer, breast cancer, head and neck cancer, and lung adenocarcinoma [22][23][24][25][26]. Femi et al demonstrated that mutation in RYR2 was a prognosis biomarker of cervical cancer and breast cancer [27].…”

“…Femi et al demonstrated that mutation in RYR2 was a prognosis biomarker of cervical cancer and breast cancer [27]. Cimas et al found that mutation in RYR2 was associated with favorable outcome in basal-like breast tumors expressing PD-1/PD-L1 [22]. Wang et al reported that RYR2 mutation was a signi cant biomarker for suggesting high TMB in lung adenocarcinoma [26].…”

Breast Cancer Heterogeneity and Response to Novel Therapeutics

“…Other mechanisms of resistance to immune checkpoint blockade include the loss of β2-microglobulin, which impairs antigen presentation, and JAK1 or JAK2 mutations which make tumor cells insensitive to interferon gamma [113]. Recent studies have identified genomic correlates of response to immune checkpoint blockade which may help identify immunotherapy responsive tumors [114][115][116].…”