Intrinsic Genetic and Transcriptomic Patterns Reflect Tumor Immune Subtypes Facilitating Exploring Possible Combinatory Therapy.

Yong Xu,Daixi Li,Lu Xie,Guangrong Qin,Zhenhao Liu,David L Gibbs

doi:10.3389/fmolb.2020.00053

Abstract

The classification of immune subtypes was based on immune signatures highlighting the tumor immuno-microenvironment. It was found that immune subtypes associated with mutation and expression patterns in the tumor. How the intrinsic genetic and transcriptomic alterations contribute to the immune subtypes and how to select drug combinations from both targeted drugs and immune therapeutic drugs according to different immune subtypes are still not clear. Through statistical analysis of genetic alterations and transcriptional profiles of breast invasive carcinoma (BRCA) samples, we found significant differences in the number of somatic missense mutations and frameshift deletions among the different immune subtypes. The high mutation load for somatic missense mutations and frameshift deletions may be explained by the high frequency of mutations and high expression of DNA double-strand break repair pathway genes. Extensive analysis of signaling pathways in both the genetic and transcriptomic levels reveals significantly altered pathways such as tumor protein Tumor Protein P53 (TP53) and receptor tyrosine kinase (RTK)/RAS signaling pathways among different subtypes. Drug targets in the signaling pathways such as mitogen-activated protein kinase kinase kinase 1 (MAP3K1) and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) show genetic alteration in specific subtypes, which may be potential targets for patients of a specific subtype. More drug targets which show transcriptional difference among immune subtypes were discovered, such as cyclin-dependent kinase (CDK)4, CDK6, Erb-B2 receptor tyrosine kinase 2 (ERBB2), etc. Moreover, differences in functional activity between tumor growth and immune-related pathways also elucidate the extrinsic factors of differences in prognosis and suggest potential drug combinations for different immune subtypes. These results help to explain how intrinsic alterations are associated with the immune subtypes and provide clues for possible combination therapy for different immune subtypes.

Highlights

In recent years, growing evidence has shown that immunosuppression in the tumor microenvironment (TME) is a major obstacle for effective antitumor therapy in patients (Munn and Bronte, 2016)
Through the integrative analysis of gene mutations, DNA damage response, and oncogenic signaling, we find an association of these pathways with immune subtypes and identified targeted drugs which are associated with different immune subtypes in breast invasive carcinoma
Using breast invasive carcinoma in the The Cancer Genome Atlas (TCGA) dataset as an example, five immune subtypes can be detected according to the pan-cancer immune subtyping (Thorsson et al, 2018) (Figure 1A)

Summary

Introduction

In recent years, growing evidence has shown that immunosuppression in the tumor microenvironment (TME) is a major obstacle for effective antitumor therapy in patients (Munn and Bronte, 2016). The relationship between the infiltration level of immune cells in solid tumors and prognosis has been reported (Fridman et al, 2017). Cancer immunotherapy demonstrates tremendous success in improving prognosis of some cancer types, including breast invasive carcinoma and melanomas (Li et al, 2016; Naik et al, 2019). Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies have been shown to be effective in treating multiple malignancies (Gang et al, 2018); the drug efficacy depends on the mutational load (Hugo et al, 2016). Breast invasive carcinoma is a widely investigated tumor type with targeted drugs for different genetic subtypes. The Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) inhibitor alpelisib was approved in 2019 by the US Food and Drug Administration (FDA) for the treatment of PIK3CA-mutated hormone receptorpositive advanced breast invasive carcinoma as it significantly increases the progression-free survival for patients (Turner et al, 2015); human epidermal growth factor (EGF) receptor 2 human epidermal growth factor receptor-2 (HER2) antibodies such as trastuzumab and lapatinib can be used to treat HER2-positive patients; talazoparib, a poly (ADP-ribose) polymerase (PARP) inhibitor was approved in 2018 for the treatment of patients with breast cancer gene (BRCA) mutations and HER2-negative advanced or metastatic breast invasive carcinoma

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