MCM4 Is a Novel Biomarker Associated With Genomic Instability, BRCAness Phenotype, and Therapeutic Potentials in Soft-Tissue Sarcoma.

Qi Liu,Jun Wang,Yiqi Xu,Yucheng Fu,Weibin Zhang,Yuhui Shen,Zhijian Jin,Qiyuan Bao

doi:10.3389/fcell.2021.666376

Qi Liu, Jun Wang + Show 6 more

Open Access

https://doi.org/10.3389/fcell.2021.666376

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Abstract

Soft-tissue sarcoma (STS) is represented by a heterogeneous group of rare malignancies with various molecular oncogenesis. Therapies targeting DNA repair pathways in STS have achieved minimal progress, potentially due to the lack of molecular biomarker(s) beyond the histology subtype. In this report, we comprehensively analyzed the expression profiles of 100 liposarcomas (LPSs), the most common STS subtype, in comparison with 21 adipose tissues from multiple GEO datasets to identify the potential prognostic and therapeutic biomarker for LPS. Furthermore, we investigated TCGA database, our archived tumor samples, and patient-derived tumor cell cultures (PTCCs) as a validation. We identified a total of 69 common differentially expressed genes (DEGs) among public datasets, with mini-chromosome maintenance protein 4 (MCM4) identified as a novel biomarker correlated with patients’ clinical staging and survival outcome. MCM4-high expression LPS was characterized by MCM4 copy number increase, genomic instability, and BRCAness phenotype compared with the MCM4-low expression counterpart. In contrast, the mutational and the immune landscape were minimally different between the two groups. Interestingly, the association of MCM4-high expression with genomic instability and BRCAness were not only validated in LPS samples from our institution (n = 66) but also could be expanded to the pan-sarcoma cohort from TCGA database (n = 263). Surprisingly, based on four sarcoma cell lines and eight PTCCs (three LPS and five other sarcoma), we demonstrated that MCM4 overexpression tumors were therapeutically sensitive to PARP inhibitor (PARPi) and platinum chemotherapy, independent of the histology subtypes. Our study, for the first time, suggested that MCM4 might be a novel prognostic biomarker, associated with dysregulated DNA repair pathways and potential therapeutic vulnerability in STS.

Highlights

Soft-tissue sarcoma (STS) is represented by a heterogeneous group (>70 subtypes) of rare malignancies with a variety of molecular oncogenesis
After dichotomizing 60 LPS cases into mini-chromosome maintenance protein 4 (MCM4)-high (n = 30) and low (n = 30) expression subsets, we found that the overall survival was drastically worse in MCM4-high patients than the MCM4-low counterpart (Figure 2B)
In parallel with what we found in LPS, the MCM4 expression was positively correlated with genomic instability in STS (R = 0.498, p < 0.001; Figure 4G)

Summary

Introduction

Soft-tissue sarcoma (STS) is represented by a heterogeneous group (>70 subtypes) of rare malignancies with a variety of molecular oncogenesis. The prognostic and predictive biomarker(s) beyond histology-based classification is still lacking. Liposarcoma (LPS) is one of the most common types of STS in the extremities and retroperitoneum with a variety of molecular pathogenesis (Crago and Brennan, 2015). Studies have shown that the primary pathological assessment of LPS results in a 25% misclassification of the histologic subtypes, indicating a pathological and morphological continuum of LPS tumor cells (de Vreeze et al, 2010). Patient stratification based on histology alone is insufficient for the prognostication and management of sarcoma. Novel histology-independent biomarker(s) for tailored prognosis and therapeutic regimen is as-yet to be exploited in LPS as well as in other histology subtypes

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Conclusion