Prognostic Value and Potential Regulatory Mechanism of Alternative Splicing in Geriatric Breast Cancer.

Wang Ma,Yaxuan Wang,Bingjie Li,Xin Li

doi:10.3390/genes11020200

Abstract

Breast cancer has the highest mortality and morbidity among women, especially in elderly women over 60 years old. Abnormal alternative splicing (AS) events are associated with the occurrence and development of geriatric breast cancer (GBC), yet strong evidence is lacking for the prognostic value of AS in GBC and the regulatory network of AS in GBC, which may highlight the mechanism through which AS contributes to GBC. In the present study, we obtained splicing event information (SpliceSeq) and clinical information for GBC from The Cancer Genome Atlas, and we constructed a GBC prognosis model based on AS events to predict the survival outcomes of GBC. Kaplan–Meier analysis was conducted to evaluate the predictive accuracy among different molecular subtypes of GBC. We conducted enrichment analysis and constructed a splicing network between AS and the splicing factor (SF) to examine the possible regulatory mechanisms of AS in GBC. We constructed eight prognostic signatures with very high statistical accuracy in predicting GBC survival outcomes from 45,421 AS events of 10,480 genes detected in 462 GBC patients; the prognostic model based on exon skip (ES) events had the highest accuracy, indicating its significant value in GBC prognosis. The constructed regulatory SF–AS network may explain the potential regulatory mechanism between SF and AS, which may be the mechanism through which AS events contribute to GBC survival outcomes. The findings confirm that AS events have a significant prognostic value in GBC, and we found a few effective prognostic signatures. We also hypothesized the mechanism underlying AS in GBC and discovered a potential regulatory mechanism between SF and AS.

Highlights

Breast cancer, which has the highest mortality and morbidity rate among women in the world, has placed a heavy burden on global public health, especially in developing countries
Previous studies have shown that estrogen receptor (ER) and progesterone receptor (PR) positives are higher in geriatric breast cancer (GBC), with less overexpression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and ki67 [6]
alternative splicing (AS) can cause the generated messenger RNA (mRNA) to be degraded by nonsense-mediated mRNA decay, changing the quality and quantity of protein products [44,45]

Summary

Introduction

Breast cancer, which has the highest mortality and morbidity rate among women in the world, has placed a heavy burden on global public health, especially in developing countries. In the United States, 43% of breast cancers are recognized in women aged older than 65 years. Age is undoubtedly the biggest hazard factor in breast cancer [2,3,4]. A statistically significant difference exists in the distribution of molecular subtypes between geriatric and young breast cancer patients, and less aggressive Luminal A and Luminal B tumor subtypes are more common in geriatric patients [5]. Previous studies have shown that estrogen receptor (ER) and progesterone receptor (PR) positives are higher in geriatric breast cancer (GBC), with less overexpression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and ki67 [6].

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Conclusion