Identification of proteomic markers for prediction of the response to 5-Fluorouracil based neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients

Jianan Wang; Jiayu Liu; Jinyang Wang; Shijian Wang; Feifei Li; Ruibing Li; Peng Liu; Mianyang Li; Chengbin Wang

doi:10.1186/s12935-022-02530-0

Identification of proteomic markers for prediction of the response to 5-Fluorouracil based neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients

Cancer Cell Int. 2022 Mar 15;22(1):117. doi: 10.1186/s12935-022-02530-0.

Authors

Jianan Wang^{1

2}, Jiayu Liu¹, Jinyang Wang^{1

3}, Shijian Wang⁴, Feifei Li⁵, Ruibing Li¹, Peng Liu⁵, Mianyang Li⁶, Chengbin Wang⁷

Affiliations

¹ Department of Laboratory Medicine, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China.
² Medical School of Chinese PLA, Beijing, 100853, China.
³ School of Laboratory Medicine, Weifang Medical College, Weifang, 261053, Shandong, China.
⁴ Nankai University School of Medicine, Nankai University, Tianjin, 300071, China.
⁵ Department of Pathology, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China.
⁶ Department of Laboratory Medicine, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China. limianyang301@163.com.
⁷ Department of Laboratory Medicine, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China. wangchengbin@301hospital.com.cn.

Abstract

Background: Neoadjuvant chemoradiotherapy (nCRT) prior to surgery is the standard treatment for patients with locally advanced rectal cancer (LARC), while parts of them show poor therapeutic response accompanied by therapy adverse effects. Predictive biomarkers for nCRT response could facilitate the guidance on treatment decisions but are still insufficient until now, which limits the clinical applications of nCRT in LARC patients.

Methods: In our study, 37 formalin-fixed paraffin-embedded tumor biopsies were obtained from patients with LARC before receiving 5-fluorouracil based nCRT. Proteomics analyses were conducted to identify the differentially expressed proteins (DEPs) between total responders (TR) and poor responders (PR). The DEPs were validated via ROC plotter web tool and their predictive performance was evaluated by receiver operating characteristic analysis. Functional enrichment analyses were performed to further explore the potential mechanisms underlying nCRT response.

Results: Among 3,998 total proteins, 91 DEPs between TR and PR were screened out. HSPA4, NIPSNAP1, and SPTB all with areas under the curve (AUC) ~ 0.8 in the internal discovery cohort were independently validated by the external mRNA datasets (AUC ~ 0.7), and their protein levels were linearly correlated with the graded responses to nCRT in the internal cohort. The combination of HSPA4 and SPTB could distinctly discriminate the TR and PR groups (AUC = 0.980, p < 0.0001). Moreover, multiple combinations of the three proteins realized increased specificity and/or sensitivity, while achieving favorable predictive value when moderate responders were introduced into the ROC analysis. Pathways including DNA damage repair, cell cycle, and epithelial mesenchymal transition were involved in nCRT response according to the enrichment analysis results.

Conclusions: HSPA4, SPTB and NIPSNAP1 in tumor biopsies and/or their optional combinations might be potential predictive markers for nCRT response in patients with LARC. The DEPs and their related functions have implications for the potential mechanisms of treatment response to nCRT in patients with LARC.

Keywords: Locally advanced rectal cancer; Neoadjuvant chemoradiotherapy; Predictive marker; Proteomics.