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Selecting Multiple Biomarker Subsets with Similarly Effective Binary Classification Performances
Published on: October 11, 2018
Metabolism-related ALDH1B1 acts as potential predictor and therapeutic target for primary gastrointestinal diffuse
Qiqi Qiao1, Bingyu Liu2, Juanjuan Shang2
1Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, 250021, Shandong, China.
Abstract:
Primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) is the most common extra-nodal DLBCL. Metabolism-related factors have been associated with tumor progression, but the relationship between abnormal metabolism and prognosis of PGI-DLBCL remains unelucidated. In our study, consensus clustering based on metabolism-related genes classified PGI-DLBCL patients into two metabolic subtypes, and poor prognosis was associated with immunosuppressive microenvironment. A prognostic signature based on five metabolism-related genes (APOE, ALDH6 A1, PLOD2, IKBKB and ALDH1B1) was developed. Patients in high-risk group had a worse prognosis, with an immunosuppressive microenvironment. Moreover, 159 PGI-DLBCL patients were enrolled and divided into training cohort (n = 87) and validation cohort (n = 72). Univariate and multivariate Cox regression analysis showed metabolism-related factors were independent prognostic factors in PGI-DLBCL. A novel model (A-IPI score) combining APOA and NCCN-IPI was developed, and A-IPI score was better than NCCN-IPI score in predicting the prognosis of PGI-DLBCL patients. Furthermore, immunohistochemistry showed that ALDH1B1 was highly expressed in PGI-DLBCL and patients with high ALDH1B1 expression displayed worse prognosis. Moreover, cell proliferation assay revealed that the treatment with IGUANA-1, ALDH1B1 inhibitor, suppressed cell proliferation in DLBCL and IGUANA-1 exerted synergistic anti-tumor effects with PI3K inhibitor duvelisib. Additionally, we found that immune scores, ESTIMATE scores, and stromal scores were higher and the immune checkpoints (CTLA-4, PD-1, PD-L1) were down-regulated in patients with high ALDH1B1 expression. Collectively, our study constructed a novel metabolism-related prognostic model and highlighted the potential of metabolism-related gene ALDH1B1 as prognostic biomarker and drug target in PGI-DLBCL, providing new insights for the development of precision therapies in PGI-DLBCL patients.
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