Pancreatic ductal adenocarcinoma with a high expression of alcohol dehydrogenase 1B is associated with less aggressive features and a favorable prognosis

Kohei Chida; Masanori Oshi; Arya Mariam Roy; Takumi Sato; Itaru Endo; Kazuaki Takabe

Pancreatic ductal adenocarcinoma with a high expression of alcohol dehydrogenase 1B is associated with less aggressive features and a favorable prognosis

Am J Cancer Res. 2023 Aug 15;13(8):3638-3649. eCollection 2023.

Authors

Kohei Chida¹, Masanori Oshi^{1

2}, Arya Mariam Roy³, Takumi Sato^{1

4}, Itaru Endo², Kazuaki Takabe^{1

2

5

6

7

8

9}

Affiliations

¹ Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, NY 14263, USA.
² Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine Yokohama, Kanagawa 236-0004, Japan.
³ Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center Buffalo, NY 14263, USA.
⁴ Department of Medical Science, The University of Tokyo Tokyo 113-8654, Japan.
⁵ Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York Buffalo, NY 14263, USA.
⁶ Department of Breast Surgery and Oncology, Tokyo Medical University Tokyo 160-8402, Japan.
⁷ Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences Niigata 951-8510, Japan.
⁸ Department of Breast Surgery, Fukushima Medical University School of Medicine Fukushima 960-1295, Japan.
⁹ Department of Breast Surgery, Roswell Park Comprehensive Cancer Center Buffalo, NY 14263, USA.

PMID: 37693153
PMCID: PMC10492124

Abstract

Alcohol dehydrogenase (ADH) oxidizes alcohol into acetaldehyde (AA), which is a known carcinogen. Aldehyde dehydrogenase (ALDH) oxidizes AA into acetate. Therefore, pancreatic cancer that expresses a high level of ADH1B that generates more AA is expected to be associated with aggressive cancer. On the other hand, given that the differentiated cells that retain their cellular functions typically exhibit lower proliferation rates, it remains unclear whether pancreatic adenocarcinoma (PDAC) with high ADH1B gene expression is linked to aggressive features in patients. The Cancer Genome Atlas (n = 145) was used to obtain data of PDAC patients and GSE62452 cohort (n = 69) was used as a validation cohort. PDAC with high ADH1B expression was associated with less cancer cell proliferation as evidenced by lower MKI67 expression and lower histological grade; with a higher fraction of stromal cells consistent with less proliferative cancer. PDAC with high ADH1B expression also had lower homologous recombination deficiency and mutation rates, lower KRAS and TP53 mutation rates. ADH1B expression correlated with ALDH2 expression in PDAC, but not with DNA repair genes. High ADH1B expression PDAC was associated with high infiltration of anti-cancerous CD8⁺ T cells and pro-cancerous M2 macrophages but with lower levels of Th1 T cells, with a higher cytolytic activity. PDAC patients with a high ADH1B expression had better disease-specific survival (DSS) and overall survival (OS) and ADH1B was an independent prognostic biomarker for both DSS (HR = 0.89, 95% CI = 0.80-0.99, P = 0.045) and OS (HR = 0.90, 95% CI = 0.82-0.99, P = 0.044) in multivariate analysis. In conclusion, PDAC with high ADH1B expression had less cell proliferation and malignant features, along with higher immune cell infiltration, and had a better prognosis.

Keywords: ADH1B; Pancreatic ductal adenocarcinoma; alcohol metabolism; gene expression; prognosis; signaling.