Abstract 2452: Clinical importance of nicotinamide nucleotide transhydrogenase in obesity-associated colorectal cancer

Abstract Background: Obesity is increasing worldwide, and many associated diseases are emerging as global health problems. There is a relationship between body mass and the risk of developing colorectal cancer (CRC). However, predictive biomarkers of survival with body mass remain elusive. Therefore, we aimed to identify novel clinically relevant biomarkers for obesity-associated CRC. Methods: We searched for biomarker candidates in The Cancer Genome Atlas CRC cohort. We divided the TCGA CRC cohort (n=268) data into 3 groups (healthy weight CRC group [HT], adjacent normal tissue from the HT group [AN]), and obesity CRC group [OT]). Candidates were validated by survival analysis after immunohistochemistry in an independent cohort of 420 patients. Results: The gene expression levels of NNT, PANK3, PPARGC1B, RTL6, FAM220A, and TMEM9 were associated with survival in overweight and obese patients with CRC from TCGA cohort. These findings were validated using protein expression data from our independent cohort. In our patient cohort, the hazard ratio (HR) of the subgroup of low NNT versus that of high NNT in terms of 5-year event-free survival (EFS) was 2.20 (adjusted for age and sex, 95% CI: 1.01-4.80, p < 0.05) among patients of obesity-associated CRC. When both TNM staging and NNT expression were considered, patients of obesity-associated CRC with low NNT expression and advanced stage III-IV cancer had a HR of 21.20 (adjusted for age and sex, 95% CI: 2.88-156.08, p < 0.01) compared to those with high NNT expression and early stage I-II cancer. However, when patients of obesity-associated CRC with high NNT expression and advanced stage III-IV cancer were compared to those with high NNT expression and early stage I-II cancer, the former subgroup had a HR of 8.39 (adjusted for age and sex, 95% CI: 1.03-68.39, p < 0.05) in terms of the 5-year EFS. Finally, when the 5-year disease-specific survival analysis was performed, the patients of obesity-associated CRC with low NNT expression and advanced stage III-IV cancer were found to have a HR of 14.05 (adjusted for age and sex, 95% CI: 1.89-104.38, P = 0.01) compared to those with high NNT expression and early stage I-II cancer. Furthermore, low NNT expression results in the inactivation of several metabolic pathways, including ROS-related pathways. Conclusions: NNT is a novel and promising CRC prognostic biomarker for overweight and obese patients. It can provide clinicians with early indicators of patient prognosis and aid in appropriate treatment selection. Citation Format: Soyeon Jeong, Sungjin Park, Jungsuk An, Myunghee Kang, Seungyoon Nam, Jung Ho Kim. Clinical importance of nicotinamide nucleotide transhydrogenase in obesity-associated colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2452.