1. Department of Pathology, Chi Mei Medical Center, Liouying, Tainan, Taiwan;
2. Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan;
3. Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan;
4. Division of General Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan;
5. Department of Health & Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan;
6. Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan;
7. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan;
8. Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan;
9. Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan;
10. Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;
11. Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan;
12. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan;
13. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan;
14. Department of Medical Image, Chi Mei Medical Center, Tainan, Taiwan;
15. Department of Leisure, Recreation, and Tourism Management, Southern Taiwan.
Pei-Ling Hsieh and Ching-Yih Lin contributed equally as co-last authors of this work.
Objective: Neoadjuvant concurrent chemoradiotherapy (CCRT) is an increasingly common therapeutic strategy for locally advanced rectal cancer, but stratification of risk and final outcomes remain a major challenge. Transcobalamin 1 (TCN1), a vitamin B12 (cobalamin)-binding protein, regulates cobalamin homeostasis. High expression of TCN1 have been reported in neoplasms such as breast cancer and hepatocellular carcinoma. However, little is known about the relevance of TCN1 to rectal cancer receiving CCRT. This study examined the predictive and prognostic impact of TCN1 expression in patients with rectal cancer following neoadjuvant CCRT.
Methods: Through data mining from a published transcriptome of rectal cancers (GSE35452), we identified upregulation of TCN1 gene as the most significantly predicted poor response to CCRT among ion transport-related genes (GO:0006811). We evaluated TCN1 immunohistochemistry and performed an H-score analysis on endoscopic biopsy specimens from 172 rectal cancer patients receiving neoadjuvant CCRT followed by curative surgery. Expression levels of TCN1 were further correlated with clinicopathologic features, therapeutic response, tumor regression grade (TRG) and survivals including metastasis-free survival (MeFS), disease-specific survival (DSS) and recurrent-free survival (LRFS).
Results: TCN1 overexpression was significantly related to advanced post-treatment tumor (T3, T4; p<0.001) and nodal status (N1, N2; p<0.001), vascular invasion (p=0.003) and inferior tumor regression grade (p < 0.001). In survival analyses, TCN1 overexpression was significantly associated with shorter DSS (p<0.0001), MeFS (p=0.0002) and LRFS (p=0.0001). Furthermore, it remained an independent prognosticator of worse DSS (p=0.002, hazard ratio=3.344), MeFS (p=0.021, hazard ratio=3.015) and LRFS (p=0.037, hazard ratio=3.037) in the multivariate comparison.
Conclusion: Overexpression of TCN1 is associated with poor therapeutic response and adverse outcomes in rectal cancer patients receiving CCRT, justifying the potential prognostic value of TCN1 in rectal cancer receiving CCRT.
Keywords: TCN1, Transcobalamin 1, CCRT, chemoradiotherapy, rectal cancer.