Abstract LB551: Critical role of necroptosis in colorectal carcinogenesis
Authors: Zhu Xiangzhu , Su Timothy , Li Yong , Yu Chang , Deng Xinqing , Shubin Eugene , Zheng Wei , Murff Harvey J. , Ness Reid M. , Shrubsole Martha J. , Dai Qi 
Published: June 2022

Background: Unlike apoptosis, necroptosis, a programmed necrosis discovered in the past decade, elicits robust adaptive immune responses, including inflammatory cascade, against bacterial infection. However, no human study has yet examined the role of necroptosis in colorectal carcinogenesis.

Methods: To compare the roles of necroptosis (TRPM7, pMLKL) with inflammation (COX-2), apoptosis (BAX, TUNEL) and cell proliferation (Ki67) biomarkers across the colorectal carcinogenesis spectrum, we evaluated the trends of biomarker levels from normal colorectal mucosa, to small adenoma, large adenomas and early stages of CRC in tissue microarray (TMA). Furthermore, we compared whether these biomarkers in rectal biopsies can predict the risk of developing metachronous polyp/adenoma.

Results: In TMA, we revealed that levels of TRPM7, did not apparently change from normal mucosa (median=1.1) to small adenoma (median=0.8), but then substantially dropped in large adenoma (median=0.1) only to rise dramatically increased in early colorectal cancer (median=7.4) (P for trend=0.004). pMLKL, tended to decrease during carcinogenesis, although not significantly. Ki67 linearly and significantly increased during carcinogenesis (Ptrend=0.002). Similar to Ki67, levels of BAX and TUNEL increased significantly during carcinogenesis, but BAX started to drop in early carcinogenesis. Thus, compared to TRPM7, a necroptosis biomarker, BAX, an apoptosis biomarker, had an almost completely opposite trend during carcinogenesis. COX-2 intensity in the epithelium, but not the stroma, increased in carcinogenesis (Ptrend=0.01). Of 124/227 participants who had follow-up colonoscopy within 5 years, 69 (55.6%) were identified as having metachronous polyp/adenoma. For single biomarker analysis, overexpression of COX-2 was significantly associated with an increased risk of metachronous polyp OR=3.61 ( 95% CI: 1.05-2.47, Ptrend=0.02) and adenoma (OR=3.58, 95% CI 0.96-3.36, Ptrend=0.04). Higher expression of TRPM7 was associated with risk of recurrent polyp and adenoma in a dose-response manner although it did not reaching statistically significance. According to the results of single biomarker analysis and biological plausibility, we combined COX-2 with two necroptosis biomarkers, i.e., pMLKL, TRPM7 and two apoptosis biomarkers (BAX and TUNEL) to generate composite index scores using factor analysis. Several of these composite scores were strongly associated with a 3- to 5-fold increased of metachronous polyp and/or adenoma risk in the highest quartile including COX-2 with pMLKL, COX-2 and TRPM7, BAX and TRPM7 and COX-2 with BAX. The results were similar after the exclusion of recurrence within one year after the completion of the PPCCT.

Conclusion: Necroptosis plays a key role in colorectal carcinogenesis. Combining necroptosis biomarkers with inflammation and apoptosis biomarkers can improve the prediction of risk of metachronous polyp/adenoma compared to using necroptosis, inflammation or apoptosis biomarkers alone.

Citation Format: Xiangzhu Zhu, Timothy Su, Yong Li, Chang Yu, Xinqing Deng, Eugene Shubin, Wei Zheng, Harvey J. Murff, Reid M. Ness, Martha J. Shrubsole, Qi Dai. Critical role of necroptosis in colorectal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB551.