Guo-Chen Liu1, Ran-Yi Liu2, Jun-Ping Yan3, Xin An4, Wu Jiang5, Yi-Hong Ling6, Jie-Wei Chen6, Jin-Xin Bei2, Xiao-Yu Zuo2, Mu-Yan Cai6, Ze-Xian Liu2, Zhi-Xiang Zuo2, Ji-Hong Liu1, Zhi-Zhong Pan5, Pei-Rong Ding5. 1. Department of Gynecologic Oncology, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P. R. China. 2. Department of Experimental Research, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P. R. China. 3. Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, P. R. China. 4. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P. R. China. 5. Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P. R. China. 6. Department of Pathology, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P. R. China.
Abstract
Background: Previous studies demonstrated that prognosis of germline deficiency in mismatch repair protein (dMMR) was different from that of sporadic dMMR. The underlying mechanism has not been studied. Methods: From a prospectively maintained database, we collected dMMR colorectal cancer (CRC) patients identified by postoperative immunohistochemistry screening. According to genetic test, patients were grouped as Lynch-associated or sporadic dMMR. We compared the clinical-pathological features, prognosis, and immunoreactive differences between the two groups. By whole-exome sequencing and neoantigen detection pipeline, mutational frequencies and neoantigen burdens were also compared. All statistical tests were two-sided. Results: Sixty-seven sporadic dMMR and 85 Lynch-associated CRC patients were included in the study. Sporadic dMMR patients were older (P < .001) and their tumors were poorly differentiated (P = .03). The survival was better in the Lynch-associated group (P = .001). After adjustment, the difference still remained statistically significant (hazard ratio = 0.29, 95% confidence interval = 0.09 to 0.95, P = .04). The scores of Crohn's-like reaction (CRO; P < .001), immunoreactions in the invasive margin (IM; P = .01), tumor stroma (TS; P = .009), and cancer nest (CN; P = .02) of the Lynch-associated group were statistically significantly higher. The numbers of CD3+, CD8+, Foxp3+ tumor-infiltrating lymphocytes (TILs) in IM; CD3+, CD4+ TILs in TS; and CD3+, CD4+, CD8+ TILs in CN were statistically significantly higher in Lynch-associated dMMR patients. Based on the 16 patients who under went whole-exome sequencing, there were also more somatic mutations and neoantigen burdens in the Lynch-associated group compared with the sporadic dMMR group (439/pt vs 68/pt, P = .006; 628/pt vs 97/pt, P = .009). Conclusions: There are heterogeneities in dMMR CRCs. Lynch-associated dMMR patients present with more somatic mutations and neoantigens compared with sporadic dMMR, which probably results in stronger immunoreactions and survival improvement.
Background: Previous studies demonstrated that prognosis of germline deficiency in mismatch repair protein (dMMR) was different from that of sporadic dMMR. The underlying mechanism has not been studied. Methods: From a prospectively maintained database, we collected dMMRcolorectal cancer (CRC) patients identified by postoperative immunohistochemistry screening. According to genetic test, patients were grouped as Lynch-associated or sporadic dMMR. We compared the clinical-pathological features, prognosis, and immunoreactive differences between the two groups. By whole-exome sequencing and neoantigen detection pipeline, mutational frequencies and neoantigen burdens were also compared. All statistical tests were two-sided. Results: Sixty-seven sporadic dMMR and 85 Lynch-associated CRCpatients were included in the study. Sporadic dMMRpatients were older (P < .001) and their tumors were poorly differentiated (P = .03). The survival was better in the Lynch-associated group (P = .001). After adjustment, the difference still remained statistically significant (hazard ratio = 0.29, 95% confidence interval = 0.09 to 0.95, P = .04). The scores of Crohn's-like reaction (CRO; P < .001), immunoreactions in the invasive margin (IM; P = .01), tumor stroma (TS; P = .009), and cancer nest (CN; P = .02) of the Lynch-associated group were statistically significantly higher. The numbers of CD3+, CD8+, Foxp3+ tumor-infiltrating lymphocytes (TILs) in IM; CD3+, CD4+ TILs in TS; and CD3+, CD4+, CD8+ TILs in CN were statistically significantly higher in Lynch-associated dMMRpatients. Based on the 16 patients who under went whole-exome sequencing, there were also more somatic mutations and neoantigen burdens in the Lynch-associated group compared with the sporadic dMMR group (439/pt vs 68/pt, P = .006; 628/pt vs 97/pt, P = .009). Conclusions: There are heterogeneities in dMMR CRCs. Lynch-associated dMMRpatients present with more somatic mutations and neoantigens compared with sporadic dMMR, which probably results in stronger immunoreactions and survival improvement.
Authors: Mark A Glaire; Neil Aj Ryan; Marieke E Ijsselsteijn; Katarzyna Kedzierska; Sofia Obolenski; Reem Ali; Emma J Crosbie; Tjalling Bosse; Noel Fcc de Miranda; David N Church Journal: J Pathol Date: 2022-04-01 Impact factor: 9.883
Authors: Elaine Tan; Junmin Whiting; Hao Xie; Iman Imanirad; Estrella Carballido; Seth Felder; Jessica Frakes; Quanxing Mo; Christine Walko; Jennifer B Permuth; Katelyn Sommerer; Richard Kim; Daniel A Anaya; Jason B Fleming; Ibrahim Halil Sahin Journal: Oncologist Date: 2022-03-11