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Abstract
Overexpression of the BCL2 protein has been reported as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, there are currently no standardized criteria for evaluating BCL2 protein expression. We aimed to evaluate the prognostic value of BCL2 expression determined by immunohistochemistry (IHC), incorporating both the staining intensity and proportion, in patients with de novo DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment. We defined tumors with BCL2 expression in nearly all tumor cells with a uniformly strong intensity by IHC as BCL2 super-expressor. The BCL2 super-expressors (n = 35) showed significantly worse event-free survival (EFS; HR, 1.903; 95% CI, 1.159-3.126, P = 0.011) and overall survival (OS; HR, 2.467; 95% CI, 1.474-4.127, P = 0.001) compared with the non-BCL2 super-expressors (n = 234) independent of the international prognostic index (IPI), cell of origin (COO), and double expressor status in the training set (n = 269). The adverse prognostic impact of BCL2 super-expression was confirmed in the validation set (n = 195). When the survival outcomes were evaluated in the entire cohort (n = 464), BCL2 super-expressor group was significantly associated with inferior EFS and OS regardless of IPI, COO, MYC expression, and stages. BCL2 super-expressors had genetic aberrations enriched in the NOTCH and TP53 signaling pathways. This study suggests that the BCL2 super-expressor characterizes a distinct subset of DLBCL with a poor prognosis and warrants further investigation as a target population for BCL-2 inhibitors.

Affiliations

Jin Roh #  1 , Hyungwoo Cho #  2 , Hyo-Kyung Pak  3 , Yoon Sei Lee  4 , Sang-Wook Lee  5 , Jin-Sook Ryu  6 , Eun Jin Chae  7 , Kyung Won Kim  7 , Jooryung Huh  8 , Yoon Seok Choi  9 , Seong Hyun Jeong  9 , Cheolwon Suh  2 , Dok Hyun Yoon  10 , Chan-Sik Park  11
1 Department of Pathology, Ajou University School of Medicine, Suwon, Korea.
2 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
3 Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
4 Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
5 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
6 Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
7 Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
8 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
9 Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea.
10 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. dhyoon@amc.seoul.kr.
11 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. csikpark@amc.seoul.kr.
# Contributed equally.