Xu-Monette Zijun Y, Deng Qipan, Manyam Ganiraju C, Tzankov Alexander, Li Ling, Xia Yi, Wang Xiao-Xiao, Zou Dehui, Visco Carlo, Dybkær Karen, Li Jun, Zhang Li, Liang Han, Montes-Moreno Santiago, Chiu April, Orazi Attilio, Zu Youli, Bhagat Govind, Richards Kristy L, Hsi Eric D, Choi William W L, van Krieken J Han, Huh Jooryung, Ponzoni Maurilio, Ferreri Andrés J M, Parsons Ben M, Møller Michael B, Wang Sa A, Miranda Roberto N, Piris Miguel A, Winter Jane N, Medeiros L Jeffrey, Li Yong, Young Ken H
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio.
Clin Cancer Res. 2016 Jul 15;22(14):3593-605. doi: 10.1158/1078-0432.CCR-15-2296. Epub 2016 Feb 29.
MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of patients with DLBCL, and to evaluate the clinical significance of MYC mutations in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy.
We identified MYC mutations in 750 patients with DLBCL using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP-treated patients.
The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions) and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3' untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline SNP encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts.
Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis. Clin Cancer Res; 22(14); 3593-605. ©2016 AACR.
MYC是许多癌症中的关键驱动癌基因，其以易位和过表达形式的失调与淋巴瘤发生及弥漫性大B细胞淋巴瘤（DLBCL）的进展有关。MYC的突变谱及其在DLBCL中的作用尚不清楚。本研究旨在确定一大组DLBCL患者中MYC突变的谱，并评估MYC突变在接受利妥昔单抗、环磷酰胺、多柔比星、长春新碱和泼尼松（R-CHOP）免疫化疗的DLBCL患者中的临床意义。
我们使用桑格测序法在750例DLBCL患者中鉴定MYC突变，并评估602例接受R-CHOP治疗患者的预后意义。
MYC突变在DNA水平的频率为33.3%（编码序列或非翻译区的突变），在蛋白质水平为16.1%（非同义突变）。大多数非同义突变与更好的生存结果相关；相反，T58和F138突变（与MYC重排相关）以及在3'非翻译区发生的几个突变与明显更差的生存结果相关。然而，这些突变很少发生（仅在约2%的DLBCL中）。编码Myc-N11S变体的种系单核苷酸多态性（在6.5%的研究队列中观察到）与患者明显更好的生存相关，并导致小鼠异种移植瘤的致瘤性降低。
DLBCL中存在多种类型的MYC基因突变，对Myc功能和临床结果有不同影响。与MYC基因易位和过表达不同，大多数MYC基因突变可能在驱动淋巴瘤发生中不起作用。《临床癌症研究》；22(14)；3593 - 605。©2016美国癌症研究协会。
