Abstract Introduction: DNA mismatch repair (MMR) is a major mechanism cells use to repair erroneous insertion or deletion of bases during DNA replication. MMR deficiency (MMR-d), including rare germline mutations (Lynch syndrome) and somatic inactivation, has been extensively studied in solid tumors, such as colon, endometrial, pancreatic, and ovarian cancers. The prevalence of MMR-d in solid tumors ranges from 1% - 20% of somatic defects, and patients with MMR-d tumors have a longer overall survival. It is also well-known that MMR is an integral part of activation-induced cytidine deaminase (AID)-mediated somatic hypermutation and immunoglobulin class switch processes in normal mature B lymphocytes, while mice deficient in the MMR genes are prone to develop T and B cell lymphomas. It is also known that follicular lymphoma (FL) carries a high degree of somatic hypermutation with some heterogeneity induced by AID. Our understanding of MMR status in human blood cancers, especially in FL remains very limited. One could hypothesize that MMR-d status could permit cells to acquire and sustain high-degree of mutation rates, better sensitivity to DNA damaging chemotherapy while hindering rapid cell proliferation, which could manifest to a better prognosis in patients. Herein, we conducted an exploratory analysis to understand the frequency of MMR-d status and its prognostic significance in FL. Methods: Following approval of the Institution Review Board, we assessed the expression of MMR proteins; MLH1, PMS2 and MSH6 on formalin fixed paraffin embedded (FFPE) lymph node tissue obtained from patients with FL by immunohistochemistry (IHC) using standard methods on Ventana Benchmark XT automated stainers (Ventana Medical Systems, Tucson, AZ). Dako (clone ES05), Cell Marque (clone EPR3947) and Biocare (clone BC/44) antibodies were used to stain MLH1, PMS2 and MSH6, respectively. Fifty cases of FL with existing FFPE blocks were selected randomly. The expression of MLH1, PMS2 and MSH6 proteins in the tumor cells was scored as 0, +1 or +2, (Figure 1A). Cases with absence of the IHC signal (score of 0) in any one of the three proteins were classified as MMR-d. Progression free survival at 12 months (PFS12) or 24 months (PFS24) was defined as being free from disease progression or death at 12 or 24 months, respectively. All time-to-event analyses were done from the time of diagnosis. Results: Fifty patients with FL were included in the study. The median age at diagnosis was 65 years (range 34-85) and 58% were females. At initial diagnosis, 36 (72%) patients had advanced stage (stage 3, n=8, stage 4, n=28) disease. Of the 50 patients, 26 (52%) required treatment; chemotherapy (n=14), radiation treatment alone (n=9), surgery alone (n=3). Out of the 50 patients, 23 (46%) were classified as MMR-d due to lack of expression of one of the three assessed proteins: MLH1 (n=1, 2%), PMS2 (n=11, 22%) and MSH6 (n=19, 38%). The patient who had MLH1 loss had concomitant PMS2 loss. Stage IV disease was observed in 52% of the MMR-d patients and 59% in the MMR proficient (MMR-p) patients, p=0.77. Median age at diagnosis was 62 (range: 34-84) years and 67 (range: 34-85) years in MMR-d and MMR-p patients, respectively, p=0.1. FLIPI score was similar between the MMR-d [low n=10 (43%), intermediate n=9 (39%), high n=4 (18%)] and MMR-p [low n=5 (18%), intermediate n=14 (52%), high n=8 (30%)] patients, p=0.16. Fourteen (61%) of MMR-d patients required initiation of therapy upon diagnosis compared to 12 (44%) of MMR-p patients, p=0.27. The median follow-up for the entire cohort was 17 years [95% confidence interval (CI): 11.7-29.4]. The median overall survival (OS) of MMR-d patients was 10 years (95%CI: 7.8-20.7) compared to 6 years (95%CI: 4.5-NR) in MMR-p patients, p=0.036, Figure 1B. In patients with MMR-d and MMR-p, 83% and 55% achieved PFS12, p=0.04 and 65% and 41% achieved PFS24, p=0.08, respectively. After adjusting for FLIPI score, MMR status remained associated with OS (MMR-d HR: 0.51, 95%CI: 0.2-1.02, p=0.05). Discussion and Conclusion: In this pilot study, MMR-d in the FL tumors was common (46%) and, as predicted, was associated with a favorable OS. Association of MMR-d status with PFS in general and patients with early progression (short PFS12 and PFS24) and relationship of MMR-d with types of therapy need further study in large FL datasets. Figure 1 Figure 1. Disclosures Paludo: Karyopharm: Research Funding. King: Celgene/BMS: Research Funding. Maurer: Celgene: Research Funding; Genentech: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding.

中文翻译：

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滤泡性淋巴瘤肿瘤的错配修复缺陷很常见，并且与良好的总体生存率相关

摘要 简介：DNA错配修复（MMR）是细胞在DNA复制过程中修复碱基错误插入或缺失的主要机制。MMR 缺陷 (MMR-d)，包括罕见的种系突变 (Lynch 综合征) 和体细胞失活，已在结肠癌、子宫内膜癌、胰腺癌和卵巢癌等实体瘤中得到广泛研究。MMR-d 在实体瘤中的患病率在 1% - 20% 的躯体缺陷中，MMR-d 肿瘤患者的总生存期更长。众所周知，MMR 是正常成熟 B 淋巴细胞中激活诱导的胞苷脱氨酶 (AID) 介导的体细胞超突变和免疫球蛋白类别转换过程的一个组成部分，而 MMR 基因缺陷的小鼠则容易产生 T 和 B细胞淋巴瘤。众所周知，滤泡性淋巴瘤 (FL) 携带高度的体细胞超突变，并具有由 AID 诱导的一些异质性。我们对人类血癌，尤其是 FL 中 MMR 状态的了解仍然非常有限。可以假设 MMR-d 状态可以使细胞获得并维持高度的突变率，对 DNA 破坏性化学疗法具有更好的敏感性，同时阻碍细胞的快速增殖，这可能表明患者的预后更好。在这里，我们进行了探索性分析，以了解 MMR-d 状态的频率及其在 FL 中的预后意义。方法：在机构审查委员会批准后，我们​​评估了 MMR 蛋白的表达；MLH1, PMS2 和 MSH6 在福尔马林固定石蜡包埋 (FFPE) 淋巴结组织上通过免疫组织化学 (IHC) 使用 Ventana Benchmark XT 自动染色机 (Ventana Medical Systems, Tucson, AZ) 上的标准方法从 FL 患者获得。Dako（克隆 ES05）、Cell Marque（克隆 EPR3947）和 Biocare（克隆 BC/44）抗体分别用于染色 MLH1、PMS2 和 MSH6。随机选择了 50 例具有现有 FFPE 块的 FL。MLH1、PMS2 和 MSH6 蛋白在肿瘤细胞中的表达评分为 0、+1 或 +2（图 1A）。在三种蛋白质中的任何一种中没有 IHC 信号（得分为 0）的病例被归类为 MMR-d。12 个月 (PFS12) 或 24 个月 (PFS24) 无进展生存期分别定义为在 12 个月或 24 个月时无疾病进展或死亡。所有的事件发生时间分析都是从诊断时开始进行的。结果：50 名 FL 患者被纳入研究。诊断时的中位年龄为 65 岁（范围 34-85 岁），58% 为女性。初步诊断时，36 名 (72%) 患者患有晚期（第 3 期，n=8，第 4 期，n=28）疾病。在 50 名患者中，26 名（52%）需要治疗；化疗（n = 14），单独的放射治疗（n = 9），单独的手术（n = 3）。在 50 名患者中，23 名 (46%) 被归类为 MMR-d，原因是三种评估蛋白之一缺乏表达：MLH1 (n=1, 2%)、PMS2 (n=11, 22%) 和MSH6 (n=19, 38%)。MLH1 丢失的患者伴随有 PMS2 丢失。52% 的 MMR-d 患者和 59% 的 MMR 熟练 (MMR-p) 患者观察到 IV 期疾病，p=0.77。诊断时的中位年龄为 62 岁（范围：MMR-d 和 MMR-p 患者分别为 34-84）岁和 67（范围：34-85）岁，p=0.1。MMR-d [低 n=10 (43%)、中间 n=9 (39%)、高 n=4 (18%)] 和 MMR-p [低 n=5 (18%) 之间的 FLIPI 评分相似, 中 n=14 (52%), 高 n=8 (30%)] 患者, p=0.16。14 名 (61%) 的 MMR-d 患者在诊断后需要开​​始治疗，而 12 名 (44%) 的 MMR-p 患者需要开始治疗，p=0.27。整个队列的中位随访时间为 17 年 [95% 置信区间 (CI)：11.7-29.4]。MMR-d 患者的中位总生存期 (OS) 为 10 年 (95%CI: 7.8-20.7)，而 MMR-p 患者的中位总生存期 (OS) 为 6 年 (95%CI: 4.5-NR)，p=0.036，图 1B。在 MMR-d 和 MMR-p 患者中，83% 和 55% 的患者达到 PFS12，p=0.04，65% 和 41% 的患者分别达到 PFS24，p=0.08。调整 FLIPI 分数后，MMR 状态仍然与 OS 相关（MMR-d HR：0.51，95%CI：0.2-1.02，p=0.05）。讨论和结论：在这项初步研究中，FL 肿瘤中的 MMR-d 很常见（46%），并且正如预期的那样，与良好的 OS 相关。MMR-d 状态与一般 PFS 和早期进展患者（短 PFS12 和 PFS24）的关联以及 MMR-d 与治疗类型的关系需要在大型 FL 数据集中进一步研究。图 1 图 1. 披露 Paludo：Karyopharm：研究经费。King：Celgene/BMS：研究经费。Maurer：Celgene：研究经费；基因泰克：研究经费；Kite Pharma：实体董事会或咨询委员会的成员；Morphosys：实体董事会或咨询委员会的成员资格，研究经费；Nanostring：研究经费；辉瑞：咨询、实体董事会或咨询委员会的成员资格。Nowakowski：Celgene，NanoString Technologies，MorphoSys：研究经费；Celgene、MorphoSys、Genentech、Selvita、Debiopharm Group、Kite/Gilead：咨询、实体董事会或咨询委员会成员资格。Witzig：Karyopharm Therapeutics、Celgene/BMS、Incyte、Epizyme：咨询、实体董事会或咨询委员会成员；Celgene/BMS、Acerta Pharma、Kura Oncology、Acrotech Biopharma、Karyopharm Therapeutics：研究资金。Genentech、Selvita、Debiopharm Group、Kite/Gilead：咨询、实体董事会或咨询委员会的成员资格。Witzig：Karyopharm Therapeutics、Celgene/BMS、Incyte、Epizyme：咨询、实体董事会或咨询委员会成员；Celgene/BMS、Acerta Pharma、Kura Oncology、Acrotech Biopharma、Karyopharm Therapeutics：研究资金。Genentech、Selvita、Debiopharm Group、Kite/Gilead：咨询、实体董事会或咨询委员会的成员资格。Witzig：Karyopharm Therapeutics、Celgene/BMS、Incyte、Epizyme：咨询、实体董事会或咨询委员会成员；Celgene/BMS、Acerta Pharma、Kura Oncology、Acrotech Biopharma、Karyopharm Therapeutics：研究资金。