文章：

高体细胞突变和新抗原负荷与多发性骨髓瘤的无进展生存期缩短相关

High somatic mutation and neoantigen burden are correlated with decreased progression-free survival in multiple myeloma

原文发布日期：2017-09-22

DOI: 10.1038/bcj.2017.94

类型: Original Article

开放获取: 是

英文摘要：

Tumor-specific mutations can result in immunogenic neoantigens, both of which have been correlated with responsiveness to immune checkpoint inhibitors in highly mutagenic cancers. However, early results of single-agent checkpoint inhibitors in multiple myeloma (MM) have been underwhelming. Therefore, we sought to understand the relationship between mutation and neoantigen landscape of MM patients and responsiveness to therapies. Somatic mutation burden, neoantigen load, and response to therapy were determined using interim data from the MMRF CoMMpass study (NCT01454297) on 664 MM patients. In this population, the mean somatic and missense mutation loads were 405.84(s=608.55) and 63.90(s=95.88) mutations per patient, respectively. There was a positive linear relationship between mutation and neoantigen burdens (R2=0.862). The average predicted neoantigen load was 23.52(s=52.14) neoantigens with an average of 9.40(s=26.97) expressed neoantigens. Survival analysis revealed significantly shorter progression-free survival (PFS) in patients with greater than average somatic missense mutation load (N=163, 0.493 vs 0.726 2-year PFS, P=0.0023) and predicted expressed neoantigen load (N=214, 0.555 vs 0.729 2-year PFS, P=0.0028). This pattern is maintained when stratified by disease stage and cytogenetic abnormalities. Therefore, high mutation and neoantigen load are clinically relevant risk factors that negatively impact survival of MM patients under current standards of care.

摘要翻译： 

肿瘤特异性突变可导致免疫原性新抗原的产生，这两者在高突变性癌症中均与免疫检查点抑制剂的治疗反应相关。然而，单药检查点抑制剂在多发性骨髓瘤（MM）中的初步研究结果并不理想。因此，我们试图探讨多发性骨髓瘤患者的突变及新抗原特征与治疗反应之间的关系。基于MMRF CoMMpass研究（NCT01454297）对664例MM患者的期中数据，我们分析了体细胞突变负荷、新抗原负荷与治疗反应的关系。该人群中，每位患者平均体细胞突变负荷和错义突变负荷分别为405.84（标准差=608.55）和63.90（标准差=95.88）个突变。突变负荷与新抗原负荷呈正线性关系（R2=0.862）。平均预测新抗原负荷为23.52（标准差=52.14）个新抗原，其中平均表达新抗原为9.40（标准差=26.97）个。生存分析显示，体细胞错义突变负荷高于平均水平（163例患者，2年无进展生存率0.493 vs 0.726，P=0.0023）及预测表达新抗原负荷高于平均水平（214例患者，2年无进展生存率0.555 vs 0.729，P=0.0028）的患者无进展生存期显著缩短。按疾病分期和细胞遗传学异常进行分层分析后，这一规律仍然存在。因此，高突变负荷和高新抗原负荷是影响当前标准治疗方案下多发性骨髓瘤患者生存的临床相关风险因素。

原文链接：

High somatic mutation and neoantigen burden are correlated with decreased progression-free survival in multiple myeloma