Hofmann Jonathan N, Landgren Ola, Landy Rebecca, Kemp Troy J, Santo Loredana, McShane Charlene M, Shearer Joseph J, Lan Qing, Rothman Nathaniel, Pinto Ligia A, Pfeiffer Ruth M, Hildesheim Allan, Katki Hormuzd A, Purdue Mark P
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
JNCI Cancer Spectr. 2019 Dec 16;4(2):pkz104. doi: 10.1093/jncics/pkz104. eCollection 2020 Apr.
Experimental and clinical studies have implicated certain chemokines and angiogenic cytokines in multiple myeloma (MM) pathogenesis. To investigate whether systemic concentrations of these markers are associated with future MM risk and progression from its precursor, monoclonal gammopathy of undetermined significance (MGUS), we conducted a prospective study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.
We measured concentrations of 45 immunologic and pro-angiogenic markers in sera from 241 MM case patients, 441 participants with nonprogressing MGUS, and 258 MGUS-free control participants using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. We also evaluated absolute risk of progression using weighted Kaplan-Meier estimates. All statistical tests were two-sided.
Prediagnostic levels of six markers were statistically significantly elevated among MM case patients compared with MGUS-free control participants using a false discovery rate of 10% (EGF, HGF, Ang-2, CXCL12, CCL8, and BMP-9). Of these, three angiogenesis markers were associated with future progression from MGUS to MM: EGF (fourth vs first quartile: OR = 3.01, 95% CI = 1.61 to 5.63, = .00028), HGF (OR = 2.59, 95% CI = 1.33 to 5.03, = .015), and Ang-2 (OR = 2.14, 95% CI = 1.15 to 3.98, = .07). A composite angiogenesis biomarker score substantially stratified risk of MGUS progression to MM beyond established risk factors for progression, particularly during the first 5 years of follow-up (areas under the curve of 0.71 and 0.64 with and without the angiogenesis marker score, respectively).
Our prospective findings provide new insights into mechanisms involved in MM development and suggest that systemic angiogenesis markers could potentially improve risk stratification models for MGUS patients.
实验和临床研究表明，某些趋化因子和血管生成细胞因子与多发性骨髓瘤（MM）的发病机制有关。为了研究这些标志物的全身浓度是否与未来MM风险以及从不明意义的单克隆丙种球蛋白病（MGUS）这一前驱病变发展为MM相关，我们在前列腺、肺、结直肠癌和卵巢癌筛查试验中开展了一项前瞻性研究。
我们使用基于Luminex的多重检测和酶联免疫吸附测定法，测量了241例MM病例患者、441例病情无进展的MGUS患者以及258例无MGUS的对照参与者血清中45种免疫和促血管生成标志物的浓度。使用多变量逻辑回归估计比值比（OR）和95%置信区间（CI）。我们还使用加权Kaplan-Meier估计值评估进展的绝对风险。所有统计检验均为双侧检验。
与无MGUS的对照参与者相比，MM病例患者中六种标志物的诊断前水平在错误发现率为10%时具有统计学显著升高（表皮生长因子[EGF]、肝细胞生长因子[HGF]、血管生成素-2[Ang-2]、CXC趋化因子配体12[CXCL12]、C-C趋化因子配体8[CCL8]和骨形态发生蛋白-9[BMP-9]）。其中，三种血管生成标志物与MGUS未来进展为MM相关：EGF（第四四分位数与第一四分位数相比：OR = 3.01，95%CI = 1.61至5.63，P = 0.00028）、HGF（OR = 2.59，95%CI = 1.33至5.03，P = 0.015）和Ang-2（OR = 2.14，95%CI = 1.15至3.98，P = .07）。一个复合血管生成生物标志物评分在既定的进展风险因素之外，显著分层了MGUS进展为MM的风险，特别是在随访的前5年（有和没有血管生成标志物评分时曲线下面积分别为0.71和0.64）。
我们的前瞻性研究结果为MM发生机制提供了新见解，并表明全身血管生成标志物可能会改善MGUS患者的风险分层模型。
