Bogen Dominik, Brunner Clemens, Walder Diana, Ziegler Andrea, Abbasi Reza, Ladenstein Ruth L, Noguera Rosa, Martinsson Tommy, Amann Gabriele, Schilling Freimut H, Ussowicz Marek, Benesch Martin, Ambros Peter F, Ambros Inge M
Department of Tumor Biology, CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
S2IRP, CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
Int J Cancer. 2016 Jul 1;139(1):153-63. doi: 10.1002/ijc.30050. Epub 2016 Mar 22.
Amplification of MYCN is the signature genetic aberration of 20-25% of neuroblastoma and a stratifying marker associated with aggressive tumor behavior. The detection of heterogeneous MYCN amplification (hetMNA) poses a diagnostic dilemma due to the uncertainty of its relevance to tumor behavior. Here, we aimed to shed light on the genomic background which permits hetMNA in neuroblastoma and tied the occurrence to other stratifying markers and disease outcome. We performed SNP analysis using Affymetrix Cytoscan HD arrays on 63 samples including constitutional DNA, tumor, bone marrow and relapse samples of 26 patients with confirmed hetMNA by MYCN-FISH. Tumors of patients ≤18m were mostly aneuploid with numeric chromosomal aberrations (NCAs), presented a prominent MNA subclone and carried none or a few segmental chromosomal aberrations (SCAs). In older patients, tumors were mostly di- or tetraploid, contained a lower number of MNA cells and displayed a multitude of SCAs including concomitant 11q deletions. These patients often suffered disease progression, tumor dissemination and relapse. Restricted to aneuploid tumors, we detected chromosomes with uniparental di- or trisomy (UPD/UPT) in almost every sample. UPD11 was exclusive to tumors of younger patients whereas older patients featured UPD14. In this study, the MNA subclone appears to be constraint by the tumor environment and thus less relevant for tumor behavior in aggressive tumors with a high genomic instability and many segmental aberrations. A more benign tumor background and lower tumor stage may favor an outgrowth of the MNA clone but tumors generally responded better to treatment.
MYCN基因扩增是20%-25%神经母细胞瘤的标志性基因畸变，也是与侵袭性肿瘤行为相关的分层标志物。异质性MYCN基因扩增（hetMNA）的检测因其与肿瘤行为相关性的不确定性而带来诊断难题。在此，我们旨在阐明允许神经母细胞瘤中出现hetMNA的基因组背景，并将其发生与其他分层标志物及疾病转归联系起来。我们使用Affymetrix Cytoscan HD芯片对63个样本进行了单核苷酸多态性（SNP）分析，这些样本包括26例经MYCN荧光原位杂交（FISH）确诊为hetMNA患者的外周血DNA、肿瘤组织、骨髓及复发样本。≤18个月患者的肿瘤大多为非整倍体，伴有染色体数目畸变（NCA），呈现出显著的MNA亚克隆，且无或仅有少数节段性染色体畸变（SCA）。在年龄较大的患者中，肿瘤大多为二倍体或四倍体，MNA细胞数量较少，并显示出多种SCA，包括同时存在的11q缺失。这些患者常出现疾病进展、肿瘤播散及复发。限于非整倍体肿瘤，我们在几乎每个样本中都检测到了单亲二体或三体（UPD/UPT）染色体。UPD11仅见于较年轻患者的肿瘤，而年龄较大患者的肿瘤以UPD14为特征。在本研究中，MNA亚克隆似乎受肿瘤环境的限制，因此在基因组不稳定高且有许多节段性畸变的侵袭性肿瘤中与肿瘤行为的相关性较小。更良性的肿瘤背景和较低的肿瘤分期可能有利于MNA克隆的生长，但肿瘤总体上对治疗反应较好。
