Lindqvist Carl Mårten, Nordlund Jessica, Ekman Diana, Johansson Anna, Moghadam Behrooz Torabi, Raine Amanda, Övernäs Elin, Dahlberg Johan, Wahlberg Per, Henriksson Niklas, Abrahamsson Jonas, Frost Britt-Marie, Grandér Dan, Heyman Mats, Larsson Rolf, Palle Josefine, Söderhäll Stefan, Forestier Erik, Lönnerholm Gudmar, Syvänen Ann-Christine, Berglund Eva C
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Hum Mutat. 2015 Jan;36(1):118-28. doi: 10.1002/humu.22719.
Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.
儿童急性淋巴细胞白血病（ALL）的基因组特征已确定在具有明确遗传畸变的患者中基因和信号通路的不同改变模式。为了扩展ALL中已知体细胞变异的范围，我们对三名B细胞前体患者进行了全基因组和转录组测序，其中一名携带t(12;21)ETV6-RUNX1易位，两名没有已知的原发性遗传畸变，以及一名T-ALL患者。我们发现每个患者都有独特的基因组，包含已知和先前未检测到的基因组畸变。通过对168名患者进行靶向测序，我们确定KMT2D和KIF1B为新的推定驱动基因。我们还鉴定出一个推定的调控非编码变异，它与生长因子MDK的过表达一致。我们的结果有助于加深对导致ALL的生物学机制的理解，并表明调控变异可能对癌症发展比迄今所认识到的更为重要。ALL中遗传畸变的异质性使得全基因组测序特别适合在研究和诊断应用中分析体细胞变异。
