Anoshkin Kirill, Zosen Denis, Karandasheva Kristina, Untesco Maxim, Volodin Ilya, Alekseeva Ekaterina, Parfenenkova Anna, Snegova Eugenia, Kim Aleksandr, Dorofeeva Marina, Kutsev Sergei, Strelnikov Vladimir
Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia.
Faculty of Mathematics and Natural Sciences, University of Oslo, PO Box 1068, Blindern, 0316 Oslo, Norway.
Heliyon. 2022 Aug 19;8(8):e10291. doi: 10.1016/j.heliyon.2022.e10291. eCollection 2022 Aug.
Chordoma associated with tuberous sclerosis complex (TSC) is an extremely rare tumor that was described only in 13 cases since 1975. Сhordoma itself is a malignant slow-growing bone tumor thought to arise from vestigial or ectopic notochordal tissue. Chordoma associated with TSC differs from chordoma in the general pediatric population in the median age, where the diagnosis of TSC-associated chordoma is 6.2 months, whereas for chordoma in the general pediatric population it is set to 12 years. The majority of TSC-associated chordomas are localized in skull-based and sacrum regions, and rare in the spine. Chordomas are genetically heterogeneous tumors characterized by chromosomal instability (CIN), and alterations involving PI3K-AKT signaling pathway genes and chromatin remodeling genes. Here we present the 14th case of chordoma associated with TSC in a 1-year-old pediatric patient. Alongside biallelic inactivation of the gene, molecular genetic analysis revealed CIN and involvement of epigenetic regulation genes. In addition, we found the engagement of and apolipoprotein B editing complex (APOBEC3) genes that were not yet seen in chordomas before. Amplification of may epigenetically silence the gene, whereas amplification of genes can explain the frequent occurrence of CIN in chordomas. We also found that gene is located in the region with gain status, which may suggest the ineffectiveness of potential EGFR monotherapy. Thus, molecular genetic analysis carried out in this study broadens the horizons of possible approaches for targeted therapies with potential applications for personalized medicine.
与结节性硬化症（TSC）相关的脊索瘤是一种极其罕见的肿瘤，自1975年以来仅在13例病例中被描述。脊索瘤本身是一种恶性生长缓慢的骨肿瘤，被认为起源于残留或异位的脊索组织。与TSC相关的脊索瘤在中位年龄上与一般儿科人群中的脊索瘤不同，TSC相关脊索瘤的诊断年龄为6.2个月，而一般儿科人群中脊索瘤的诊断年龄为12岁。大多数与TSC相关的脊索瘤位于颅底和骶骨区域，在脊柱中罕见。脊索瘤是具有遗传异质性的肿瘤，其特征是染色体不稳定（CIN），以及涉及PI3K-AKT信号通路基因和染色质重塑基因的改变。在此，我们报告一名1岁儿科患者中与TSC相关的脊索瘤的第14例病例。除了该基因的双等位基因失活外，分子遗传学分析还揭示了CIN和表观遗传调控基因的参与。此外，我们发现了之前在脊索瘤中未见的基因和载脂蛋白B编辑复合体（APOBEC3）基因的参与。基因的扩增可能在表观遗传上使该基因沉默，而基因的扩增可以解释脊索瘤中CIN的频繁发生。我们还发现基因位于具有增益状态的区域，这可能提示潜在的表皮生长因子受体（EGFR）单药治疗无效。因此，本研究中进行的分子遗传学分析拓宽了靶向治疗可能方法的视野，具有个性化医疗的潜在应用价值。
