K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Norway; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Acta Oncol. 2024 Jul 22;63:586-591. doi: 10.2340/1651-226X.2024.40730.
While soft tissue sarcomas affect younger patients, few studies have assessed the distribution of underlying pathogenic germline variants.
We retrospectively identified all pediatric and young adult patients (0-22 years) at Haukeland University Hospital, Norway (1981-2019), through clinical and pathological records. We identified n = 46 eligible patients. From these 46 patients, adequate material representing normal tissue was available for n = 41 cases (n = 24 diagnosed with rhabdomyosarcoma, 9 with synovial sarcomas, 2 with Ewing sarcomas, and 6 without further classification), with matching tumor tissue for n = 40. Normal tissue samples were analyzed for germline pathogenic variants (PVs) by targeted sequencing of 360 cancer genes.
Out of the 41 analyzed cases, we found PVs or likely PVs in 7 (17%). These variants were found in TP53, MUTYH, FANCC, DICER1, FANCA, MYO3A, and MYO5B. Supporting the causality of these PVs, four cases revealed loss of heterozygosity (LOH) of the wild-type allele in the tumor tissue, one patient with a PV in DICER1 had a second somatic variant in DICER1, and a patient with a PV in TP53 had the altered allele amplified in the tumor. For three out of five with available family history, a history of other cancers in relatives was recorded. Among genes with variants of uncertain significance, CHD1L was of particular interest, revealing a stop-gain and a missense variant.
A high fraction of young patients with soft tissue sarcoma harbor PVs. Among the genes affected, we substantiate a potential role of MYO5B and propose a potential role for MYO3A.
虽然软组织肉瘤影响年轻患者，但很少有研究评估潜在致病种系变异的分布。
我们通过临床和病理记录，回顾性地确定了挪威哈肯大学医院（1981-2019 年）所有儿科和青年患者（0-22 岁）。我们确定了 46 名符合条件的患者。在这 46 名患者中，有 41 例（24 例诊断为横纹肌肉瘤，9 例滑膜肉瘤，2 例尤因肉瘤，6 例无进一步分类）有足够的正常组织材料，40 例有匹配的肿瘤组织。通过对 360 个癌症基因进行靶向测序，分析正常组织样本中的种系致病性变异（PVs）。
在所分析的 41 例病例中，我们发现了 7 例（17%）PV 或可能的 PV。这些变体存在于 TP53、MUTYH、FANCC、DICER1、FANCA、MYO3A 和 MYO5B 中。这些 PV 的存在支持了其因果关系，在肿瘤组织中，有 4 例发现了野生型等位基因的杂合性丢失（LOH），1 例 DICER1 中的 PV 患者有第二个体细胞变异，1 例 TP53 中的 PV 患者的肿瘤中扩增了改变的等位基因。在有可用家族史的 5 例患者中，有 3 例记录了亲属中有其他癌症的病史。在有意义不确定的变异基因中，CHD1L 特别引人注目，显示出一个终止密码子和一个错义变异。
很大一部分患有软组织肉瘤的年轻患者携带有 PVs。在受影响的基因中，我们证实了 MYO5B 的潜在作用，并提出了 MYO3A 的潜在作用。
