背景:虽然软组织肉瘤影响年轻患者,很少有研究评估潜在致病种系变异的分布。
方法:我们回顾性地确定了豪克兰大学医院的所有儿童和年轻成人患者(0-22岁),挪威(1981-2019),通过临床和病理记录。我们确定了n=46名合格患者。从这46名患者中,n=41例(n=24诊断为横纹肌肉瘤,9伴有滑膜肉瘤,2与尤因肉瘤,和6没有进一步分类),与匹配的肿瘤组织为n=40。通过360个癌症基因的靶向测序分析正常组织样品的种系致病变体(PV)。
结果:在41个分析病例中,我们在7例(17%)中发现了PVs或可能的PVs。这些变体在TP53,MUTYH,FANCC,DICER1,FANCA,MYO3A,MYO5B支持这些PV的因果关系,4例显示肿瘤组织中野生型等位基因杂合性(LOH)缺失,一名DICER1中的PV患者在DICER1中具有第二个体细胞变异体,一名在TP53中具有PV的患者在肿瘤中扩增了改变的等位基因.有家族病史的五分之三,记录了亲属中其他癌症的病史。在具有不确定意义的变异的基因中,CHD1L特别感兴趣,揭示了一个止损和一个错觉变体。
结论:年轻的软组织肉瘤患者中有很高比例的肺静脉。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。
BACKGROUND: While soft tissue sarcomas affect younger patients, few studies have assessed the distribution of underlying pathogenic germline variants.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.