Purpose: Desmoid tumors are bland fibroblastic tumors that do not metastasize but have a high rate of local recurrence. Previously published studies proposed two different transcriptomic signatures to predict relapse. Molecular heterogeneity has been well established in high-grade sarcomas but little is known about molecular variability within locally aggressive tumors such as desmoids. Experimental Design: We performed transcriptomic profiling of 31 specimens from 20 primary desmoid tumors to identify genes predictive of relapse. We also performed multi-omic analysis including DNA methylation, copy number alterations, point mutations and gene expression on 24 specimens from different regions of primary and recurrent desmoid tumors from 3 patients (7-9 specimens per patient). Results: We observed highly variable expression of transcriptomic prognostic signatures, both in patients who did or did not progress. Signatures associated with favorable and unfavorable outcome were detected in different regions within the same tumor. Further multi-omic studies showed remarkable intra- and inter-tumor heterogeneity of genomic, epigenomic and transcriptomic patterns. The transcriptomic profiles showed the highest degree of variability within tumors and between primary and recurrent tumors from the same patient. Conclusions: This study shows an unexpected degree of intra- and inter-tumor heterogeneity in desmoid tumors. Our analysis indicates that molecular analysis of a single tumor biopsy may underestimate the magnitude of molecular alterations in desmoid tumors. Our study also shows that recurrent desmoid tumors acquire multiple new molecular alterations. Thus, molecular heterogeneity is an important consideration in drug development and validation of prognostic and predictive biomarkers for desmoid tumors.

中文翻译：

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硬纤维瘤的基因组、表观基因组和转录组肿瘤间和肿瘤内异质性


目的：硬纤维瘤是平淡的成纤维细胞瘤，不会转移但局部复发率高。先前发表的研究提出了两种不同的转录组特征来预测复发。分子异质性在高级别肉瘤中已得到充分证实，但对局部侵袭性肿瘤（如硬纤维瘤）内的分子变异性知之甚少。实验设计： 我们对来自 20 例原发性硬纤维瘤的 31 份标本进行了转录组学分析，以确定预测复发的基因。我们还对 3 例患者 （每例 7-9 例） 来自原发性和复发性硬纤维瘤不同区域的 24 个标本进行了多组学分析，包括 DNA 甲基化、拷贝数改变、点突变和基因表达。结果： 我们观察到转录组学预后特征的表达高度可变，无论是在有进展还是没有进展的患者中。在同一肿瘤的不同区域检测到与有利和不良结果相关的特征。进一步的多组学研究表明，基因组、表观基因组和转录组模式的肿瘤内和肿瘤间异质性显著。转录组学谱显示，同一患者的肿瘤内以及原发性肿瘤和复发性肿瘤之间的变异程度最高。结论： 本研究显示了硬纤维瘤中意想不到的肿瘤内和肿瘤间异质性程度。我们的分析表明，单次肿瘤活检的分子分析可能低估了硬纤维瘤分子改变的幅度。我们的研究还表明，复发性硬纤维瘤获得多种新的分子改变。 因此，分子异质性是硬纤维瘤药物开发和验证预后和预测生物标志物的重要考虑因素。