Whole transcriptome RNA-seq of primary desmoid tumors

IntroductionDesmoid tumors are bland fibroblastic tumors with little histologic variation between different regions of the tumor. While desmoid tumors do not metastasize, they have a high rate of local recurrence after complete resection and no reliable predictors of clinical behavior exist. Previously published studies proposed two different transcriptomic prognostic signatures but they have not been implemented in the clinical practice. The presence of molecular intra- and inter-tumor heterogeneity has been well established in other, higher grade, sarcomas but little is known about molecular variability within histologically bland lesions. In this study, we sought to examine the extent of intra- and inter-tumoral clonal heterogeneity of desmoid tumors, which may contribute to their pathogenesis and possible relapse.MethodsWe performed a transcriptomic profiling of 31 specimens from 20 primary desmoid tumors, and an in-depth multi-omic analysis including DNA methylation, DNA copy number alterations, point mutations and gene expression on 24 specimens from different areas of primary and recurrent desmoid tumors from 3 patients (7-9 specimens per patient).ResultsThe variability of expression of the two previously published transcriptomic prognostic signatures was observed both in patients who did and did not progress. Gene expression signatures associated with favorable and unfavorable outcome were detected in different regions within the same tumor. Further multi-omic studies of three patients, showed a remarkable heterogeneity of DNA methylation, DNA copy number alterations, point mutations and gene expression between different regions of their primary and recurrent tumors. We discovered the evidence for subclonal alterations in different areas of individual tumors. Among the four types of data, the transcriptomic profiles showed the highest degree of variability within tumors and between primary and recurrent tumors from the same patient.ConclusionsThis study shows an unexpected degree of intra- and inter-tumor heterogeneity in desmoid tumors. Our analysis indicates that even in this histologically monotonous lesion, molecular analysis of a single tumor biopsy may underestimate the magnitude of molecular alterations. Our study also shows that recurrent desmoid tumors acquire multiple molecular alterations that are not present in the patient-matched primary tumor. We demonstrate that molecular intra- and inter-tumor heterogeneity is an important consideration in drug development and validation of prognostic and predictive biomarkers for these tumors.