Genomic, Epigenomic, and Transcriptomic Inter- and Intratumor Heterogeneity in Desmoid Tumors

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.

We performed transcriptomic profiling of 31 specimens from 20 primary desmoid tumors to identify genes predictive of relapse. We also performed multiomic 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 three patients (7-9 specimens per patient).

We observed highly variable expression of transcriptomic prognostic signatures both in patients who did and did not progress. Signatures associated with favorable and unfavorable outcomes were detected in different regions within the same tumor. Further multiomic studies showed remarkable intra- and intertumor 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.

This study shows an unexpected degree of intra- and intertumor 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.