In:
Molecular Oncology, Wiley, Vol. 11, No. 11 ( 2017-11), p. 1495-1507
Kurzfassung:
Desmoid‐type fibromatosis ( DF ) is a rare mesenchymal lesion with high risk of local recurrence. Specific β‐catenin mutations (S45F) appeared to be related to this higher risk compared to T41A‐mutated or wild‐type ( WT ). We explored the influence of both mutations and WT on structure stability and affinity of β‐catenin for α‐catenin and the pattern of gene expression that may influence DF behavior. Using 33 surgically resected primary DF s harboring T41A ( n = 14), S45F ( n = 10), or WT ( n = 9), we performed a comparative molecular analysis by protein/protein interaction modeling, gene expression by DASL microarrays, human inflammation gene panel, and assessment of immune system‐based biomarkers by immunohistochemistry. Mutated proteins were more stable than WT and formed a weaker complex with α‐catenin. Consensus unsupervised gene clustering revealed the presence of two DF group‐mutated (T41A + S45F) and WT ( P = 0.0047). The gene sets ‘Inflammatory‐Defense‐Humoral Immune Response’ and ‘ Antigen Binding’ were significantly enriched in T41A. The deregulation of 16 inflammation‐related genes was confirmed. Low numbers of T cells and tumor‐associated macrophages ( TAM ) infiltrating the tumors and low/absent PD ‐1/ PD ‐L1 expression were also identified. We demonstrated that mutated DF s (T41A or S45F) and WT are two distinct molecular subgroups with regard to β‐catenin stability, α‐catenin affinity, and gene expression profiling. A different inflammation signature characterized the two mutated groups, suggesting mediation either by T41A or by S45F. Finally, all mutated cases showed a low number of TIL and TAM cells and a low or absent expression of PD ‐1 and PD ‐L1 consistent with β‐catenin activation insensitive to checkpoint blockade.
Materialart:
Online-Ressource
ISSN:
1574-7891
,
1878-0261
DOI:
10.1002/mol2.2017.11.issue-11
DOI:
10.1002/1878-0261.12101
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2017
ZDB Id:
2322586-5