TY - JOUR
T1 - β-Catenin in desmoid-type fibromatosis
T2 - deep insights into the role of T41A and S45F mutations on protein structure and gene expression
AU - Colombo, Chiara
AU - Belfiore, Antonino
AU - Paielli, Nicholas
AU - De Cecco, Loris
AU - Canevari, Silvana
AU - Laurini, Erik
AU - Fermeglia, Maurizio
AU - Pricl, Sabrina
AU - Verderio, Paolo
AU - Bottelli, Stefano
AU - Fiore, Marco
AU - Stacchiotti, Silvia
AU - Palassini, Elena
AU - Gronchi, Alessandro
AU - Pilotti, Silvana
AU - Perrone, Federica
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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 DFs 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 DFs (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.
AB - 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 DFs 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 DFs (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.
KW - desmoid-type fibromatosis
KW - gene expression
KW - modeling
KW - β-catenin mutation
UR - http://www.scopus.com/inward/record.url?scp=85033229791&partnerID=8YFLogxK
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U2 - 10.1002/1878-0261.12101
DO - 10.1002/1878-0261.12101
M3 - Article
AN - SCOPUS:85033229791
VL - 11
SP - 1495
EP - 1507
JO - Molecular Oncology
JF - Molecular Oncology
SN - 1574-7891
IS - 11
ER -