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The Hippo pathway is an evolutionarily conserved modulator of developmental biology with a key role in tissue and organ size regulation under homeostatic conditions. Like other signaling pathways with a significant role in embryonic development, the deregulation of Hippo signaling contributes to oncogenesis. Central to the Hippo pathway is a conserved cascade of adaptor proteins and inhibitory kinases that converge and regulate the activity of the oncoproteins YAP and TAZ, the final transducers of the pathway. Elevated levels and aberrant activation of YAP and TAZ have been described in many cancers. Though most of the studies describe their pervasive activation in epithelial neoplasms, there is increasing evidence pointing out its relevance in mesenchymal malignancies as well. Interestingly, somatic or germline mutations in genes of the Hippo pathway are scarce compared to other signaling pathways that are frequently disrupted in cancer. However, in the case of sarcomas, several examples of genetic alteration of Hippo members, including gene fusions, have been described during the last few years. Here, we review the current knowledge of Hippo pathway implication in sarcoma, describing mechanistic hints recently reported in specific histological entities and how these alterations represent an opportunity for targeted therapy in this heterogeneous group of neoplasm., E.d.Á.’s laboratory is supported by ISCIIIFEDER (PI20/00003) to E.d.Á., Consejería de Salud y Familias, Junta de Andalucía (PE-0186-2018) to E.d.Á. and (PI-0061-2020) to C.S.-A. and E.d.Á., GEIS (Beca José María Buesa) to A.T.A., GEIS-Fundación Mari Paz Jiménez Casado (Beca Trienal a la Investigación en Sarcomas) to J.D.-M., Fundación CRIS Contra el Cáncer, Asociación Pablo Ugarte, Fundación María García Estrada and CIBERONC. C.S.-A. is supported by the European Social Fund and the Junta de Andalucía (Talento Doctores 2020, DOC_01473), J.O.-P. is granted by a pre-doctoral fellowship from the VI Plan Propio from the Universidad de Sevilla; A.T.A. is supported Juan de la Cierva Incorporación fellowship (IJC-2018-036767-I), and J.D.-M. is supported by CIBERONC (CB16/12/00361).

This article belongs to the Special Issue Diagnosis and Treatment for Bone Tumor and Sarcoma., [Simple Summary] A solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that can arise at any body location. Local or distant recurrences occur in a significant proportion of cases, but these recurrences are difficult to predict using clinical or pathological features. A specific genetic alteration, the gene fusion NAB2-STAT6, is considered to be the defining driver mutation, and different fusion variants seem to account for specific clinical and pathological features, but their prognostic value remains controversial. We inspected a series of 83 SFTs with a high rate of recurrence to evaluate the clinical significance of several potential biomarkers in addition to gene fusion. Our findings confirm previous observations and uncover novel associations of molecular alterations with clinical features, adding additional evidence for their potential application as molecular biomarkers that are helpful to predict the course of the disease., [Abstract] Risk stratification of solitary fibrous tumor (SFT) patients based on clinicopathological features has limited efficacy, especially in predicting late relapse or metastasis. The hallmark alteration of SFT is the gene fusion NAB2-STAT6, whose prognostic value remains controversial. As biological knowledge of this entity has increased in recent years, new molecular alterations have emerged that could be helpful to refine current risk models. Here, we evaluated NAB2-STAT6 fusion variants and other molecular alterations in a series of 83 SFTs that are enriched in progressing cases. Gene fusion variants were identified by targeted RNA-seq in the whole series, whereas TERT promoter (pTERT) mutations were inspected by Sanger sequencing in a subset of 18 cases. Immunohistochemical assays were performed to assess BCOR and NTRK expression as well as P53 mutation status in 45, 44, and 44 cases, respectively. While confirming the associations of gene fusion variants with clinicopathological parameters, our results do not prove their prognostic value. Pan-TRK immunoexpresion correlated with recurrence/progression, P53 staining associated with higher mitotic counts, and pTERT mutations were enriched in cases with fatal outcome. An intriguing correlation was found for BCOR protein expression with gene fusion variants, size, and tumor location., This research was funded by the Junta de Andalucía (PI-0061-2020) to C.S.-A. and E.A. and the GEIS-Fundación Mari Paz Jiménez Casado (IV beca trienal) to J.D.-M., C.S.-A. was supported by the European Social Fund and the Junta de Andalucía (Talento Doctores 2020, DOC_01473), and J.D.-M. was supported by CIBERONC (CB16/12/00361). E.d.Á.’s laboratory is supported by the ISCIII-FEDER (PI20/00003), CIBERONC (CB16/12/00361), Asociación Pablo Ugarte, Fundación CRIS contra el cancer, Asociación Candela Riera, and Fundación María García Estrada.