Gastrointestinal stromal tumors are sarcomas of the digestive tract characterized by mutations mainly located in the c-KIT or in the platelet-derived growth factor receptor (PDGFR)-alpha genes. Mutations in the BRAF gene have also been described. Our purpose is to define the distribution of c-KIT, PDGFR and BRAF mutations in a population-based cohort of gastrointestinal stromal tumors (GIST) patients and correlate them with anatomical site, risk classification and survival. In addition, as most of the GIST patients have a long survival, second cancers are frequently diagnosed in them. We performed a second primary cancer risk assessment. Our analysis was based on data from Tarragona and Girona Cancer Registries. We identified all GIST diagnosed from 1996 to 2006 and performed a mutational analysis of those in which paraffin-embedded tissue was obtained. Observed (OS) and relative survival (RS) were calculated according to risk classifications and mutational status. Multivariate analysis of variables for observed survival and was also done. A total of 132 GIST cases were found and we analyzed mutations in 108 cases. We obtained 53.7% of mutations in exon 11 and 7.4% in exon 9 of c-KIT gene; 12% in exon 18 and 1.9% in exon 12 of PDGFR gene and 25% of cases were wild type GIST. Patients with mutations in exon 11 of the c-KIT gene had a 5-year OS and RS of 59.6% and 66.3%, respectively. Patients with mutations in exon 18 of the PDGFR gene had a 5-year OS and RS of 84.6% and 89.7%. In multivariate analysis, only age and risk group achieved statistical significance for observed survival. GIST patients had an increased risk of second cancer with a hazard ratio of 2.47. This population-based study shows a spectrum of mutations in the c-KIT and PDGFR genes in GIST patients similar to that previously published. The OS and RS of GIST with the exon 18 PDGFR gene mutation could indicate that this subgroup of patients may be less aggressive and have a good prognosis, although less sensitive to treatment at recurrence. In our study, GIST patients have an increased risk of developing a second neoplasm.

Molecular factors influencing prognosis in leiomyosarcomas (LMS) remain poorly understood. Given that LMS arise from smooth muscle and that the dystrophin gene (DMD) has been suggested as a tumor suppressor in this tumor type, this study investigated dystrophin expression and somatic mutations in DMD, and dystrophin–glycoprotein complex (DGC) and dysferlin (DYSF) coding genes as prognostic biomarkers in LMS. Seventy-seven patients with LMS were retrospectively included in the study. Dystrophin expression was evaluated by immunohistochemistry. The presence of DMD point mutations were determined using next-generation sequencing (NGS), and DMD copy-number variants were assessed by multiplex ligation-dependent probe amplification (MLPA) technique. Low dystrophin expression was observed in 66% of tumors and showed a nominal association with tumor grade, with 76% of grade 3, 58% of grade 2, and 33% of grade 1 tumors showing low dystrophin expression (p = 0.046). Dystrophin expression was not associated with overall survival (OS), nor with recurrence-free survival (RFS) in localized cases or progression-free survival (PFS) in metastatic cases. However, dystrophin expression was significantly associated with shorter OS (p = 0.006) and RFS (p = 0.003) in patients with localized grade 2 tumors. Mutations in DMD, DGC-coding genes and DYSF were identified in 59% of tumors, but no significant associations were found with pathological, molecular, or survival data. Loss of dystrophin expression was common in LMS tumors and was associated with high-grade tumors in our cohort. Nonetheless, the role of dystrophin as a prognostic biomarker of survival was only observed in patients with localized grade 2 tumors in this exploratory, hypothesis-generating study, and therefore needs further validation.