Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in primary mediastinal and diffuse large B-cell lymphomas (DLBCL). Currently, the prognostic relevance of these mutations in DLBCL is unknown. To evaluate the value of the SOCS1 mutation status as a prognostic biomarker in DLBCL patients, we performed full-length SOCS1 sequencing in tumors of 154 comprehensively characterized DLBCL patients. We identified 90 SOCS1 mutations in 16% of lymphomas. With respect to molecular consequences of mutations, we defined two distinct subtypes: those with truncating (major) and those with non-truncating mutations (minor), respectively. The SOCS1 mutated subgroup or the minor/major subtypes cannot be predicted on clinical grounds; however, assignment of four established gene-expression profile-based classifiers revealed significant associations of SOCS1 major cases with germinal center and specific pathway activation pattern signatures. Above all, SOCS1 major cases have an excellent overall survival, even better than the GCB-like subgroup. SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group. The SOCS1 mutation subsets retained prognostic significance in uni- and multivariate analyses. Together our data indicate that assessment of the SOCS1 mutation status is a single gene prognostic biomarker in DLBCL.

BackgroundThe incidence of melanoma, particularly in older patients, has steadily increased over the past few decades. Activating mutations of BRAF, the majority occurring in BRAFV600, are frequently detected in melanoma; however, the prognostic significance remains unclear. This study aimed to define the probability and distribution of BRAFV600 mutations, and the clinico-pathological factors that may affect BRAF mutation status, in patients with advanced melanoma using next-generation sequencing.Materials and methodsThis was a non-interventional, retrospective study of BRAF mutation testing at two German centers, in Heidelberg and Tübingen. Archival tumor samples from patients with histologically confirmed melanoma (stage IIIB, IIIC, IV) were analyzed using PCR amplification and deep sequencing. Clinical, histological, and mutation data were collected. The statistical influence of patient- and tumor-related characteristics on BRAFV600 mutation status was assessed using multiple logistic regression (MLR) and a prediction profiler.ResultsBRAFV600 mutation status was assessed in 453 samples. Mutations were detected in 57.6% of patients (n = 261), with 48.1% (n = 102) at the Heidelberg site and 66.0% (n = 159) at the Tübingen site. The decreasing influence of increasing age on mutation probability was quantified. A main effects MLR model identified age (p = 0.0001), center (p = 0.0004), and melanoma subtype (p = 0.014) as significantly influencing BRAFV600 mutation probability; ultraviolet (UV) exposure showed a statistical trend (p = 0.1419). An interaction model of age versus other variables showed that center (p<0.0001) and melanoma subtype (p = 0.0038) significantly influenced BRAF mutation probability; age had a statistically significant effect only as part of an interaction with both UV exposure (p = 0.0110) and melanoma subtype (p = 0.0134).ConclusionsThis exploratory study highlights that testing center, melanoma subtype, and age in combination with UV exposure and melanoma subtype significantly influence BRAFV600 mutation probability in patients with melanoma. Further validation of this model, in terms of reproducibility and broader relevance, is required.

No abstract

No abstract

No abstract

419 Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in Hodgkin, primary mediastinal and diffuse large B-cell lymphomas (DLBCL). In the primary mediastinal B-cell lymphoma line MedB-1, mutated SOCS1 abnormally stabilizes phospho-JAK2, thereby enhances STAT signaling leading to continuous proliferation. Here, we evaluated the prognostic value of SOCS1 mutations by full-length gene sequencing of SOCS1 in 154 comprehensively characterized DLBCL cases. By sequence analysis, we identified 90 SOCS1 mutations in 16% of lymphomas. We defined two distinct subtypes with respect to putative mutational consequences: those predicting the full-length (minor) and a truncated protein (major), respectively. Neither the SOCS1 mutation group, nor minor/major subgroups can be distinguished by clinical phenotype; however, assignment of four established expression-based classifiers revealed significant associations of SOCS1 major cases with germinal center- and specific pathway activation pattern signatures. Above all, SOCS1 major cases had an excellent overall survival, even better than the GCB-like subgroup (see Figure). SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group (see Figure). SOCS1 mutation subsets retain prognostic significance in uni- and multivariate analyses. Thus, if a SOCS1 mutation is present, the mutation type is an important single gene prognostic biomarker in DLBCL. Disclosures: No relevant conflicts of interest to declare.