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An abstract of the article "Evaluation of risk factors for mortality and longterm survival after repair of acute type-A aortic dissection in 836 patients" by B. Tutkun and colleagues is presented.

Background: Clear cell renal cell carcinoma (ccRCC) is the dominant subtype of renal cancer. With currently available therapies, cure of advanced and metastatic ccRCC is achieved only in rare cases. Here, we developed a workflow integrating different -omics technologies to identify ccRCC-specific HLA-presented peptides as potential drug targets for ccRCC immunotherapy., Methods: We analyzed HLA-presented peptides by MS-based ligandomics of 55 ccRCC tumors (cohort 1), paired non-tumor renal tissues, and 158 benign tissues from other organs. Pathways enriched in ccRCC compared to its cell type of origin were identified by transcriptome and gene set enrichment analyses in 51 tumor tissues of the same cohort. To retrieve a list of candidate targets with involvement in ccRCC pathogenesis, ccRCC-specific pathway genes were intersected with the source genes of tumor-exclusive peptides. The candidates were validated in an independent cohort from The Cancer Genome Atlas (TCGA KIRC, n = 452). DNA methylation (TCGA KIRC, n = 273), somatic mutations (TCGA KIRC, n = 392), and gene ontology (GO) and correlations with tumor metabolites (cohort 1, n = 30) and immune-oncological markers (cohort 1, n = 37) were analyzed to characterize regulatory and functional involvements. CD8 + T cell priming assays were used to identify immunogenic peptides. The candidate gene EGLN3 was functionally investigated in cell culture., Results: A total of 34,226 HLA class I- and 19,325 class II-presented peptides were identified in ccRCC tissue, of which 443 class I and 203 class II peptides were ccRCC-specific and presented in ≥ 3 tumors. One hundred eighty-five of the 499 corresponding source genes were involved in pathways activated by ccRCC tumors. After validation in the independent cohort from TCGA, 113 final candidate genes remained. Candidates were involved in extracellular matrix organization, hypoxic signaling, immune processes, and others. Nine of the 12 peptides assessed by immunogenicity analysis were able to activate naïve CD8 + T cells, including peptides derived from EGLN3. Functional analysis of EGLN3 revealed possible tumor-promoting functions., Conclusions: Integration of HLA ligandomics, transcriptomics, genetic, and epigenetic data leads to the identification of novel functionally relevant therapeutic targets for ccRCC immunotherapy. Validation of the identified targets is recommended to expand the treatment landscape of ccRCC.

Background: Stratification of cancer patients to identify those with worse prognosis is increasingly important. Through in silico analyses, we recently developed a gene expression-based prognostic score (S3-score) for clear cell renal cell carcinoma (ccRCC), using the cell type-specific expression of 97 genes within the human nephron. Herein, we verified the score using whole-transcriptome data of independent cohorts and extend its application for patients with metastatic disease receiving tyrosine kinase inhibitor treatment. Finally, we sought to improve the signature for clinical application using qRT-PCR., Methods: A 97 gene-based S3-score (S3 97 ) was evaluated in a set of 52 primary non-metastatic and metastatic ccRCC patients as well as in 53 primary metastatic tumors of sunitinib-treated patients. Gene expression data of The Cancer Genome Atlas (n = 463) was used for platform transfer and development of a simplified qRT-PCR-based 15-gene S3-score (S3 15 ). This S3 15 -score was validated in 108 metastatic and non-metastatic ccRCC patients and ccRCC-derived metastases including in part several regions from one metastasis. Univariate and multivariate Cox regression stratified by T, N, M, and G were performed with cancer-specific and progression-free survival as primary endpoints., Results: The S3 97 -score was significantly associated with cancer-specific survival (CSS) in 52 ccRCC patients (HR 2.9, 95% Cl 1.0-8.0, P Log-rank  = 3.3 × 10 -2 ) as well as progression-free survival in sunitinib-treated patients (2.1, 1.1-4.2, P Log-rank  = 2.2 × 10 -2 ). The qRT-PCR based S3 15 -score performed similarly to the S3 97 -score, and was significantly associated with CSS in our extended cohort of 108 patients (5.0, 2.1-11.7, P Log-rank  = 5.1 × 10 -5 ) including metastatic (9.3, 1.8-50.0, P Log-rank  = 2.3 × 10 -3 ) and non-metastatic patients (4.4, 1.2-16.3, P Log-rank  = 1.6 × 10 -2 ), even in multivariate Cox regression, including clinicopathological parameters (7.3, 2.5-21.5, P Wald  = 3.3 × 10 -4 ). Matched primary tumors and metastases revealed similar S3 15 -scores, thus allowing prediction of outcome from metastatic tissue. The molecular-based qRT-PCR S3 15 -score significantly improved prediction of CSS by the established clinicopathological-based SSIGN score (P = 1.6 × 10 -3 )., Conclusion: The S3-score offers a new clinical avenue for ccRCC risk stratification in the non-metastatic, metastatic, and sunitinib-treated setting.