Science (American Association for the Advancement of Science), 2018-02, Vol.359 (6377), p.801-806
- Miao, Diana
- Margolis, Claire A
- Gao, Wenhua
- Voss, Martin H
- Li, Wei
- Martini, Dylan J
- Norton, Craig
- Bossé, Dominick
- Wankowicz, Stephanie M
- Cullen, Dana
- Horak, Christine
- Wind-Rotolo, Megan
- Tracy, Adam
- Giannakis, Marios
- Hodi, Frank Stephen
- Drake, Charles G
- Ball, Mark W
- Allaf, Mohamad E
- Snyder, Alexandra
- Hellmann, Matthew D
- Ho, Thai
- Motzer, Robert J
- Signoretti, Sabina
- Kaelin, Jr, William G
- Choueiri, Toni K
- Van Allen, Eliezer M
2018
Details
- Autor(en) / Beteiligte
- Miao, Diana
- Margolis, Claire A
- Gao, Wenhua
- Voss, Martin H
- Li, Wei
- Martini, Dylan J
- Norton, Craig
- Bossé, Dominick
- Wankowicz, Stephanie M
- Cullen, Dana
- Horak, Christine
- Wind-Rotolo, Megan
- Tracy, Adam
- Giannakis, Marios
- Hodi, Frank Stephen
- Drake, Charles G
- Ball, Mark W
- Allaf, Mohamad E
- Snyder, Alexandra
- Hellmann, Matthew D
- Ho, Thai
- Motzer, Robert J
- Signoretti, Sabina
- Kaelin, Jr, William G
- Choueiri, Toni K
- Van Allen, Eliezer M
- Titel
- Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma
- Ist Teil von
- Science (American Association for the Advancement of Science), 2018-02, Vol.359 (6377), p.801-806
- Ort / Verlag
- United States: The American Association for the Advancement of Science
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- American Association for the Advancement of Science
- Beschreibungen/Notizen
- Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the gene ( = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies ( = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and -deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0036-8075eISSN: 1095-9203DOI: 10.1126/science.aan5951Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6035749
- Format
- –
- Schlagworte
- Apoptosis, B7-H1 Antigen - antagonists & inhibitors, Cancer, Carcinoma, Renal Cell - genetics, Carcinoma, Renal Cell - therapy, Cell death, Cell survival, Chromatin remodeling, Chromosomal Proteins, Non-Histone - genetics, Clear cell-type renal cell carcinoma, Cohort Studies, CTLA-4 Antigen - antagonists & inhibitors, CTLA-4 protein, Cytokines, Cytotoxicity, Drugs, Exome - genetics, Gene expression, Gene Expression Profiling, Genomics, Humans, Hypoxia, Immune checkpoint inhibitors, Immunity, Immunosuppressive agents, Immunotherapy - methods, Inhibitors, Interferon, Janus kinase, Kidney cancer, Kidney Neoplasms - genetics, Kidney Neoplasms - therapy, Lymphocytes T, Metastases, Metastasis, Mutation, Narcotics, Patients, PD-1 protein, PD-L1 protein, Programmed Cell Death 1 Receptor - antagonists & inhibitors, Regression analysis, Signaling, Sucrose, Sugar, SWI/SNF complex, Therapy, Transcription factors, Transcription Factors - genetics, Transducers, Tumor cells, Tumors