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Ref Type Journal Article
PMID (29301960)
Authors Miao D, Margolis CA, Gao W, Voss MH, Li W, Martini DJ, Norton C, Bossé D, Wankowicz SM, Cullen D, Horak C, Wind-Rotolo M, Tracy A, Giannakis M, Hodi FS, Drake CG, Ball MW, Allaf ME, Snyder A, Hellmann MD, Ho T, Motzer RJ, Signoretti S, Kaelin WG, Choueiri TK, Van Allen EM
Title Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.
Journal Science (New York, N.Y.)
Vol 359
Issue 6377
Date 2018 Feb 16
URL
Abstract Text 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 PBRM1 gene (P = 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 (P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PBRM1 S681R missense unknown PBRM1 S681R lies within the Bromo domain 5 of the Pbrm1 protein (UniProt.org). S681R has been identified in the scientific literature (PMID: 29301960), but has not been biochemically characterized and therefore, its effect on Pbrm1 protein function is unknown (PubMed, Dec 2021).
PBRM1 W141_L145delinsC indel unknown PBRM1 W141_L145delinsC results in a deletion of five amino acids of the Pbrm1 protein from amino acids 141 to 145, combined with the insertion of a cysteine (C) at the same site (UniProt.org). W141_L145delinsC has been identified in the scientific literature (PMID: 29301960), but has not been biochemically characterized and therefore, its effect on Pbrm1 protein function is unknown (PubMed, Sep 2021).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PBRM1 inact mut clear cell renal cell carcinoma sensitive Nivolumab Clinical Study - Cohort Actionable In a clinical study, renal clear cell carcinoma patients harboring PBRM1 loss-of-function mutations demonstrated improved response to immune checkpoint therapies including Opdivo (nivolumab) alone or in combination with Yervoy (ipilimumab), and Tecentriq (atezolizumab), potentially due to the distinct expression profile of immune-related genes in these patients (PMID: 29301960). 29301960
PBRM1 K154fs clear cell renal cell carcinoma predicted - sensitive Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in partial response in a patient with renal clear cell carcinoma harboring PBRM1 K154fs (PMID: 29301960). 29301960
PBRM1 K619fs clear cell renal cell carcinoma predicted - sensitive Ipilimumab + Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) and Yervoy (ipilimumab) combination treatment resulted in partial response in a patient with renal clear cell carcinoma harboring PBRM1 K619fs (PMID: 29301960). 29301960
PBRM1 N463fs clear cell renal cell carcinoma predicted - sensitive Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in partial response in a patient with renal clear cell carcinoma harboring PBRM1 N463fs (PMID: 29301960). 29301960
PBRM1 G2fs clear cell renal cell carcinoma no benefit Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in progressive disease in a patient with renal clear cell carcinoma harboring PBRM1 G2fs (PMID: 29301960). 29301960
PBRM1 N609fs clear cell renal cell carcinoma no benefit Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in progressive disease in a patient with renal clear cell carcinoma harboring PBRM1 N609fs (PMID: 29301960). 29301960
PBRM1 R941fs clear cell renal cell carcinoma no benefit Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in progressive disease in a patient with renal clear cell carcinoma harboring PBRM1 R941fs (PMID: 29301960). 29301960
PBRM1 Y106* clear cell renal cell carcinoma predicted - sensitive Ipilimumab + Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) and Yervoy (ipilimumab) combination treatment resulted in complete response in a patient with renal clear cell carcinoma harboring PBRM1 Y106* (PMID: 29301960). 29301960
PBRM1 inact mut clear cell renal cell carcinoma sensitive Atezolizumab Clinical Study - Cohort Actionable In a clinical study, renal clear cell carcinoma patients harboring PBRM1 loss-of-function mutations demonstrated improved response to immune checkpoint therapies including Opdivo (nivolumab) alone or in combination with Yervoy (ipilimumab), and Tecentriq (atezolizumab), potentially due to the distinct expression profile of immune-related genes in these patients (PMID: 29301960). 29301960
PBRM1 Y331* clear cell renal cell carcinoma predicted - sensitive Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in complete response in a patient with renal clear cell carcinoma harboring PBRM1 Y331* (PMID: 29301960). 29301960
PBRM1 A249fs clear cell renal cell carcinoma no benefit Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in progressive disease in a patient with renal clear cell carcinoma harboring PBRM1 A249fs (PMID: 29301960). 29301960
PBRM1 E291* clear cell renal cell carcinoma no benefit Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in progressive disease in a patient with renal clear cell carcinoma harboring PBRM1 E291* (PMID: 29301960). 29301960
PBRM1 inact mut clear cell renal cell carcinoma sensitive Ipilimumab + Nivolumab Clinical Study - Cohort Actionable In a clinical study, renal clear cell carcinoma patients harboring PBRM1 loss-of-function mutations demonstrated improved response to immune checkpoint therapies including Opdivo (nivolumab) alone or in combination with Yervoy (ipilimumab), and Tecentriq (atezolizumab), potentially due to the distinct expression profile of immune-related genes in these patients (PMID: 29301960). 29301960
PBRM1 S681R clear cell renal cell carcinoma predicted - sensitive Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in partial response in a patient with renal clear cell carcinoma harboring PBRM1 S681R (PMID: 29301960). 29301960
PBRM1 K621* clear cell renal cell carcinoma no benefit Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in progressive disease in a patient with renal clear cell carcinoma harboring PBRM1 K621* (PMID: 29301960). 29301960
PBRM1 Y608fs clear cell renal cell carcinoma no benefit Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in progressive disease in a patient with renal clear cell carcinoma harboring PBRM1 Y608fs (PMID: 29301960). 29301960
PBRM1 W141_L145delinsC clear cell renal cell carcinoma no benefit Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in progressive disease in a patient with renal clear cell carcinoma harboring PBRM1 W141_L145delinsC (PMID: 29301960). 29301960
PBRM1 K135fs clear cell renal cell carcinoma predicted - sensitive Nivolumab Case Reports/Case Series Actionable In a clinical study, Opdivo (nivolumab) treatment resulted in stable disease in a patient with renal clear cell carcinoma harboring PBRM1 K135fs (PMID: 29301960). 29301960