Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Science (New York, N.Y.)	359	6377	2018 Feb 16	801-806	Science

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 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, Jul 2024).
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, Jul 2024).

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	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 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 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 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 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 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 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 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 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 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 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
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 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 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 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 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 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 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