Prevalence of SWI/SNF genomic alterations in cancer and association with the response to immune checkpoint inhibitors: A systematic review and meta-analysis

ARID2, a rare cause of Coffin‐Siris syndrome: A novel microdeletion at 12q12q13.11 causing severe short stature and literature review

“…This is in contrast to the ARID1B pathogenic variants resulting in CCS9, where GHRH‐GH‐IGF1 deficiency was found in these patients and mice, and GH treatment can effectively improve their growth retardation (Celen et al, 2017). On the other hand, accumulating evidences suggest that SWI/SNF functions as a tumor suppressor in some cancers, and somatic ARID2 gene inactivation pathogenic variants have been reported to exist in hepatitis C virus‐related liver cancer, acute myeloid leukemia, melanoma, lung cancer and colorectal cancer (Bluemn et al, 2022; Sun & Cheng, 2022; Wang, Qin, et al, 2022; Zhu et al, 2022). Although no patient with germline ARID2 deficiency have developed malignancy, hepatoblastoma, papillary thyroid cancer and schwannomatosis have been reported in individuals with germline ARID1A, ARID1B and SMARCB1 pathogenic variant, respectively (Gossai et al, 2015; Tsurusaki et al, 2012; Vengoechea et al, 2014).…”

GNE-235: A Lead Compound Selective for the Second Bromodomain of PBRM1

“…After typical workup and purification, a cottony white solid was obtained (49 mg, 52%). 1 H NMR (400 MHz, [D 6 ]DMSO) δ = 14.18 (s, 1H), 7.91 (dd, J = 8.3, 1.6 Hz, 1H), 7.61 (s, 1H), 7.24 (td, J = 7.5, 1.6 Hz, 1H), 6.94−6.85 (m, 2H), 6.24 (s, 2H), 3.69 (td, J = 6.4, 4.0 Hz, 1H), 3.27−3.17 (R)-2-(6-Amino-5-(2-methylpiperidin-1-yl)pyridazin-3-yl)phenol (14). Synthesis proceeded as outlined for 10, starting from 107 mg of 39 (0.47 mmol) and yielding 100.6 mg of purified 14 (75%).…”

“…10,11 Loss-of-function mutation of PBRM1 in ccRCC was reported to be associated with a positive clinical response to immune checkpoint inhibitors, 12 although this finding remains controversial. 13,14 It has therefore been of high recent interest to understand the functional role of PBRM1 in the PBAF complex and the molecular and biological consequences of PBRM1 loss, both on its own and in combination with other 3p tumor suppressors. 15−22 PBRM1 is unique among human bromodomain proteins for its six tandem bromodomains, "reader" domains that typically bind to acetylated lysine residues.…”

“…Polybromo-1 (PBRM1; BAF180; PB1) is a characteristic subunit of the large chromatin remodeling complex PBAF (polybromo-associated BAF), which is a functionally distinct variant of the BRG/BRM-associated factor (BAF) complex. − PBRM1 loss is a frequent event in clear-cell renal cell carcinoma (ccRCC), and PBRM1 is thus thought to function as a tumor suppressor. − Additional complexity arises from the presence of PBRM1 in a gene cluster on chromosome 3p21 that includes BAP1 and SETD2 , additional chromatin regulators, and tumor suppressors whose concurrent loss with PBRM1 is implicated in clear-cell renal cell carcinoma (ccRCC) progression. , This gene cluster lies near VHL (located at 3p25), the loss of which is the major initiation event in ccRCC. , Loss-of-function mutation of PBRM1 in ccRCC was reported to be associated with a positive clinical response to immune checkpoint inhibitors, although this finding remains controversial. , It has therefore been of high recent interest to understand the functional role of PBRM1 in the PBAF complex and the molecular and biological consequences of PBRM1 loss, both on its own and in combination with other 3p tumor suppressors. − …”

SMARCB1-Deficient Cancers: Novel Molecular Insights and Therapeutic Vulnerabilities

“…Current estimates indicate that 1.4% of all cancers contain SMARCB1 alterations (1152 out of 84,646 queried samples found on AACR Project GENIE Cohort v11.0) [ 12 ]. However, a recent meta-analysis examining 10,849 patients from 15 studies found that 5% of cases had alterations in SMARCB1 [ 13 ].…”