SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies

Saqcena, Mahesh; Leandro‐García, Luis Javier; Mååg, Jesper L.V.; Tchekmedyian, Vatche; Krishnamoorthy, Gnana P.; Tamarapu, Prasanna P.; Tiedje, Vera; Reuter, Vincent; Knauf, Jeffrey A.; Stanchina, Elisa de; Xu, Bin; Liao, Xiao-Hui; Refetoff, Samuel; Ghossein, Ronald; Chi, Ping; Ho, Alan L.; Koche, Richard P.; Fagin, James A.

doi:10.1158/2159-8290.cd-20-0735

Cited by 71 publications

(47 citation statements)

References 92 publications

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Section: Discussionsupporting

confidence: 91%

“…Recently, Saqcena et al . demonstrated that mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage genes in BRAF‐mutant thyroid tumours, resulting in insensitivity to the redifferentiation effects of mitogen‐activated protein kinase blockade 39 . This may be in line with our findings in multivariate Cox regression, where any loss of SMARCA4 expression and global loss of SMARCA2 expression cancelled significant effects of BRAF V600E mutation in multivariate analysis.…”

Section: Discussionsupporting

confidence: 88%

“…Our findings confirm other studies suggesting that loss of SMARCA4, SMARCA2 or SMARCB1 expression is more commonly associated with morphologically poorly differentiated tumours. 10,39 It is worth noting that, in cases with only focal loss of expression, the onset of SWI/SNF complex deficiency was associated with morphological dedifferentiation. Whereas any loss of SMARCB1 expression and global loss of SMARCA2 expression were associated with statistically significant shorter OS, the shorter OS in the SMARCA4-deficient group was not shown to be statistically significant.…”

Section: Discussionmentioning

confidence: 99%

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Switch/sucrose‐non‐fermentable (SWI/SNF) complex (SMARCA4, SMARCA2, INI1/SMARCB1)‐deficient colorectal carcinomas are strongly associated with microsatellite instability: an incidence study in 4508 colorectal carcinomas

et al. 2022

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Aims Loss of expression of mammalian switch/sucrose‐non‐fermentable (SWI/SNF) [BRG1/BRM‐associated factor (BAF)] complex subunits, including SMARCA4, SMARCA2 and INI1/SMARCB1 (termed SWI/SNF complex deficiency), has been reported in colorectal carcinomas (CRCs) but its frequency and clinical significance are uncertain. Methods and results We performed immunohistochemistry for SMARCA4, SMARCA2 and SMARCB1 on 4508 consecutive resected CRCs. Loss of SMARCA4 expression was found in 13 cases (0.3%), loss of SMARCA2 expression was found in 59 cases (1.3%), and loss of SMARCB1 expression was found in 21 cases (0.4%). Some CRCs showed loss of expression of more than one subunit, so that 84 CRCs (1.7%) were deficient for at least one component. SWI/SNF complex deficiency was associated with higher grade, a right‐sided location, mismatch repair deficiency, and BRAF V600E mutation (P < 0.05); 5.8% of mismatch repair‐deficient (MMRd) cases and 5.4% of BRAF V600E‐mutant cases were SWI/SNF complex‐deficient, as compared with 0.9% and 0.4% of mismatch repair‐proficient and BRAF‐wild‐type cases (P < 0.001). Any loss of SMARCB1 expression and global loss of SMARCA2 expression were associated with statistically significant worse overall survival, whereas SMARCA4‐deficient cases showed a trend only towards poor overall survival (P = 0.121). In multivariate analysis, any loss of SMARCA4 expression and global loss of SMARCA2 expression were associated with worse survival [odds ratio (OR) 3.33, P = 0.019; and OR 3.39, P < 0.001]. Of particular note, among the subgroup of cases that were MMRd and BRAF V600E‐mutated (otherwise considered to be a good prognostic group), loss of SMARCA4 expression was associated with much worse median survival (10.5 months versus 110.9 months; P = 0.003). Conclusions SWI/SNF complex deficiency is rare in CRC but is enriched in MMRd cases. Identifying these cases has morphological associations and prognostic significance, and in the future may have potential therapeutic implications.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Switch/sucrose‐non‐fermentable (SWI/SNF) complex (SMARCA4, SMARCA2, INI1/SMARCB1)‐deficient colorectal carcinomas are strongly associated with microsatellite instability: an incidence study in 4508 colorectal carcinomas

et al. 2022

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“…However, mutations in these genes occur in a small fraction of HCC. Mutations in chromatin regulatory proteins were also reported at low frequency, similar to other clinically aggressive thyroid cancers (22,24,32,33). Overall, these studies were consistent with the notion that HCC represented a molecularly distinct form of thyroid cancer.…”

Section: Low Frequency Of Canonical Fdtc Driver Mutationssupporting

confidence: 79%

Genetics, Diagnosis, and Management of Hürthle Cell Thyroid Neoplasms

McFadden

Sadow

2021

Front. Endocrinol.

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Hürthle cell lesions have been a diagnostic conundrum in pathology since they were first recognized over a century ago. Controversy as to the name of the cell, the origin of the cell, and even which cells in particular may be designated as such still challenge pathologists and confound those treating patients with a diagnosis of “Hürthle cell” anything within the diagnosis, especially if that anything is a sizable mass lesion. The diagnosis of Hürthle cell adenoma (HCA) or Hürthle cell carcinoma (HCC) has typically relied on a judgement call by pathologists as to the presence or absence of capsular and/or vascular invasion of the adjacent thyroid parenchyma, easy to note in widely invasive disease and a somewhat subjective diagnosis for minimally invasive or borderline invasive disease. Diagnostic specificity, which has incorporated a sharp increase in molecular genetic studies of thyroid tumor subtypes and the integration of molecular testing into preoperative management protocols, continues to be challenged by Hürthle cell neoplasia. Here, we provide the improving yet still murky state of what is known about Hürthle cell tumor genetics, clinical management, and based upon what we are learning about the genetics of other thyroid tumors, how to manage expectations, by pathologists, clinicians, and patients, for more actionable, precise classifications of Hürthle cell tumors of the thyroid.

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“…However, the investigations of genotype–phenotype correlations regarding the alterations in FGs in PTCs are very limited. A previous study using mouse thyroid cancer cell lines showed that loss of SWI/SNF subunits was related to radioiodine refractoriness and resistant to MAPK inhibitor-based redifferentiation therapies in BRAF V600E -mutant PTCs, which needs validation in humans [ 17 ]. Mutations in PI3K/AKT/mTOR pathway were reported frequently in advanced thyroid cancers (PDTC or ATC) especially in metastatic or recurrent cases, and also in follicular thyroid carcinomas [ 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAFV600E-Mutant Advanced Papillary Thyroid Carcinoma

Song

Jin

Jang

et al. 2021

Cancers

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The prognosis of BRAFV600E-mutant papillary thyroid carcinoma (PTC) ranges from indolent to highly aggressive courses. To better define the genetic diversity of this subtype, we evaluated the survival according to the presence of an additional mutation in genes encoding functional groups (FGs) in BRAFV600E-mutant advanced PTC patients. Targeted next-generation sequencing was performed in primary tumors of 50 BRAFV600E-mutant PTCs with distant metastasis or aggressive variants. The mutation in genes encoding FGs included alterations in histone methyltransferases, SWI/SNF subunit, and the PI3K/AKT/mTOR pathway. The primary outcome was overall survival (OS). Fifteen patients only had the BRAFV600E-mutation (group 1), 22 had BRAFV600E and mutation other than FGs (group 2), and 13 had BRAFV600E and FG mutation (group 3). OS was significantly lower in patients with FG mutations (p = 0.001) than those without, and group 3 patients had the worst survival (p = 0.004). OS significantly varied among none, one, or two FG mutation sites (p = 0.005). Presence of FG mutation was independently associated with increased mortality (hazard ratio 11.65, 95% confidence interval 1.39–97.58, p = 0.024). Coexistence of mutations in BRAFV600E and genes encoding FGs was associated with high mortality. Identification of FG mutation in BRAFV600E-mutant PTCs may be valuable in risk stratifying this subtype.

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SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies

Cited by 71 publications

References 92 publications

Switch/sucrose‐non‐fermentable (SWI/SNF) complex (SMARCA4, SMARCA2, INI1/SMARCB1)‐deficient colorectal carcinomas are strongly associated with microsatellite instability: an incidence study in 4508 colorectal carcinomas

Switch/sucrose‐non‐fermentable (SWI/SNF) complex (SMARCA4, SMARCA2, INI1/SMARCB1)‐deficient colorectal carcinomas are strongly associated with microsatellite instability: an incidence study in 4508 colorectal carcinomas

Genetics, Diagnosis, and Management of Hürthle Cell Thyroid Neoplasms

Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAFV600E-Mutant Advanced Papillary Thyroid Carcinoma

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