SMARCB1/INI1-deficient sinonasal carcinoma shows methylation of RASSF1 gene: A clinicopathological, immunohistochemical and molecular genetic study of a recently described entity

Laco, Ján; Chmelařová, Marcela; Vošmiková, Hana; Sieglová, Kateřina; Bubancova, Ivana; Dundr, Pavel; Němejcová, Kristýna; Michálek, Jaroslav; Čelakovský, Petr; Mottl, Radovan; Sirák, Igor; Vošmik, Milan; Ryška, Aleš

doi:10.1016/j.prp.2016.10.012

Cited by 23 publications

(13 citation statements)

References 44 publications

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“…Chmelarova et al [14] found significant differences in promoter methylation in CDH13, ESR1, RASSF1, and TP73 genes between malignant tumors and normal sinonasal tissue. In our previous study, we detected methylation of APC, CDH13, RASSF1, TIMP3, and TP73 genes in the SMARCB1/INI1-deficient sinonasal carcinomas [42]. Regarding the present series, two NMCs showed methylation of RASSF1 gene using both MS-MLPA and MSP, while the remaining case was unmethylated.…”

Section: Discussionsupporting

confidence: 54%

“…There were found no associations with the exposure to chemical substances or smoking and all NMCs tested negative for HPV and EBV so far [2,6]. Interestingly, all SMARCB1/INI1-deficient sinonasal carcinomas tested also negative for NUT expression, indicating that these genetic alterations are mutually exclusive, but the number of analyzed cases is currently too low to draw a definite conclusion [39][40][41][42].…”

Section: Discussionmentioning

confidence: 85%

“…Although the number of types of sinonasal malignancies is already quite high, yet another new tumor entities have been recently described, making the microscopic diagnostics even more challenging [38]. These include NUT midline carcinoma (NMC) [1,6,8], SMARCB1/INI1-deficient carcinoma [39][40][41][42], HPV-related carcinoma with adenoid cystic-like features [43], renal cell-like adenocarcinoma [44], and biphenotypic sinonasal sarcoma [45].…”

Section: Discussionmentioning

confidence: 99%

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Analysis of DNA methylation and microRNA expression in NUT (nuclear protein in testis) midline carcinoma of the sinonasal tract: a clinicopathological, immunohistochemical and molecular genetic study

Laco¹,

Kovaříková²,

Chmelařová³

et al. 2018

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The aim of this study was a detailed clinicopathological investigation of sinonasal NUT midline carcinoma (NMC), including analysis of DNA methylation and microRNA (miRNA) expression. Three (5%) cases of NMC were detected among 56 sinonasal carcinomas using immunohistochemical screening and confirmed by fluorescence in situ hybridization. The series comprised 2 males and 1 female, aged 46, 60, and 65 years. Two tumors arose in the nasal cavity and one in the maxillary sinus. The neoplasms were staged pT1, pT3, and pT4a (all cN0M0). All patients were treated by radical resection with adjuvant radiotherapy. Two patients died 3 and 8 months after operation, but one patient (pT1 stage; R0 resection) experienced no evidence of disease at 108 months. Microscopically, all tumors consisted of infiltrating nests of polygonal cells with vesicular nuclei, prominent nucleoli and basophilic cytoplasm. Abrupt keratinization was present in only one case. Immunohistochemically, there was a diffuse expression of cytokeratin (CK) cocktail, CK7, p40, p63, and SMARCB1/INI1. All NMCs tested negative for EBV and HPV infection. Two NMCs showed methylation of RASSF1 gene. All other genes (APC, ATM, BRCA1, BRCA2, CADM1, CASP8, CD44, CDH13, CDKN1B, CDKN2A, CDKN2B, CHFR, DAPK1, ESR1, FHIT, GSTP1, HIC1, KLLN, MLH1a, MLH1b, RARB, TIMP3, and VHL) were unmethylated. All NMCs showed upregulation of miR-9 and downregulation of miR-99a and miR-145 and two cases featured also upregulation of miR-21, miR-143, and miR-484. In summary, we described three cases of sinonasal NMCs with novel findings on DNA methylation and miRNA expression, which might be important for new therapeutic strategies in the future.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Analysis of DNA methylation and microRNA expression in NUT (nuclear protein in testis) midline carcinoma of the sinonasal tract: a clinicopathological, immunohistochemical and molecular genetic study

Laco¹,

Kovaříková²,

Chmelařová³

et al. 2018

neo

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“…Sinonasal carcinomas represent 5% of head and neck carcinomas, affecting patients in their fifth decade and are associated with a 5-year survival rate of approximately 50% [98]. SMARCB1-deficient sinonasal carcinoma, underlined by SMARCB1 deletions, represents approximately 10% of sinonasal carcinomas [99]. As in MRT, their genome seems to be highly stable as demonstrated in the only case assessed by next-generation sequencing [100], suggesting that loss of SMARCB1 is likely the driving event of tumorigenesis.…”

Section: Smarcb1 Is Instrumental In Epigenetic Regulation and Cell Cymentioning

confidence: 99%

BAFfling pathologies: Alterations of BAF complexes in cancer

2018

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To activate or repress specific genes, chromatin is constantly modified by chromatin-remodeling complexes. Among these complexes, the SWItch/Sucrose Non-Fermenting (SWI/SNF) complex, also referred to as BRG1-Associated Factor (BAF) complex, moves the nucleosome along chromatin using energy provided by ATP hydrolysis. In mammalian organisms, the SWI/SNF complex is composed of 10-15 subunits, depending on cell type, and a defect in one of these subunits can have dramatic consequences. In this review we will focus on the alterations identified in the SWI/SNF (BAF) complex subunits that lead to cancerous pathologies. While SMARCB1 was the first mutated subunit to be reported in a majority of malignant rhabdoid tumors, the advent of next-generation sequencing allowed the discovery of mutations in various SWI/SNF subunits within a broad spectrum of cancers. In most cases, the mutation leads to a loss of expression or to a truncated subunit unable to perform its function. Even though it is now commonly acknowledged that approximately 20% of all cancers present a mutation in a SWI/SNF subunit, some cancers are associated to a specific alteration of a SWI/SNF subunit, which acts either as tumor suppressor genes or as oncogenes, and therefore constitute diagnostic or prognostic biomarkers. Consistently, therapeutic strategies targeting SWI/SNF subunits or the genes affected downstream have been revealed to treat cancers.

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“…In addition, approximately 20-30% of these tumors harbor transcriptionally active high risk human papillomavirus infection 7 . More recently, it has been demonstrated that sinonasal cancer is also driven by epigenetic alterations [8][9] . Currently, DNA methylation is one of the most broadly studied and wellcharacterized epigenetic modifications.…”

Section: Introductionmentioning

confidence: 99%

Elevated DNA methylation in malignant tumors of the sinonasal tract and its association with patient survival

Chmelařová¹,

Laco²,

Kovaříková³

et al. 2018

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Epigenetic modifications have been recognized as an important mechanism underlying carcinoma progression. DNA methylation plays an important role in cancer biology and represents potentially heritable changes in gene expression that do not involve DNA sequence. The aim of this study was to investigate promoter methylation of selected genes in sinonasal carcinoma by comparison with noncancerous sinonasal tissue. Methods. To search for epigenetic events (methylation in 25 tumor suppressor genes) we used MS-MLPA (Methylationspecific multiplex ligation-dependent probe amplification) to compare methylation status of 59 formalin fixed, paraffin embedded tissue samples of sinonasal carcinomas with 18 control samples. The most important changes in methylation were confirmed using MSP (Methylation specific PCR). Detected alterations in methylation were compared with clinicopathological characteristics. Results. Using a 20% cut-off for methylation (MS-MLPA), we found significantly higher methylation in GATA5 (P=0.0005), THSB1 (P=0.0002) and PAX5 (P=0.03) genes in the sinonasal cancer group compared to the control group. Methylation in five or more genes was associated with impaired overall survival (P=0.017). Conclusion. These findings provide evidence that alterations in methylation profile may be one of the major mechanisms in sinonasal carcinogenesis. In addition, changes in methylation could potentially be used as prognostic factors of sinonasal carcinoma and may have implications for future individualized therapy based on epigenetic changes.

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SMARCB1/INI1-deficient sinonasal carcinoma shows methylation of RASSF1 gene: A clinicopathological, immunohistochemical and molecular genetic study of a recently described entity

Cited by 23 publications

References 44 publications

Analysis of DNA methylation and microRNA expression in NUT (nuclear protein in testis) midline carcinoma of the sinonasal tract: a clinicopathological, immunohistochemical and molecular genetic study

Analysis of DNA methylation and microRNA expression in NUT (nuclear protein in testis) midline carcinoma of the sinonasal tract: a clinicopathological, immunohistochemical and molecular genetic study

BAFfling pathologies: Alterations of BAF complexes in cancer

Elevated DNA methylation in malignant tumors of the sinonasal tract and its association with patient survival

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