SMARCA4 (BRG1) and SMARCB1 (INI1) expression in TTF-1 negative neuroendocrine carcinomas including merkel cell carcinoma

Gandhi, Jatin; Akber, Alnoor; Sadiq, Qandeel; Solares, Jorge; Gradowski, Joel F.

doi:10.1016/j.prp.2021.153341

Cited by 10 publications

(9 citation statements)

References 34 publications

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“…The tumors in our cohort expressed neuroendocrine markers and thus needed to be differentiated from LCNEC of the lung. LCNEC of the lung with BRG1 loss had been previously reported by Gandhi et al23 LCNEC typically demonstrated organoid or trabecular growth and rosette-like structures. The most frequent neuroendocrine markers in LCNEC were CD56 (92%-100%), CgA (80%-85%), and Syn (50%-60%) 1.…”

Section: Discussionmentioning

confidence: 54%

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Expanding the Immunophenotype Spectrum of SMARCA4-Deficient Non-Small Cell Lung Carcinomas: A Case Series with Neuroendocrine Markers Expression

et al. 2021

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Aims. In recent years, SMARCA4-deficient nonsmall cell lung cancer (NSCLC) has been recognized as a distinct new subtype of lung cancer, which is characterized by loss of SMARCA4 (Brahma-related gene-1 [BRG1]) protein expression. Only a limited number of SMARCA4-deficient NSCLC case series have been reported, and their clinicopathological features have not yet been fully elucidated. Our main aim was to analyze the clinical history, histology, immunohistochemistry, and molecular pathology of 5 SMARCA4-deficient NSCLC patients with poorly differentiated or undifferentiated histology and neuroendocrine markers expression. Methods and results. Five patients with complete loss of nuclear BRG1 immunostaining were identified among 53 patients of poorly differentiated/undifferentiated NSCLC. We then performed immunohistochemical staining and gene mutation analysis using a real-time polymerase chain reaction. All patients were male aged between 58 and 82 years (average 67.6 years), with smoking exposure. Histologically, the tumors had a relatively monotonous morphology and showed solid nest-like, sheet-like growth, and geographic necrosis. Thyroid transcription factor 1, cytokeratin 7, and Napsin A were all negative (5 of 5). Moreover, all tumors showed a variable expression of neuroendocrine markers, including synaptophysin, chromogranin A and CD56. Hot spot epidermal growth factor receptor/anaplastic large-cell lymphoma kinase/c-ros oncogene 1 mutations were not detected in any of the 5 tumors. Conclusions. To the best of our knowledge, this is the first study that has reported the poorly differentiated morphology with a frequent expression of neuroendocrine markers. Our results have expanded the immunophenotype spectrum of SMARCA4-deficient NSCLC. However, the clinicopathological significance of this subset of SMARCA4-deficient NSCLC should be further clarified in larger series studies.

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Section: Discussionmentioning

confidence: 54%

“…In this study, TTF-1 was negative in all tumors, which was consistent with previous studies. 11,14 Gandhi et al23 described 1 case of TTF-1-negative small cell lung carcinoma and 1 case of TTF-1-negative large-cell neuroendocrine carcinoma (LCNEC) of the lung with BRG1 loss. Our results also showed negative CK7 staining in all tumors.…”

Section: Discussionmentioning

confidence: 99%

Expanding the Immunophenotype Spectrum of SMARCA4-Deficient Non-Small Cell Lung Carcinomas: A Case Series with Neuroendocrine Markers Expression

et al. 2021

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“…Loss of this tumor suppressor component of the SWI/SNF complex has been described in some non-cutaneous neuroendocrine tumors, and might initiate transition from epithelial to round cell phenotype. 36 – 39 However, in previous studies of MCC, SMARCA4 mutation was not a frequent event, and protein expression was retained. 3 , 4 , 36 Thus, the role for SMARCA4 mutation in our cases remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“… 36 – 39 However, in previous studies of MCC, SMARCA4 mutation was not a frequent event, and protein expression was retained. 3 , 4 , 36 Thus, the role for SMARCA4 mutation in our cases remains unclear. Overall, we found no single genomic event that was consistently restricted to the MCC component in every case.…”

Section: Discussionmentioning

confidence: 99%

Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors

Harms

Verhaegen

et al. 2022

Modern Pathology

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Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma without a known dysplastic precursor. In some cases, MCC is associated with SCCIS in the overlying epidermis; however, the MCC and SCCIS populations display strikingly different morphologies, and thus far a relationship between these components has not been demonstrated. To better understand the relationship between these distinct tumor cell populations, we evaluated 7 pairs of MCC-SCCIS for overlapping genomic alterations by cancer profiling panel. A subset was further characterized by transcriptional profiling and immunohistochemistry. In 6 of 7 MCC-SCCIS pairs there was highly significant mutational overlap including shared TP53 and/or RB1 mutations. In some cases, oncogenic events previously implicated in MCC ( MYCL gain, MDM4 gain, HRAS mutation) were detected in both components. Although FBXW7 mutations were enriched in MCC, no gene mutation was unique to the MCC component across all cases. Transcriptome analysis identified 2,736 differentially expressed genes between MCC and SCCIS. Genes upregulated in the MCC component included Polycomb repressive complex targets; downregulated transcripts included epidermal markers, and immune genes such as HLA-A . Immunohistochemical studies revealed increased expression of SOX2 in the MCC component, with diminished H3K27Me3, Rb, and HLA-A expression. In summary, MCC-SCCIS pairs demonstrate clonal relatedness. The shift to neuroendocrine phenotype is associated with loss of Rb protein expression, decrease in global H3K27Me3, and increased expression of Merkel cell genes such as SOX2 . Our findings suggest an epidermal origin of MCC in this setting, and to our knowledge provide the first molecular evidence that intraepithelial squamous dysplasia may represent a direct precursor for small cell carcinoma.

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“…For instance, an analysis conducted using The Cancer Genome Atlas (TCGA) revealed that NSCLC patients with TP53 variants had significantly shorter survival rates than those without [36]. With regard to SMARCB1, gene variants and loss of expression were reported in up to 5% of NSCLC cases and have been associated with poor clinical outcome [37]. The SMAD4 pathway has been identified as a potential target for tumor treatment [38].…”

Section: Discussionmentioning

confidence: 99%

Single Circulating-Tumor-Cell-Targeted Sequencing to Identify Somatic Variants in Liquid Biopsies in Non-Small-Cell Lung Cancer Patients

Barbirou

Miller

Manjunath

et al. 2022

CIMB

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Non-small-cell lung cancer (NSCLC) accounts for most cancer-related deaths worldwide. Liquid biopsy by a blood draw to detect circulating tumor cells (CTCs) is a tool for molecular profiling of cancer using single-cell and next-generation sequencing (NGS) technologies. The aim of the study was to identify somatic variants in single CTCs isolated from NSCLC patients by targeted NGS. Thirty-one subjects (20 NSCLC patients, 11 smokers without cancer) were enrolled for blood draws (7.5 mL). CTCs were identified by immunofluorescence, individually retrieved, and DNA-extracted. Targeted NGS was performed to detect somatic variants (single-nucleotide variants (SNVs) and insertions/deletions (Indels)) across 65 oncogenes and tumor suppressor genes. Cancer-associated variants were classified using OncoKB database. NSCLC patients had significantly higher CTC counts than control smokers (p = 0.0132; Mann–Whitney test). Analyzing 23 CTCs and 13 white blood cells across seven patients revealed a total of 644 somatic variants that occurred in all CTCs within the same subject, ranging from 1 to 137 per patient. The highest number of variants detected in ≥1 CTC within a patient was 441. A total of 18/65 (27.7%) genes were highly mutated. Mutations with oncogenic impact were identified in functional domains of seven oncogenes/tumor suppressor genes (NF1, PTCH1, TP53, SMARCB1, SMAD4, KRAS, and ERBB2). Single CTC-targeted NGS detects heterogeneous and shared mutational signatures within and between NSCLC patients. CTC single-cell genomics have potential for integration in NSCLC precision oncology.

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SMARCA4 (BRG1) and SMARCB1 (INI1) expression in TTF-1 negative neuroendocrine carcinomas including merkel cell carcinoma

Cited by 10 publications

References 34 publications

Expanding the Immunophenotype Spectrum of SMARCA4-Deficient Non-Small Cell Lung Carcinomas: A Case Series with Neuroendocrine Markers Expression

Expanding the Immunophenotype Spectrum of SMARCA4-Deficient Non-Small Cell Lung Carcinomas: A Case Series with Neuroendocrine Markers Expression

Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors

Single Circulating-Tumor-Cell-Targeted Sequencing to Identify Somatic Variants in Liquid Biopsies in Non-Small-Cell Lung Cancer Patients

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