Determining Whether YAP1 and POU2F3 Are Antineuroendocrine Factors

Matsuoka, Ryota; Kawai, Hitomi; Ito, Takeshi; Matsubara, Daisuke

doi:10.1016/j.jtho.2022.07.001

Cited by 5 publications

(7 citation statements)

References 15 publications

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“…2 This might be because all cases of YAP1 and almost all cases of POU2F3 were tested on whole slides, as well as differences in antibodies or IHC protocols. However, under the assumption that the loss of YAP1 defines neuroendocrine differentiation, our results may be more reasonable given the low NE expression characteristic of NEC-P. SCLC-Y is likely to have been established from a minor component of non-NE cells exhibiting YAP1 in classic SCLC, 6,7 so it should not be applied to primary SCLC. However, YAP1 also contributes to cancer cell proliferation as an effector of the Hippo pathway in various cancers, and high YAP1 expression is associated with drug resistance.…”

Section: Figure 2 Graphic Date Of Morphologic Features By 7 Types (Re...mentioning

confidence: 87%

“…2,3 YAP1 (SCLC-Y) was also initially recognized as a non-NE phenotype SCLC, but SCLC-Y is a cell-line-based concept considered inapplicable to primary SCLC. [2][3][4][5][6][7] For each subtype, different effects of immunotherapy or molecular-targeted therapy in models or patients have been suggested. 4,8,9 POU2F3 is a lineage-defining transcription factor involved in the generation of tuft cells, which are epithelial chemosensory cells distributed in many organs, including the respiratory tract.…”

Section: Introductionmentioning

confidence: 99%

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POU2F3-Expressing Small Cell Lung Carcinoma and Large Cell Neuroendocrine Carcinoma Show Morphologic and Phenotypic Overlap

Jimbo,

Ohbayashi,

Takeda

et al. 2023

American Journal of Surgical Pathology

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Considering the differences in protein expression in small cell lung carcinoma (SCLC) by molecular classification, it is likely that there are differences in morphology, but the relationship between molecular classification and morphology has not been examined. Furthermore, there are limited reports concerning this molecular classification for large cell neuroendocrine carcinoma (LCNEC) and SCLC simultaneously. Therefore, we investigated the relationship between immunohistochemistry-based molecular classification and morphology, protein expression, and clinical features of 146 consecutive resection specimens of pulmonary neuroendocrine carcinoma (NEC), focusing mainly on POU2F3, the master transcription factor involved in tuft cell generation. POU2F3-dominant SCLC (n=24) and LCNEC (n=14) showed overlap in cytomorphology, while non-POU2F3-dominant SCLC (n=71) and LCNEC (n=37) showed distinct differences in cytomorphology. In addition, POU2F3-dominant NEC exhibited significantly more abundant tumor stroma, more prominent nest formation, more frequent bronchial intraepithelial involvement, and less frequent background fibrosis than non-POU2F3-dominant NEC. Immunohistochemically, POU2F3-dominant SCLC and LCNEC were characterized by lower expression of TTF-1, CEA, and neuroendocrine markers and higher expression of bcl-2, c-Myc, and c-kit. Clinically, POU2F3-dominant NEC had a significantly better prognosis than non-POU2F3-dominant NEC for recurrence-free survival. POU2F3-dominant NEC had a higher smoking index than non-POU2F3-dominant NEC. POU2F3-dominant NEC forms a unique population, exhibiting intermediate morphologic features between SCLC and LCNEC, with distinct protein expression as tuft cell-like carcinoma. Recognition of this unique subtype may provide clues for solving the long-standing issues of NEC and appropriate therapeutic stratification. It is important to accurately identify POU2F3-expressing carcinomas by immunohistochemistry and to analyze their clinicopathological features.

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Section: Figure 2 Graphic Date Of Morphologic Features By 7 Types (Re...mentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

POU2F3-Expressing Small Cell Lung Carcinoma and Large Cell Neuroendocrine Carcinoma Show Morphologic and Phenotypic Overlap

Jimbo,

Ohbayashi,

Takeda

et al. 2023

American Journal of Surgical Pathology

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“…SCLC-P is a “variant” phenotype associated with low/negative expression of NE markers and is mutually exclusive of both ASCL1 and NEUROD1 13,14 . It was suggested that the classification of SCLC-Y was established primarily from the analysis of cell lines, and it should not be applied to the classification of primary SCLC 22 . Gay et al 10 redefined the fourth subtype of SCLC as SCLC-I, which could derive greater benefit from immune checkpoint blockade.…”

Section: Discussionmentioning

confidence: 99%

“…Chen et al 18 has indicated a potential predictive value of YAP1 protein for immunotherapy efficacy. However, the latest studies implied that YAP1 expression was either entirely absent or present only at a low level, and thus SCLC-Y failed to be confirmed 13,20–22 . Gay et al 10 identified a triple-negative SCLC-I subtype in place of the SCLC-Y subtype, referring to the SCLC subtype with low/negative expression levels of ASCL1, NEUROD1, and POU2F3.…”

mentioning

confidence: 99%

“…However, the latest studies implied that YAP1 expression was either entirely absent or present only at a low level, and thus SCLC-Y failed to be confirmed. 13,[20][21][22] Gay et al 10 identified a triple-negative SCLC-I subtype in place of the SCLC-Y subtype, referring to the SCLC subtype with low/negative expression levels of ASCL1, NEUROD1, and POU2F3. Further studies confirmed that the SCLC-I subtype had a better outcome and could derive greater benefit from immune checkpoint blockade.…”

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confidence: 99%

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Pou2f3

Wang

Jin

Zheng

et al. 2023

American Journal of Surgical Pathology

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POU2F3 (POU class 2 homeobox 3) is a novel transcription factor used to define the special molecular subtype of small cell lung cancer (SCLC) known as SCLC-P. Nevertheless, the sensitivity and specificity of POU2F3 immunohistochemical (IHC) staining have not been fully investigated. In this study, we explored the expression of POU2F3 by IHC in a large cohort of SCLC clinical samples (n=246), other common lung cancer types (n=2207), and various other cancer types (n=194). The results showed that POU2F3 was strongly nuclear stained in 13.41% (33/246) of SCLC cases, with negative or minimal labeling for thyroid transcription factor-1 and neuroendocrine (NE) markers. Compared with POU2F3-negative SCLC, SCLC-P harbored fewer TP53 and RB1 mutations. POU2F3 was also expressed in 3.13% (8/256) of squamous cell carcinomas (SCCs) and 20% (2/10) of large cell NE carcinomas (LCNECs), whereas other lung cancer types were negative. In addition to lung cancer, POU2F3 was positive in 22.2% (4/18) of thymic tumors. All other tumors were POU2F3-negative except for thymic carcinoma, although sparsely distributed weak nuclear staining was observed in lung adenocarcinoma, cervical SCC, and colorectal carcinoma. The sensitivity and specificity of POU2F3 in NE-low/negative SCLC were 82.1% and 99.4%, respectively. Notably, some rare unique patterns of POU2F3 expression were observed. One case of thymic SCC was characterized by diffuse and uniform cytomembrane staining. One case of esophageal NE tumor was nuclear-positive, while the normal proliferating squamous epithelium was strongly membrane-stained. This is the largest cohort of clinical samples to confirm that POU2F3 is a highly sensitive and specific diagnostic marker for NE-low/negative SCLC.

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