Alterations of expression of Rb, p16INK4A and cyclin D1 in non-small cell lung carcinoma and their clinical significance

Brambilla, Élisabeth; Moro, D.; Gazzéri, Sylvie; Brambilla, Christian

doi:10.1002/(sici)1096-9896(199908)188:4<351::aid-path385>3.0.co;2-w

Cited by 110 publications

(82 citation statements)

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“…15,32,39,40 It was also reported that cyclin D1 overexpression was a favorable prognostic factor in non-small-cell lung carcinoma. 16 In the present study, none of these factors correlated with patient survivals within the individual tumor categories, suggesting that their prognostic significance is tumor-type specific.…”

Section: Discussionmentioning

confidence: 99%

“…These results might reflect a genetic difference between large-cell neuroendocrine carcinoma and small-cell carcinoma, and a similarity between large-cell neuroendocrine carcinoma and non-small-cell lung carcinoma. 15,[31][32][33] Ki-67 is a well-established marker of cell proliferation activity and its expression is not phase specific in the cell cycle. In the present study, the mean proliferation rate determined by Ki-67 LI was 1.3, 8.6, 52.2 and 54.6% in typical carcinoids, atypical carcinoids, large-cell neuroendocrine carcinomas and small-cell carcinomas, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 However, to the best of our knowledge, no data concerning cyclin B1 expression status within the context of pulmonary neuroendocrine tumors are currently available. Furthermore, although overexpression of cyclin D1 and loss of Rb or p16 expression were also reported in various solid tumors, and cyclin D1 overexpression was reported to be of prognostic importance in some tumors, [10][11][12][13][14][15][16][17][18][19] aberrations in the Rb/p16/cyclin D1 pathway (Rb pathway) are not yet well characterized in pulmonary neuroendocrine tumors. 20 Thus, the present study was carried out to analyze cyclin B1 and D1 expression status, as well as aberrations in the Rb pathway, and their relationship to tumor proliferation activity and clinical outcomes in a spectrum of pulmonary neuroendocrine tumors.…”

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Divergent cyclin B1 expression and Rb/p16/cyclin D1 pathway aberrations among pulmonary neuroendocrine tumors

et al. 2004

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A total of 111 pulmonary neuroendocrine tumors comprising 13 typical carcinoids, five atypical carcinoids, 44 large-cell neuroendocrine carcinomas and 49 small-cell carcinomas were immunohistochemically studied for dysregulated cyclin B1 expression and disruption of the Rb/p16/cyclin D1 pathway (Rb pathway), and the results were correlated with tumor proliferation activity and clinical outcome. Overexpression of cyclins B1 and D1, respectively, was detected in no and 15% typical carcinoids, 20 and 20% atypical carcinoids, 84 and 32% large-cell neuroendocrine carcinomas, 84 and 10% small-cell carcinomas. Loss of Rb and p16 expression, respectively, was observed in no and 14% typical carcinoids, no and 40% atypical carcinoids, 49 and 18% largecell neuroendocrine carcinomas, 84 and 8% small-cell carcinomas. In summary, 29% typical carcinoids, 20% atypical carcinoids, 78% large-cell neuroendocrine carcinomas and 93% small-cell carcinomas had Rb pathway aberrations. Rb pathway aberration was mostly attributed to Rb loss in small-cell carcinomas, while p16 loss and/or cyclin D1 overexpression besides Rb loss also played an important role in large-cell neuroendocrine carcinomas, while cyclin D1 overexpression was the only cause of Rb pathway aberration in carcinoid tumors. Thus, both cyclin B1-associated G2/M arrest and Rb-mediated G1 arrest are consistently compromised in highgrade large-cell neuroendocrine carcinoma and small-cell carcinoma, but are generally intact or occasionally altered in carcinoid tumor; the mechanisms involved in Rb pathway aberration among the tumor categories are different, reflecting a genetic divergence among the individual tumor categories. Cyclin B1 expression closely correlated with the Ki-67 labeling index either in the individual tumor categories or overall tumors (Po0.0001, r ¼ 0.742), suggesting that cyclin B1 is one of the key factors regulating cell proliferation in pulmonary neuroendocrine tumors. Neither cyclins B1 and D1, Rb, p16, nor Ki-67 correlated with patient survival in individual tumor categories, suggesting that the prognostic significance of these factors is tumor-type specific.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Divergent cyclin B1 expression and Rb/p16/cyclin D1 pathway aberrations among pulmonary neuroendocrine tumors

et al. 2004

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“…[24][25][26] Aberrant methylation of p16 appears to represent an early event in pulmonary carcinogenesis and is associated with p16 inactivation and loss of p16 expression. 27,28 In contrast to pulmonary small cell carcinomas, which largely retain p16 expression, pulmonary squamous cell carcinomas have demonstrated more frequent loss of expression of p16.…”

Section: Discussionmentioning

confidence: 99%

Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach

et al. 2005

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Accurate morphologic distinction between small cell carcinoma and poorly differentiated squamous cell carcinoma has critical therapeutic significance, but can be limited by crush artifact, tumor necrosis, limited tumor representation, and overlapping morphologic features. We evaluated a panel of antibodies for their efficacy in distinguishing between these neoplasms. Formalin-fixed paraffin-embedded tissue sections of small cell carcinomas and poorly differentiated squamous cell carcinomas underwent immunohistochemical staining with antibodies to thyroid transcription factor-1, p63, high molecular weight keratin, and p16(INK4A). Of 28 small cell carcinomas, 26 (93%) small cell carcinomas showed diffuse moderate or strong staining for thyroid transcription factor-1 with no staining for high molecular weight keratin and p63. In contrast, 27/28 (96%) poorly differentiated squamous cell carcinomas manifested opposite immunoreactivities, with diffuse moderate or strong staining for high molecular weight keratin and p63, and no or minimal staining for thyroid transcription factor-1. In two additional cases originally interpreted as small cell carcinoma, high molecular weight keratin highlighted small numbers of neoplastic large cells, leading to reclassification as combined small cell and nonsmall cell carcinomas. p16(INK4A) expression varied widely in poorly differentiated squamous cell carcinomas, but was consistently moderate or strong and diffuse in small cell carcinomas, and proved helpful in the two thyroid transcription factor-1-negative small cell carcinomas. This study demonstrates that a panel consisting of antibodies to thyroid transcription factor-1, p63, high molecular weight keratin, and p16(INK4A) is highly effective for distinguishing between small cell carcinoma and poorly differentiated squamous cell carcinoma. This panel also facilitates diagnosis of combined small cell and non-small cell carcinomas.

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“…pRb pathway is di erentially disrupted in NSCLC and high grade NE tumours. Whereas loss of pRb protein expression (through mutations and/or loss of transcription) occurs in 85% of SCLC and LCNEC (Gouyer et al, 1998), pRb function is abolished in 85% of NSCLC either through loss of p16 INK4a protein expression (Xu et al, 1996;Gazzeri et al, 1998a), and/ or cyclin D1 overexpression (Brambilla et al, 1997). As E2F1 is one key component of these two pathways (O'Connor et al, 1995;Bates et al, 1998;Kowalik et al, 1998), any alterations a ecting them, especially pRb inactivation, are thought to deregulate its activity.…”

Section: Introductionmentioning

confidence: 99%

Distinct pattern of E2F1 expression in human lung tumours: E2F1 is upregulated in small cell lung carcinoma

Eymin¹,

Gazzéri²,

Brambilla³

et al. 2001

Oncogene

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112

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The transcription factor E2F1 is a key component of cell cycle that acts to transactivate genes required for S phase entry. Thus, it plays an important role in cellular proliferation, oncogenesis and di erentiation. In order to investigate its potential implication in human lung carcinogenesis, we studied E2F1 protein expression by Western blotting and immunohistochemistry in a series of 58 human lung tumours of all histological types. We showed that E2F1 product was overexpressed in 92% (24/26) of small cell lung carcinoma (SCLC) and in 50% (5/10) of large cell neuroendocrine carcinoma (LCNEC) whereas it was undetectable in 90% (10/11) of adenocarcinoma and 82% (9/11) of squamous carcinoma when compared to corresponding normal lung. No ampli®cation was found but an increase in E2F1 mRNA expression was detected in 75% (18/24) of SCLC overexpressing E2F1 product. In these tumours and in contrast with NSCLC, upregulation of E2F1 product was associated with its nuclear accumulation and with overexpression of several of its target-genes. Moreover, E2F1 overexpression in NE lung tumours was signi®-cantly associated with a high KI67 index (P50.0001) as well as a Bcl-2:Bax ratio 41 (P50.001). Overall, these results demonstrate a distinct pattern of E2F1 expression in human lung tumours and suggest that its deregulation could be involved in the carcinogenesis of SCLC.

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Alterations of expression of Rb, p16INK4A and cyclin D1 in non-small cell lung carcinoma and their clinical significance

Cited by 110 publications

References 23 publications

Divergent cyclin B1 expression and Rb/p16/cyclin D1 pathway aberrations among pulmonary neuroendocrine tumors

Divergent cyclin B1 expression and Rb/p16/cyclin D1 pathway aberrations among pulmonary neuroendocrine tumors

Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach

Distinct pattern of E2F1 expression in human lung tumours: E2F1 is upregulated in small cell lung carcinoma

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