Genetic abnormalities and HPV status in cervical and vulvar squamous cell carcinomas

Huang, Fung‐Yu; Kwok, Yvonne K.; Lau, Elizabeth T.; Tang, Mónica; Ng, Tong Yow; Ngan, Hextan Y.S.

doi:10.1016/j.cancergencyto.2004.06.002

Cited by 55 publications

(48 citation statements)

References 26 publications

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“…Gains in the long arm of chromosome 3 were frequent in our casuistic, which is a common finding in studies on VSCC (12)(13)(14)(15) and other solid tumors (24). However, the normally concomitant findings with this imbalance (e.g., gains in chr8q and losses in chr3p and chr8p) were not observed.…”

Section: Discussionsupporting

confidence: 68%

“…However, most studies are not comparable with our findings, because they extracted DNA from FFPE (12, 13) or cell lines (14,15). Furthermore, some studies controlled for HPV, used disparate methods or lower-resolution platforms (12)(13)(14)(15).…”

Section: Discussioncontrasting

confidence: 56%

“…Wide-coverage methods, such as chromosomal and array comparative genomic hybridization (aCGH), have been used in several studies to better understand VSCC, reporting gains in 3q and 8q and losses in 3p and 8q as recurrent alterations (12)(13)(14)(15)(16). Despite these findings, most of these studies used lower-resolution CGH approaches (12)(13)(14); two used FFPE samples, which can lead to data misinterpretation (12,13); and none validated the observed alterations.…”

Section: Introductionmentioning

confidence: 99%

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An Integrative Approach Uncovers Biomarkers that Associate with Clinically Relevant Disease Outcomes in Vulvar Carcinoma

Lavorato-Rocha

Akagi

Maia

et al. 2016

Molecular Cancer Research

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Vulvar squamous cell carcinoma (VSCC) is a rare disease that has a high mortality rate ($40%). However, little is known about its molecular signature. Therefore, an integrated genomics approach, based on comparative genome hybridization (aCGH) and genome-wide expression (GWE) array, was performed to identify driver genes in VSCC. To achieve that, DNA and RNA were extracted from frozen VSCC clinical specimens and examined by aCGH and GWE array, respectively. On the basis of the integration of data using the CONEXIC algorithm, PLXDC2 and GNB3 were validated by RT-qPCR. The expression of these genes was then analyzed by IHC in a large set of formalin-fixed paraffin-embedded specimens. These analyses identified 47 putative drivers, 46 of which were characterized by copy number gains that were concomitant with overexpression and one with a copy number loss and downregulation. Two of these genes, PLXDC2 and GNB3, were selected for further validation: PLXDC2 was downregulated and GNB3 was overexpressed compared with non-neoplastic tissue. By IHC, both proteins were ubiquitously expressed throughout vulvar tissue. High expression of GNB3 and low PLXDC2 immunostaining in the same sample was significantly associated with less lymph node metastasis and greater disease-free survival. On the basis of a robust methodology never used before for VSCC evaluation, two novel prognostic markers in vulvar cancer are identified: one with favorable prognosis (GNB3) and the other with unfavorable prognosis (PLXDC2).Implications: This genomics study reveals markers that associate with prognosis and may provide guidance for better treatment in vulvar cancer.

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Section: Discussionsupporting

confidence: 68%

Section: Discussioncontrasting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

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An Integrative Approach Uncovers Biomarkers that Associate with Clinically Relevant Disease Outcomes in Vulvar Carcinoma

Lavorato-Rocha

Akagi

Maia

et al. 2016

Molecular Cancer Research

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“…This would be consistent with data from one previous study showing a high frequency of chromosome 1 and 20 gains in VIN3 but not VSCC samples (Bryndorf et al, 2004). The fact that another investigation (Huang et al, 2005) observed gains at chromosomes 1 and 20 in only 17% of metastatic tumours provides further support for this theory. Although the remaining studies provided no information on tumour stage, the authors reported frequent recurrent gains at 3q and 5p, which have been shown to correlate with pathological staging of SCC (Oga et al, 2001;Yen et al, 2001;Noguchi et al, 2003;Klussmann et al, 2009); hence, it seems likely that many of these samples were also late stage tumours.…”

Section: Snp Array Analysis Of Hpv-associated Vulval Neoplasia Kj Purmentioning

confidence: 82%

“…Limited data are available on the genetic alterations associated with VSCC and VIN precursor lesions; previous studies have used microsatellite marker analysis and metaphase comparative genomic hybridisation (CGH) rather than higher resolution arraybased techniques (Pinto et al, 1999;Jee et al, 2001;Rosenthal et al, 2001;Allen et al, 2002;Micci et al, 2003;Bryndorf et al, 2004;Huang et al, 2005). In contrast, the genetic changes associated with CIN and CxSCC have been extensively studied, most recently using array-based methods (Hidalgo et al, 2005;Wilting et al, 2006Wilting et al, , 2009Choi et al, 2007;Kloth et al, 2007;Scotto et al, 2008a, b).…”

mentioning

confidence: 99%

High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia

et al. 2010

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BACKGROUND: The incidence of human papillomavirus-associated vulval neoplasia is increasing worldwide; yet the associated genetic changes remain poorly understood. METHODS: We have used single-nucleotide polymorphism microarray analysis to perform the first high-resolution investigation of genome-wide allelic imbalance in vulval neoplasia. Our sample series comprised 21 high-grade vulval intraepithelial neoplasia and 6 vulval squamous cell carcinomas, with paired non-lesional samples used to adjust for normal copy number variation. RESULTS: Overall the most common recurrent aberrations were gains at 1p and 20, with the most frequent deletions observed at 2q, 3p and 10. Copy-neutral loss of heterozygosity at 6p was a recurrent event in vulval intraepithelial neoplasia. The pattern of genetic alterations differed from the characteristic changes we previously identified in cutaneous squamous cell carcinomas. Vulval neoplasia samples did not exhibit gain at 5p, a frequent recurrent aberration in a series of cervical tumours analysed elsewhere using an identical protocol. CONCLUSION: This series of 27 vulval samples comprises the largest systematic genome-wide analysis of vulval neoplasia performed to date. Despite shared papillomavirus status and regional proximity, our data suggest that the frequency of certain genetic alterations may differ in vulval and cervical tumours.

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Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia‐inducible transcription factor 1α/vascular endothelial growth factor–mediated pathway in immunodeficient mice

Rey¹,

Izquierdo²,

Caja³

et al. 2009

Arthritis & Rheumatism

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Objective. Hyperplasia and phenotypic changes in fibroblasts are often observed in chronic inflammatory lesions, and yet the autonomous pathogenic contribution of these changes is uncertain. The purpose of this study was to analyze the intrinsic ability of fibroblasts from chronically inflamed synovial tissue to drive cell recruitment and angiogenesis.Methods. Fibroblasts from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), as well as fibroblasts from healthy synovial tissue and healthy skin, were cultured and subcutaneously engrafted into immunodeficient mice. Cell infiltration and angiogenesis were analyzed in the grafts by immunohistochemical studies. The role of vascular endothelial growth factor (VEGF), CXCL12, and hypoxia-inducible transcription factor 1␣ (HIF-1␣) in these processes was investigated using specific antagonists or small interfering RNA (siRNA)-mediated down-regulation of HIF-1␣ in fibroblasts.Results. Inflammatory (OA and RA) synovial fibroblasts, compared with healthy dermal or synovial tissue fibroblasts, induced a significant enhancement in myeloid cell infiltration and angiogenesis in immunodeficient mice. These activities were associated with increased constitutive and hypoxia-induced expression of VEGF, but not CXCL12, in inflammatory fibroblasts compared with healthy fibroblasts. VEGF and CXCL12 antagonists significantly reduced myeloid cell infiltration and angiogenesis. Furthermore, targeting of HIF-1␣ expression by siRNA or of HIF-1␣ transcriptional activity by the small molecule chetomin in RA fibroblasts significantly reduced both responses.Conclusion. These results demonstrate that chronic synovial inflammation is associated with stable fibroblast changes that, under hypoxic conditions, are sufficient to induce inflammatory cell recruitment and angiogenesis, both of which are processes relevant to the perpetuation of chronic inflammation.Fibroblasts are ubiquitous mesenchymal cells with vital functions during development and adulthood. They synthesize the extracellular matrix components of connective tissues needed for homeostasis and reparative responses. During development, interactions between mesenchymal and other cell lineages are necessary for the formation of many organs, and fibroblasts are sufficient to provide the positional cues required for the induction and development of the different tissues (1,2). In the adult, multiple evidence points to specialized fibroblasts as a major force in the regulation of cell homing, migration, and differentiation of highly dynamic cell populations, such as cells of the immune system or the bone marrow (3,4). With regard to the pathologic

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Genetic abnormalities and HPV status in cervical and vulvar squamous cell carcinomas

Cited by 55 publications

References 26 publications

An Integrative Approach Uncovers Biomarkers that Associate with Clinically Relevant Disease Outcomes in Vulvar Carcinoma

An Integrative Approach Uncovers Biomarkers that Associate with Clinically Relevant Disease Outcomes in Vulvar Carcinoma

High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia

Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia‐inducible transcription factor 1α/vascular endothelial growth factor–mediated pathway in immunodeficient mice

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