3q26‐29 Amplification in head and neck squamous cell carcinoma: a review of established and prospective oncogenes

Davidson, Matthew; Shanks, Emma

doi:10.1111/febs.14061

Cited by 18 publications

(17 citation statements)

References 232 publications

(217 reference statements)

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“…This protein modulates cell polarization, adhesion, and migration in tumor-derived cells and is strongly associated with cancer metastasis and the expression of oncogenic factors that include KRAS, MYC, and MDR1 [33]. Upregulation of IGF2BP2 is associated with HNSCC [34]. ZNF829 hypermethylation is associated with colorectal cancer [35].…”

Section: Discussionmentioning

confidence: 99%

Epigenomic dysregulation-mediated alterations of key biological pathways and tumor immune evasion are hallmarks of gingivo-buccal oral cancer

et al. 2019

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Background: Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the most common cancer among men in India and is associated with high mortality. Although OSCC-GB is known to be quite different from tongue cancer in its genomic presentation and its clinical behavior, it is treated identically as tongue cancer. Predictive markers of prognosis and therapy that are specific to OSCC-GB are, therefore, required. Although genomic drivers of OSCC-GB have been identified by whole exome and whole genome sequencing, no epigenome-wide study has been conducted in OSCC-GB; our study has filled this gap, and has discovered and validated epigenomic hallmarks of gingivobuccal oral cancer. Methods: We have carried out integrative analysis of epigenomic (n = 87) and transcriptomic (n = 72) profiles of paired tumor-normal tissues collected from OSCC-GB patients from India. Genome-wide DNA methylation assays and RNA-sequencing were performed on high-throughput platforms (Illumina) using a half-sample of randomly selected patients to discover significantly differentially methylated probes (DMPs), which were validated on the remaining half-sample of patients. Results: About 200 genes showed significant inverse correlation between promoter methylation and expression, of which the most significant genes included genes that act as transcription factors and genes associated with other cancer types. Novel findings of this study include identification of (a) potential immunosuppressive effect in OSCC-GB due to significant promoter hypomethylation driven upregulation of CD274 and CD80, (b) significant dysregulation by epigenetic modification of DNMT3B (upregulation) and TET1 (downregulation); and (c) known drugs that can reverse the direction of dysregulation of gene expression caused by promoter methylation. Conclusions: In OSCC-GB patients, there are significant alterations in expression of key genes that (a) regulate normal cell division by maintenance of balanced DNA methylation and transcription process, (b) maintain normal physiological signaling (PPAR, B cell receptor) and metabolism (arachidonic acid) pathways, and (c) provide immune protection against antigens, including tumor cells. These findings indicate novel therapeutic targets, including immunotherapeutic, for treatment of OSCC-GB.

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Section: Discussionmentioning

confidence: 99%

Epigenomic dysregulation-mediated alterations of key biological pathways and tumor immune evasion are hallmarks of gingivo-buccal oral cancer

et al. 2019

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“…This particular amplicon is estimated to occur in greater than 20% of all human cancers [48], with amplification rates as high as 75% in invasive lung SCC [75], and between 25 and 30% in ovarian cancer [51,76,77]. In addition to lung SCC and ovarian cancer, 3q26 amplification has been documented in esophageal SCC, head and neck SCC, and cervical cancer [49,50,[78][79][80]. The most widely studied genes within 3q26 include SOX2, PRKCI, ECT2, and PIK3CA, and these genes work together to promote carcinogenesis [80].…”

Section: Discussionmentioning

confidence: 99%

“…Both Sox2 and ST6Gal-I play causal roles in promoting CSC characteristics [9,25,47]. Interestingly, the SOX2 and ST6GAL1 genes lie within the same amplicon, referred to as "3q26", which spans from 3q26-3q29 [48][49][50]. The 3q26 amplicon is one of the most commonly amplified genomic regions across many cancer types, and it functions as a multigenic driver of human cancer [48].…”

Section: Introductionmentioning

confidence: 99%

Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells

et al. 2019

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Background: The ST6Gal-I glycosyltransferase, which adds α2-6-linked sialic acids to N-glycosylated proteins is upregulated in a wide range of malignancies including ovarian cancer. Prior studies have shown that ST6Gal-Imediated sialylation of select surface receptors remodels intracellular signaling to impart cancer stem cell (CSC) characteristics. However, the mechanisms that contribute to ST6Gal-I expression in stem-like cancer cells are poorly understood. Results: Herein, we identify the master stem cell transcription factor, Sox2, as a novel regulator of ST6Gal-I expression. Interestingly, SOX2 and ST6GAL1 are located within the same tumor-associated amplicon, 3q26, and these two genes exhibit coordinate gains in copy number across multiple cancers including~25% of ovarian serious adenocarcinomas. In conjunction with genetic co-amplification, our studies suggest that Sox2 directly binds the ST6GAL1 promoter to drive transcription. ST6Gal-I expression is directed by at least four distinct promoters, and we identified the P3 promoter as the predominant promoter utilized by ovarian cancer cells. Chromatin Immunoprecipitation (ChIP) assays revealed that Sox2 binds regions proximal to the P3 promoter. To confirm that Sox2 regulates ST6Gal-I expression, Sox2 was either overexpressed or knocked-down in various ovarian cancer cell lines. Sox2 overexpression induced an increase in ST6Gal-I mRNA and protein, as well as surface α2-6 sialylation, whereas Sox2 knock-down suppressed levels of ST6Gal-I mRNA, protein and surface α2-6 sialylation. Conclusions: These data suggest a process whereby SOX2 and ST6GAL1 are coordinately amplified in cancer cells, with the Sox2 protein then binding the ST6GAL1 promoter to further augment ST6Gal-I expression. Our collective results provide new insight into mechanisms that upregulate ST6Gal-I expression in ovarian cancer cells, and also point to the possibility that some of the CSC characteristics commonly attributed to Sox2 may, in part, be mediated through the sialyltransferase activity of ST6Gal-I.

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“…These results are in agreement with the TCGA data obtained from 279 HNSCC patients [44] using the platform cBioPortal for Cancer Genomics () [45] (Supplementary Figure S3). It has been extensively demonstrated (both experimentally and in silico) that 3q26 amplicon harbors numerous genes found to be frequently and concomitantly co-amplified and overexpressed in multiple cancers [46,47]. Various genes have been highlighted as highly significant oncogenic drivers for HNSCC survival [46], including the four known driver genes PIK3CA, PRKCI, SOX2 and TP63 .…”

Section: Discussionmentioning

confidence: 99%

“…It has been extensively demonstrated (both experimentally and in silico) that 3q26 amplicon harbors numerous genes found to be frequently and concomitantly co-amplified and overexpressed in multiple cancers [46,47]. Various genes have been highlighted as highly significant oncogenic drivers for HNSCC survival [46], including the four known driver genes PIK3CA, PRKCI, SOX2 and TP63 . In silico analysis of TCGA HNSCC data included in Supplementary Figure S4 further illustrates that co-amplification of these four genes occurs frequently in HNSCC, thus showing that 3q26 amplification in HNSCC is not restricted to the SOX2 gene.…”

Section: Discussionmentioning

confidence: 99%

The Novel Role of SOX2 as an Early Predictor of Cancer Risk in Patients with Laryngeal Precancerous Lesions

Granda-Díaz

Menéndez

Pedregal‐Mallo

et al. 2019

Cancers

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The SOX2 gene located at 3q26 is frequently amplified and overexpressed in multiple cancers, including head and neck squamous cell carcinomas (HNSCC). The tumor-promoting activity and involvement of SOX2 in tumor progression has been extensively demonstrated, thereby emerging as a promising therapeutic target. However, the role of SOX2 in early stages of tumorigenesis and its possible contribution to malignant transformation remain unexplored. This study investigates for the first time SOX2 protein expression by immunohistochemistry and gene amplification by real-time PCR using a large series of 94 laryngeal precancerous lesions. Correlations with the histopathological classification and the risk of progression to invasive carcinoma were established. Nuclear SOX2 expression was frequently detected in 38 (40%) laryngeal dysplasias, whereas stromal cells and normal adjacent epithelia showed negative expression. SOX2 gene amplification was detected in 18 (33%) of 55 laryngeal dysplasias. Univariate Cox analysis showed that SOX2 gene amplification (p = 0.046) and protein expression (p < 0.001) but not histological grading (p = 0.432) were significantly associated with laryngeal cancer risk. In multivariate stepwise analysis including age, tobacco, histology, SOX2 gene amplification and SOX2 expression, SOX2 expression (HR = 3.531, 95% CI 1.144 to 10.904; p = 0.028) was the only significant independent predictor of laryngeal cancer development. These findings underscore the relevant role of SOX2 in early tumorigenesis and a novel clinical application of SOX2 expression as independent predictor of laryngeal cancer risk in patients with precancerous lesions beyond current WHO histological grading. Therefore, targeting SOX2 could lead to effective strategies for both cancer prevention and treatment.

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3q26‐29 Amplification in head and neck squamous cell carcinoma: a review of established and prospective oncogenes

Cited by 18 publications

References 232 publications

Epigenomic dysregulation-mediated alterations of key biological pathways and tumor immune evasion are hallmarks of gingivo-buccal oral cancer

Epigenomic dysregulation-mediated alterations of key biological pathways and tumor immune evasion are hallmarks of gingivo-buccal oral cancer

Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells

The Novel Role of SOX2 as an Early Predictor of Cancer Risk in Patients with Laryngeal Precancerous Lesions

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