Transcriptomic characterization of heterogeneity in paired primary and recurrent HNSCC tumors
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE186461 | GEO | 2022/04/08
REPOSITORIES: GEO
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Project description:Despite aggressive multi-modal treatment, advanced head and neck squamous cell carcinoma (HNSCC) patients are at high risk of recurrence. Matched pairs (n=38) of primary/recurrent tumors were subjected to whole exome and RNA sequencing. Mutational landscapes and genomic copy number alterations indicated diverging clonal origins in a subset of cases. Transcriptional subtyping (classical/CL, basal/BA, inflamed-mesenchymal/IMS) in primary and recurrent HNSCC (n=112) revealed more frequent CL and IMS in primary tumors with low recurrence rates and a prevalence of BA in recurrent tumors associated with p-EMT and early recurrence. 44% of matched cases underwent a subtype change from primary to recurrent tumors, preferably from IMS to BA or CL. In recurrences, HYPOXIA, P-EMT and RADIATION RESISTANCE signatures were up- and TUMOR INFLAMMATION down-regulated compared to index tumors. A therapy-induced selection of transcriptional subtypes demonstrates the importance of molecular characterization of recurrences for second-line therapy decisions to enable optimally tailored treatments.
2022-04-08 | GSE173964 | GEO
Project description:Despite aggressive multi-modal treatment, advanced head and neck squamous cell carcinoma (HNSCC) patients are at high risk of recurrence. Matched pairs (n=38) of primary/recurrent tumors were subjected to whole exome and RNA sequencing. Mutational landscapes and genomic copy number alterations indicated diverging clonal origins in a subset of cases. Transcriptional subtyping (classical/CL, basal/BA, inflamed-mesenchymal/IMS) in primary and recurrent HNSCC (n=112) revealed more frequent CL and IMS in primary tumors with low recurrence rates and a prevalence of BA in recurrent tumors associated with p-EMT and early recurrence. 44% of matched cases underwent a subtype change from primary to recurrent tumors, preferably from IMS to BA or CL. In recurrences, HYPOXIA, P-EMT and RADIATION RESISTANCE signatures were up- and TUMOR INFLAMMATION down-regulated compared to index tumors. A therapy-induced selection of transcriptional subtypes demonstrates the importance of molecular characterization of recurrences for second-line therapy decisions to enable optimally tailored treatments.
2022-04-08 | GSE173855 | GEO
Project description:Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant morbidity and mortality and frequent recurrence. Pre-NGS efforts to transcriptionally classify HNSCC into groups of varying prognosis have identified four accepted molecular subtypes of disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigated the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identified samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to atypical subtype were more resistant to bromodomain inhibitors (BETi). PRO-Seq experiments that both TCGA tumors and AT cell lines showed higher eRNA transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, HiChIP experiments suggested higher enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways were upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with high enhancer activity, resistance to BET inhibition, and signaling pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.
2022-07-20 | GSE185534 | GEO
Project description:Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant morbidity and mortality and frequent recurrence. Pre-NGS efforts to transcriptionally classify HNSCC into groups of varying prognosis have identified four accepted molecular subtypes of disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigated the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identified samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to atypical subtype were more resistant to bromodomain inhibitors (BETi). PRO-Seq experiments that both TCGA tumors and AT cell lines showed higher eRNA transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, HiChIP experiments suggested higher enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways were upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with high enhancer activity, resistance to BET inhibition, and signaling pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.
2022-07-20 | GSE185532 | GEO
Project description:Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant morbidity and mortality and frequent recurrence. Pre-NGS efforts to transcriptionally classify HNSCC into groups of varying prognosis have identified four accepted molecular subtypes of disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigated the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identified samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to atypical subtype were more resistant to bromodomain inhibitors (BETi). PRO-Seq experiments that both TCGA tumors and AT cell lines showed higher eRNA transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, HiChIP experiments suggested higher enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways were upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with high enhancer activity, resistance to BET inhibition, and signaling pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.
2022-07-20 | GSE185533 | GEO
Project description:Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant morbidity and mortality and frequent recurrence. Pre-NGS efforts to transcriptionally classify HNSCC into groups of varying prognosis have identified four accepted molecular subtypes of disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigated the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identified samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to atypical subtype were more resistant to bromodomain inhibitors (BETi). PRO-Seq experiments that both TCGA tumors and AT cell lines showed higher eRNA transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, HiChIP experiments suggested higher enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways were upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with high enhancer activity, resistance to BET inhibition, and signaling pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.
2022-07-20 | GSE185531 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE18020: Gene expression profile of N+ and N0 HNSCC GSE22055: Gene expression profile of recurrent and non-recurrent HNSCC Refer to individual Series
2010-06-10 | E-GEOD-22243 | biostudies-arrayexpress
Project description:<p>Recurrence and/or metastasis occur in more than half of patients with head and neck squamous cell carcinoma (HNSCC) and pose the greatest threats to long-term survival. The genetic alterations underlying recurrent/metastatic HNSCC are unknown. This study represents the first whole exome sequencing (WES) cohort study of patient-matched tumor pairs in recurrent or metastatic HNSCC. Synchronous lymph node metastases are genetically more similar to their paired index primary tumors than metachronous recurrent tumors are. Newly arisen mutations in recurrent or metastatic tumors, may have therapeutic implications. Several genes were found to be mutated in multiple metastatic or recurrent tumors, but not in their respective primaries, including C17orf104, ITPR3, and DDR2. DDR2 mutations have been shown to confer enhanced sensitivity to Src-family kinase (SFK) inhibitors in other malignancies. Similarly, we found HNSCC cell lines harboring endogenous and engineered DDR2 mutations to be more sensitive to the SFK inhibitor dasatinib, than those with WT DDR2. This study outlines the first compendium of somatic mutations in primary, metastatic and/or recurrent HNSCC cancers that arise in individual patients; and demonstrates how such data can be used to interrogate potential predictive/prognostic biomarkers to inform and guide personalized therapy.</p>
| phs001007 | dbGaP
Project description:Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and the human papillomavirus (HPVP+P)-driven subtype is the fastest rising in North America. Although most cases of HPV+ HNSCC respond to radiation and chemotherapy in combination with surgery, up to 20% of patients recur after primary treatment with poor prognosis. To gain insights into the mechanism of recurrence to inform patient stratification and precision treatment, we carried out RNA-seq analysis on 43 HPV+ HNSCC specimens, of which 15, including 7 recurrent tumors, were analyzed by quantitative mass spectrometry. The proteome and phosphoproteome, but not the transcriptome, were found to be distinct between the recurrent and non-recurrent tumors. Specifically, recurrent tumors featured a pro-fibrotic and immune suppressive tumor microenvironment (TME) characterized with more abundant cancer associated fibroblasts, extracellular matrix (ECM), neutrophils and suppressive myeloid cells, increased potential for epithelial-mesenchymal transition and defective T cell function, accompanied by aberrant changes in the corresponding signaling pathways. Mechanistically, kinome reprogramming played a pivotal role in mediating recurrence through regulating TME remodelling, cytoskeletal reorganization, cell adhesion, neutrophil function, and coagulation. Besides providing systems-level insights into the molecular basis of recurrence, our work led to the identification of numerous mechanism-based biomarkers and therapeutic targets that may aid future endeavours of developing prognostic biomarkers and precision medicine for recurrent HPV+ HNSCC.
2022-06-01 | PXD030343 | Pride
Project description:To look at genes/pathways differentially expressed in metastatic and primary tumor cells we performed global gene expression profiling of the 3 sets of HNSCC lines derived from primary tumors and matched metastatic sites. Illumina HT-12 v4 BeadChip arrays were used. The data suggest that HNSCC lines derived from metastatic sites exhibit phenotypes distinct from those found in cells derived from the corresponding primary tumors. Metastatic cell lines upregulated several pathways involved in stem cell self-renewal, invasion and migration, which are well known characteristics of metastatic progression. We conclude that the cell lines derived from primary patient tumors and matched metastatic sites represent a reliable model to study HNSCC metastasis.
2018-07-27 | GSE117753 | GEO