FGFR1 as a novel prognostic and predictive biomarker in squamous cell cancers of the lung and the head and neck area.
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ABSTRACT:
SUBMITTER: von Massenhausen A
PROVIDER: S-EPMC4200677 | biostudies-literature | 2013 Oct
REPOSITORIES: biostudies-literature
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FGFR1 as a novel prognostic and predictive biomarker in squamous cell cancers of the lung and the head and neck area.
von Mässenhausen Anne A Franzen Alina A Heasley Lynn L Perner Sven S
Annals of translational medicine 20131001 3
FGFR1 amplification is a genomic aberration recently identified in various types of cancer. Especially squamous cell carcinomas of the lung and the head and neck show this genetic alteration in high frequencies. In these cancers FGFR1 is not only a therapeutic target but does also serve as a biomarker that correlates with parameters of worse outcome. However, since FGFR1 amplification does not always correlate with high protein expression defining the best predictive biomarker for a FGFR1 target ...[more]
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Project description:PURPOSE:FGFR1 copy-number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors, and patient-derived xenografts (PDX) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398. EXPERIMENTAL DESIGN:FGFR1 status, expression levels, and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n = 353) were assessed for FGFR1 CNG and mRNA levels, and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n = 39) were submitted to FGFR1 copy-number detection and mRNA assays to identify putative FGFR1-dependent tumors. RESULTS:Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. Thirty-one percent of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The nonamplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398. CONCLUSIONS:FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts tyrosine kinase inhibitor sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering from HNSCC.
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Project description:The differential diagnosis between head & neck squamous cell carcinomas and lung squamous cell carcinomas is often unresolved because the histologic appearance of these two tumor types is similar. In the development of a gene expression profile test (GEP-HN-LS) that distinguishes these 2 cancer types, a collection of poorly differentiated primary and metastatic tumor specimens were used. Here we describe 76 such tumor specimens that were used for validation of GEP-HN-LS. The specimens are either head & neck squamous cell carcinomas or lung squamous cell carcinomas.
2013-03-10 | GSE44170 | GEO
Project description:The differential diagnosis between head & neck squamous cell carcinomas and lung squamous cell carcinomas is often unresolved because the histologic appearance of these two tumor types is similar. In the development of a gene expression profile test (GEP-HN-LS) that distinguishes these 2 cancer types, a collection of poorly differentiated primary and metastatic tumor specimens were used. Here we describe 76 such tumor specimens that were used for validation of GEP-HN-LS. The specimens are either head & neck squamous cell carcinomas or lung squamous cell carcinomas. All tissue specimens were formalin fixed paraffin embedded specimens. Gene expression was profiled using Affymetrix GeneChip platform.
2013-03-10 | E-GEOD-44170 | biostudies-arrayexpress
Project description:BackgroundThe differential diagnosis between metastatic head & neck squamous cell carcinomas (HNSCC) and lung squamous cell carcinomas (lung SCC) is often unresolved because the histologic appearance of these two tumor types is similar. We have developed and validated a gene expression profile test (GEP-HN-LS) that distinguishes HNSCC and lung SCC in formalin-fixed, paraffin-embedded (FFPE) specimens using a 2160-gene classification model.MethodsThe test was validated in a blinded study using a pre-specified algorithm and microarray data files for 76 metastatic or poorly-differentiated primary tumors with a known HNSCC or lung SCC diagnosis.ResultsThe study met the primary Bayesian statistical endpoint for acceptance. Measures of test performance include overall agreement with the known diagnosis of 82.9% (95% CI, 72.5% to 90.6%), an area under the ROC curve (AUC) of 0.91 and a diagnostics odds ratio (DOR) of 23.6. HNSCC (N = 38) gave an agreement with the known diagnosis of 81.6% and lung SCC (N = 38) gave an agreement of 84.2%. Reproducibility in test results between three laboratories had a concordance of 91.7%.ConclusionGEP-HN-LS can aid in resolving the important differential diagnosis between HNSCC and lung SCC tumors.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1753227817890930.
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Project description:The PD-1 receptor and its ligands PD-L1 and PD-L2 are known to be significantly involved in T-cell regulation. Recent studies suggest that PD-L1 expression in malignant tumors contributes to an immunosuppressive microenvironment and disruption of antitumoral immune response. Drugs targeting this pathway are already tested in clinical trials against several tumor entities with promising results. However, until now comprehensive data with regard to PD-L1 and PD-L2 expression in head and neck squamous cell carcinoma (HNSCC) is still lacking.We assessed PD-L1 and PD-L2 expression via immunohistochemistry in two independent cohorts of 293 HNSCC patients.A significant subset of HNSCC showed high expression levels of PD-L1. Most remarkable, we detected a strong correlation between PD-L1 expression and overall survival time in both HNSCC cohorts. Further, in multivariate cox proportional hazard models, PD-L1 dominates as the strongest prognostic factor of patient's outcome in HNSCC, leaving even tumor stage and distant metastasis behind. Moreover, strong PD-L1 expression was associated with the presence of distant metastases in a subset of cases.In summary, while the significance of PD-L2 in HNSCC seems to minor, we show that PD-L1 expression is common in HNSCC and, more importantly, a both robust and strong prognostic biomarker. In this respect, our results provide hints on further application of therapies targeting the PD-1/PD-L1 pathway in HNSCC. Investigation of response and outcome of patients receiving anti-PD-1/PD-L1 containing therapies in correlation with PD-L1 expression analysis should be an important task for the future.In spite of improved treatment options and increasing knowledge of molecular alterations in HNSCC, the survival rate has not been dramatically changed in the past decades. Pies are missing in HNSCC. One promising candidate in cancer immune therapy is PD-L1. Drugs targeting PD-L1 or its receptor PD-1 are subject of several clinical studies in different cancer entities. However, comprehensive data about PD-L1 expression in HNSCC and therefore a rational basis for anti PD-L1/PD-1 therapy in HNSCC is lacking. Here, we provide wide-ranging data about PD-L1 expression in HNSCC of all major localizations. We observed a strong correlation between expression of PD-L1 and reduced overall survival time. Furthermore, high PD-L1 expression was identified as a strong prognostic factor of patient's outcome when verified together with recognized prognostic factors.
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Project description:PurposeIt is of obvious interest to identify clinical prognosis-related oncogenes in HNSCC (head and neck squamous cell carcinoma).MethodsBased on the available datasets within the TCGA (The Cancer Genome Atlas) and the GEO (Gene Expression Omnibus) databases, the potential mechanism of action of the SEC61G (SEC61 translocon subunit gamma) gene in HNSCC tumorigenesis was explored by several bioinformatics approaches.ResultsThere was a higher expression level of SEC61G in primary HNSCC tumor tissues than in normal tissues. Moreover, highly expressed SEC61G was statistically associated with the poor survival prognosis of HNSCC patients. When HPV (human papilloma virus) was considered, we also observed a relatively lower proportion of "arm-level gain" and "high amplification" types of CNA (copy-number alteration) in the HNSCC-HPV (+) group than in the HNSCC-HPV (-) group. Additionally, we identified SEC61G CAN-correlated genes, such as CCT6A (chaperonin-containing TCP1 subunit 6A) and HUS1 (HUS1 checkpoint clamp component), and found a correlation between SEC61G copy-number segments and prognosis related to overall and progression-free survival intervals of HNSCC patients. Moreover, the molecular regulation mechanisms of the spliceosome, ribosome, proteasome degradation, cell adhesion, and immune infiltration of B and CD8+ T cells may contribute to the involvement of SEC61G in the pathogenesis of HNSCC.ConclusionsThe SEC61G gene was identified for the first time as a prognostic biomarker of HNSCC. The detailed underlying mechanism merits further research.
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Project description:Runt-related transcription factors regulate many developmental processes such as proliferation and differentiation. In this study, the function of the runt-related transcription factor 1 (RUNX1) was investigated in head and neck squamous cell carcinoma (HNSCC). Our results show that RUNX1 expression was elevated in HNSCC patients, which was greatly correlated with the N stage, tumor size, and American Joint Committee on Cancer stage. Cox proportional hazard models showed that RUNX1 could be used as a prognostic indicator for the overall survival of HNSCC patients (hazard ratio, 5.572; 95% confidence interval, 1.860-9.963; P < 0.001). Moreover, suppression of RUNX1 inhibited HNSCC cell proliferation, migration, and invasion. Using the HNSCC xenograft nude mouse model, we found that the shRUNX1-transfected tumor (sh-RUNX1) was significantly smaller both in size and weight than the control vector-transfected tumor (sh-Control). In conclusion, our results show that the elevated RUNX1 expression was correlated with tumor growth and metastasis in HNSCC, indicating that RUNX1 could be used as a biomarker for tumor recurrence and prognosis.
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Project description:Background: Head and neck squamous carcinoma (HNSC) poses a major threat to human life. The role of human papillomavirus (HPV) infection in the initiation and progression of HNSC is becoming more widely accepted. HPV-positive (HPV+) HNSC has shown unique responses to cancer therapies, which may be due to differences in immune cell infiltration. It is critical to determine how the immune responses to HPV in HNSC are regulated. Methods: Transcriptome data of HNSC from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database were analyzed. Then, the CIBERSORT algorithm was used to calculate immune cell infiltration in HNSC. FDCSP expression level was detected by qPCR in the HNSC tissues collected from the Nanfang Hospital. Results: Follicular dendritic cell secreted protein (FDCSP) was highly expressed in HPV+ HNSC, and higher expression of FDSCP was associated with a favorable prognosis. In HPV+ HNSC samples, FDCSP significantly increased the proportion of T follicular helper cells (TFHs). FDCSP expression was also found to be associated with TP53 mutation status in HPV+ HNSC. The function of FDCSP was intimately connected to chemokine pathways, particularly with the C-X-C motif chemokine ligand 13 (CXCL13). We verified that the high expression of FDCSP in HPV+ HNSC and higher FDCSP is closely related to prognosis in HNSC samples we collected by qPCR. Conclusions: Collectively, these findings may provide fresh evidence that FDCSP is a potential chemokine-associated prognostic biomarker in HPV+ HNSC.
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Project description:Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer. Early detection and management of HNSCC may prevent progression of the disease. Long non-coding RNAs (lncRNAs) may serve as prognostic biomarkers for various cancer types. The current study downloaded an RNA-Seq dataset containing 43 tumor-normal pairs. An independent t-test identified that the expression level of lncRNA LOC541471 was significantly increased in tumor tissues compared with healthy tissues. Additionally, the current study demonstrated that high lncRNA LOC541471 expression was significantly associated with increasing lymph node metastasis classification and perineural invasion. A multivariate Cox regression analysis revealed that high lncRNA LOC541471 expression levels were an independent predictor for reduced overall survival (n=487) and relapse-free survival (n=355). According to the anatomic neoplasm subdivision, HNSCC samples were classified as oropharyngeal carcinoma (n=297), oral carcinoma (n=80), laryngeal carcinoma and hypopharyngeal carcinoma (n=123). A negative association was revealed between lncRNA LOC541471 expression and overall survival in all subtypes of HNSCC. Therefore, lncRNA LOC541471 is significantly negatively associated with overall survival and relapse-free survival of patients with HNSCC and may be considered a potential prognostic factor for HNSCC.
| S-EPMC6341588 | biostudies-literature