Showing papers by "Jochen Hess published in 2013"

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Abstract: High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs.

Identification of oropharyngeal squamous cell carcinomas with active HPV16 involvement by immunohistochemical analysis of the retinoblastoma protein pathway.

Abstract: Viral oncogene RNA expression is regarded as reliable biomarker to identify oropharyngeal squamous cell carcinomas (OPSCC) with active HPV16 involvement. This study addressed whether the expression profile of the cellular proteins p16INK4a, pRb, Cyclin D1 and p53 provide surrogate marker combinations that identify OPSCC with active HPV16 in situations where only formalin-fixed biopsies are available. Protein expression was analyzed by immunohistochemistry on tissue microarrays created from 188 OPSCC of which the HPV16 DNA and RNA status had been established previously from snap-frozen biopsies. Associations of single markers and of marker combinations with HPV16 DNA, viral RNA expression patterns and overall survival as primary end point were evaluated by statistical analysis. Most tumors with active HPV16 involvement (RNA+ group; n = 40) showed a specific protein pattern, that is, high p16INK4a (80%), low pRb (85%), low Cyclin D1 (95%) and normal p53 (73%). This pattern was significantly different from the pattern observed in HPV DNA-negative tumors (HPV– group) and in HPV16 DNA-positive tumors lacking viral RNA expression patterns (RNA– group). The combination of high p16INK4a and low pRb levels was distinctly superior to p16INK4a alone; it was strongly associated with RNA+ tumors (OR 41.4, 95%CI 10.7–162.5), with improved survival (HR 0.37, 95%CI 0.2–0.8) and had best predictive values (78% sensitivity, 93% specificity, 78% PPV, 93% NPV). In conclusion, if only formalin-fixed biopsy material is available, the marker combination high p16INK4a/low pRb is well suited to identify OPSCC with biologically active HPV16 which represent a distinct OPSCC entity with improved prognosis.

Submaxillary gland androgen-regulated protein 3A expression is an unfavorable risk factor for the survival of oropharyngeal squamous cell carcinoma patients after surgery.

Abstract: Recently, increased expression of the submaxillary gland androgen-regulated protein 3A (SMR3A) was found in recurrent tumors of an orthotopic floor-of-mouth mouse tumor model after surgery. However, SMR3A expression in the pathogenesis of human malignancy and its correlation with the clinical outcome have not been addressed so far. We analyzed tissue microarrays with specimens from oropharyngeal squamous cell carcinoma (OPSCC) patients (n = 157) by immunohistochemistry and compared SMR3A expression with clinical and pathological features by statistical analysis. Strong SMR3A expression was found in almost 36 % of all primary OPSCCs. Although, SMR3A protein levels were not associated with any clinical or histopathological feature tested, univariate Kaplan-Meier analysis revealed a significant correlation between high SMR3A protein expression and poor progression-free (p = 0.02) and overall survival (p = 0.03). Furthermore, high SMR3A expression was an independent marker for poor clinical outcome [HR (SMR3A(high) vs. SMR3(low)) = 2.32; 95 % CI = 1.03-5.23] concerning overall survival in a multivariate analysis of OPSCC patients with surgery as primary therapy (n = 100). Our data demonstrate for the first time increased SMR3A protein expression in the pathogenesis of OPSCC, which serves as an unfavorable risk factor for patient survival.

The receptor for advanced glycation end products is dispensable in a mouse model of oral and esophageal carcinogenesis.

Abstract: Aberrant expression of the receptor for advanced glycation end products (RAGE) and its ligands, such as S100/Calgranulins, has been demonstrated in squamous cell carcinomas of the upper aerodigestive tract. However, the question whether RAGE signaling is causally linked with neoplastic transformation of keratinocytes in mucosal epithelia has not been addressed so far. We used the well-established mouse model of 4-nitroquinoline-1-oxide (4-NQO) induced tumorigenesis to investigate tumor development in control and RAGE-deficient (Rage(-/-)) animals. Although 4-NQO induced lesions of the tongue and the esophagus showed strong induction of the RAGE ligands S100a8 and S100a9, we did not observe any significant difference in tumor incidence or multiplicity between control and Rage(-/-) mice. Furthermore, detailed analysis of tumor sections by histological and immunohistochemical staining revealed no difference in either the size or histological architecture of dysplastic lesions, tumor cell proliferation, or the number of inflammatory immune cells in the tumor microenvironment. Finally, we detected induced transcript and protein levels of the Toll-like receptor 4 (Tlr4) in 4-NQO induced lesions, suggesting that signaling via the S100-Tlr4 axis may compensate for the lack of RAGE in early stages of tumor development. Our data demonstrate that RAGE is dispensable in the onset of genotoxic induced oral and esophageal squamous cell carcinoma and provide evidence for an alternative pathway of S100-Calgranulin signaling via Tlr4.