Loss of PTEN is associated with elevated EGFR and HER2 expression and worse prognosis in salivary gland cancer.

Department of Oral and Maxillofacial Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
British Journal of Cancer (Impact Factor: 5.08). 02/2012; 106(4):719-26. DOI: 10.1038/bjc.2011.605
Source: PubMed

ABSTRACT Activity of the tumour-suppressor gene PTEN is reduced in different types of cancer and implicates non-responsiveness to targeted therapy. This study evaluates the gene and protein status of PTEN in salivary gland carcinomas.
A total of 287 carcinomas of the major and minor salivary glands were investigated for phosphatase and tensin homologue located on chromosome 10 (PTEN) deletion and loss of PTEN expression using fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC), respectively. Results were correlated to clinicopathological parameters, long-term survival, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) (IHC and FISH) status of the tumours.
Hemizygous deletions of PTEN were found in 35 out of 232 (15.1%) carcinomas, while homozygous deletions were observed in 17 out of 232 (7.3%) tumours. Phosphatase and tensin homologue located on chromosome 10 deletion was common in certain histological subtypes and especially homozygous deletion was associated with high-grade malignancy, lymph node metastases and unfavourable long-term prognosis (P<0.001). Loss of PTEN expression was present in 59 out of 273 (21.6%) carcinomas and was significantly correlated to genomic PTEN deletion, high-grade malignancy (P<0.001), increased tumour size (P=0.036), lymph node metastases (P=0.007) and worse disease-specific survival (P=0.002). Genomic PTEN deletion, in particular homogenous deletion (P<0.001) predominantly occurred in tumours with increased gene copy number of EGFR (60.0%) and/or amplification of HER2 (63.6%). Loss of PTEN expression was frequently found in tumours overexpressing EGFR (28.6%) and/or HER2 (52.6%).
PTEN function is reduced in different types of salivary gland cancer indicating unfavourable prognosis. Its association with EGFR and HER2 signalling might affect targeted therapy.

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    ABSTRACT: IMPORTANCE Several recent US studies have documented racial disparities in head and neck cancer outcomes, but few have investigated racial and ethnic differences in salivary gland cancer (SGCA) survival. OBJECTIVE To determine whether patient race or ethnicity affects SGCA survival. DESIGN, SETTING, AND PARTICIPANTS Retrospective survival analysis of all patients with SGCA from 1988 through 2010 in the Surveillance, Epidemiology, and End Results database. MAIN OUTCOMES AND MEASURES Disease-specific survival according to race and ethnicity. End points assessed included age at diagnosis, sex, tumor grade, tumor size at diagnosis, extension at diagnosis, lymph node involvement at diagnosis, and treatment. Results were further analyzed by histologic subtype of SGCA. RESULTS Of 11 007 patients with SGCA, 1073 (9.7%) were black, and 1068 (9.7%), Hispanic. Whites' mean age at diagnosis was 63 years vs 53 and 52 years for blacks and Hispanics, respectively (P < .001). Twenty-year disease-specific survival rates for all SGCA histologic subtypes combined for whites, blacks, and Hispanics were 78%, 79%, and 81%, respectively. Unadjusted survival curves showed no significant difference between blacks and whites and an apparent advantage for Hispanics. However, multivariable Cox regression models controlling for patient, tumor, and treatment characteristics showed poorer disease-specific survival vs whites for blacks (hazard ratio [HR], 1.22 [95% CI, 1.03-1.46]; P = .03) but not for Hispanics (HR, 0.97 [0.79-1.19]; P = .77). The overall disease-specific survival disparity was due to poorer disease-specific survival for blacks vs whites with mucoepidermoid (P = .03) and squamous cell carcinomas (P = .05). Less surgical treatment for blacks than whites (57.26% vs 76.94%; P < .001) was a source of the survival disparity for squamous cell but not mucoepidermoid SGCA. CONCLUSIONS AND RELEVANCE Black race is a risk factor for poorer disease-specific survival for patients with mucoepidermoid or squamous cell carcinoma, whereas Hispanic ethnicity has no effect. Differing treatment between black and white patients affects survival in squamous cell but not mucoepidermoid SGCA. Differences in chemotherapy treatment, comorbidities, socioeconomic status, tumor genetic factors, and environmental exposures are potential but unproven additional sources of the racial survival disparities for mucoepidermoid and squamous cell SGCA.
    JAMA otolaryngology-- head & neck surgery. 04/2014; 140(6).
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    ABSTRACT: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the proliferating antigen Ki67 have been widely studied in several tumors. However, their role as indicator in non-small cell lung cancer (NSCLC) remains unknown. Here, we investigated the expression of PTEN and Ki67 in NSCLC tissues and paired normal lung tissues to identify whether these proteins are associated with lung cancer development and survival. Immunohistochemistry for PTEN and Ki67 was performed on 67 lung cancer tissues and 41 paired adjacent normal lung tissues to detect the expression of these two proteins. The expression of PTEN in NSCLC tissues (32.8%) was significantly lower than that in normal tissues (82.9%, P < 0.05). In contrast, the expression of Ki67 in NSCLC tissues (76.1%) was significantly higher than that in normal tissues (27.3%, P < 0.05). Expression of both PTEN and Ki67 were strongly associated with tumor histology, clinical stage, lymph node metastasis, differentiation and 4-year postoperative survival rate (P < 0.05). However, PTEN expression was negatively correlated with Ki67 expression (r = -0.279, P < 0.05). In conclusion, low PTEN expression and Ki67 overexpression are associated with malignant invasion and lymph node metastasis of NSCLC. These proteins may serve as diagnostic and prognostic biomarkers of NSCLC.
    Journal of biomedical research. 11/2014; 28(6):462-467.
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    ABSTRACT: Background Salivary duct carcinoma (SDC) is a highly aggressive subtype of salivary gland cancers and there is no established standard therapy for this disease. Thus, development of molecular markers for SDC will be important to guide the diagnosis and therapy of this aggressive tumor.Methods We performed next-generation sequencing using the Ion Torrent AmpliSeq cancer panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes, and we analyzed copy number variations (CNVs) of 21 genes by NanoString nCounter for 37 patients with SDC. Fluorescent in situ hybridization was also conducted to confirm ERBB2 gene amplification. Clinical records and tumor histopathology of the patients were retrospectively reviewed.ResultsGenetic alterations were detected in 29 of 37 (78.3%) tumors, including mutations in PIK3CA (N¿=¿9, 24.3%), ERBB2 (N¿=¿4, 10.8%), and EGFR (N¿=¿4, 10.8%). To our knowledge, this is the first time that ERBB2 mutations have been reported in this tumor type. Both PIK3CA and ERBB2 mutation status were associated with poor overall survival, but without statistical significance. ERBB2 amplification was strong and common in SDC and almost all cases also exhibited EGFR and ERBB3 amplifications.Conclusions This study reports the largest and most comprehensive analysis of DNA aberrations in SDC. Our results show that PIK3CA and/or ERBB2 alterations in the development of SDC might be a useful diagnostic tool and could serve as a potential therapeutic target.
    Journal of Translational Medicine 10/2014; 12(1):299. · 3.99 Impact Factor

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