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

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          Abstract

          Background:

          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.

          Methods:

          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.

          Results:

          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%).

          Conclusion:

          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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          Most cited references32

          • Record: found
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          PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

          J. Li, C. Yen, D Liaw … (1997)
          Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.
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            Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up.

            Ian Ellis, Robert Elston (1991)
            Morphological assessment of the degree of differentiation has been shown in numerous studies to provide useful prognostic information in breast cancer, but until recently histological grading has not been accepted as a routine procedure, mainly because of perceived problems with reproducibility and consistency. In the Nottingham/Tenovus Primary Breast Cancer Study the most commonly used method, described by Bloom & Richardson, has been modified in order to make the criteria more objective. The revised technique involves semiquantitative evaluation of three morphological features--the percentage of tubule formation, the degree of nuclear pleomorphism and an accurate mitotic count using a defined field area. A numerical scoring system is used and the overall grade is derived from a summation of individual scores for the three variables: three grades of differentiation are used. Since 1973, over 2200 patients with primary operable breast cancer have been entered into a study of multiple prognostic factors. Histological grade, assessed in 1831 patients, shows a very strong correlation with prognosis; patients with grade I tumours have a significantly better survival than those with grade II and III tumours (P less than 0.0001). These results demonstrate that this method for histological grading provides important prognostic information and, if the grading protocol is followed consistently, reproducible results can be obtained. Histological grade forms part of the multifactorial Nottingham prognostic index, together with tumour size and lymph node stage, which is used to stratify individual patients for appropriate therapy.
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              Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer.

              Pierre Laurent-Puig, Anne Cayre, Gilles Manceau … (2009)
              The occurrence of KRAS mutation is predictive of nonresponse and shorter survival in patients treated by anti-epidermal growth factor receptor (anti-EGFR) antibody for metastatic colorectal cancer (mCRC), leading the European Medicine Agency to limit its use to patients with wild-type KRAS tumors. However, only half of these patients will benefit from treatment, suggesting the need to identify additional biomarkers for cetuximab-based treatment efficacy. We retrospectively collected tumors from 173 patients with mCRC. All but one patient received a cetuximab-based regimen as second-line or greater therapy. KRAS and BRAF status were assessed by allelic discrimination. EGFR amplification was assessed by chromogenic in situ hybridization and fluorescent in situ hybridization, and the expression of PTEN was assessed by immunochemistry. In patients with KRAS wild-type tumors (n = 116), BRAF mutations (n = 5) were weakly associated with lack of response (P = .063) but were strongly associated with shorter progression-free survival (P < .001) and shorter overall survival (OS; P < .001). A high EGFR polysomy or an EGFR amplification was found in 17.7% of the patients and was associated with response (P = .015). PTEN null expression was found in 19.9% of the patients and was associated with shorter OS (P = .013). In multivariate analysis, BRAF mutation and PTEN expression status were associated with OS. BRAF status, EGFR amplification, and cytoplasmic expression of PTEN were associated with outcome measures in KRAS wild-type patients treated with a cetuximab-based regimen. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Cancer
                Journal ID (iso-abbrev): Br. J. Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Print): 14 February 2012
                Publication date (Electronic): 12 January 2012
                Volume: 106
                Issue: 4
                Pages: 719-726
                Affiliations
                [1 ]Department of Oral and Maxillofacial Surgery, University of Regensburg , Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
                [2 ]Department of Pathology, University of Regensburg , Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
                [3 ]Department of Pathology, University of Erlangen-Nuremberg , Krankenhausstraße 12, 91054 Erlangen, Germany
                [4 ]Department of Otorhinolaryngology, University of Erlangen-Nuremberg , Waldstraße 1, 91054 Erlangen, Germany
                [5 ]Department of Otorhinolaryngology, University of Regensburg , Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
                [6 ]Department of Gynecology and Obstetrics, University of Regensburg , Landshuter Straße 65, 93053 Regensburg, Germany
                Author notes
                [7]

                These authors equally contributed to the results of this work.

                Article
                Publisher Item ID: bjc2011605
                DOI: 10.1038/bjc.2011.605
                PMC ID: 3282188
                PubMed ID: 22240798
                SO-VID: 322f42fd-03c8-4d1e-baa5-6972d6a706d3
                Copyright © Copyright © 2012 Cancer Research UK
                History
                Date received : 05 July 2011
                Date revision received : 02 December 2011
                Date accepted : 21 December 2011
                Categories
                Subject: Molecular Diagnostics

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: deletion,salivary gland cancer,pten,egfr her2,prognosis
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: deletion, salivary gland cancer, pten, egfr her2, prognosis

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