Loss of heterozygosity at 15q21.3 correlates with occurrence of metastases in head and neck cancer

Poetsch, Micaela; Kleist, Britta

doi:10.1038/modpathol.3800666

Cited by 16 publications

(10 citation statements)

References 39 publications

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“…In breast cancer, the 15q21.1 region showed allelic imbalance in 8.9% of primary tumors and in 57.6% of relapses, suggesting an association with cancer progression . Similar results were found in head and neck tumors, where LOH in chromosome 15 was detected in 54% of primary tumors and in 92% of lymph node metastases . β2m gene mutations with the loss of another gene copy due to LOH in chromosome 15 are responsible for the irreversible total loss of HLA class I expression, and this phenotype has been described in various types of malignancy, in both cell lines and tumor tissues .…”

Section: Mhc‐i Heterogeneity In Primary Tumor: Its Role In Intrinsic supporting

confidence: 71%

Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype

Garrido

Romero

Aptsiauri

et al. 2014

Intl Journal of Cancer

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Intratumor heterogeneity among cancer cells is promoted by reversible or irreversible genetic alterations and by different microenvironmental factors. There is considerable experimental evidence of the presence of a variety of malignant cell clones with a wide diversity of major histocompatibility class I (MHC-I) expression during early stages of tumor development. This variety of MHC-I phenotypes may define the evolution of a particular tumor. Loss of MHC-I molecules frequently results in immune escape of MHC-negative or -deficient tumor cells from the host T cell-mediated immune response. We review here the results obtained by our group and other researchers in animal models and humans, showing how MHC-I intratumor heterogeneity may affect local oncogenicity and metastatic progression. In particular, we summarize the data obtained in an experimental mouse cancer model of a methylcholanthrene-induced fibrosarcoma (GR9), in which isolated clones with different MHC-I expression patterns demonstrated distinct local tumor growth rates and metastatic capacities. The observed "explosion of diversity" of MHC-I phenotypes in primary tumor clones and the molecular mechanism ("hard"/irreversible or "soft"/reversible) responsible for a given MHC-I alteration might determine not only the metastatic capacity of the cells but also their response to immunotherapy. We also illustrate the generation of further MHC heterogeneity during metastatic colonization and discuss different strategies to favor tumor rejection by counteracting MHC-I loss. Finally, we highlight the role of MHC-I genes in tumor dormancy and cell cycle control.Phenotypic and functional heterogeneity among cancer cells in the same tumor, a consequence of genetic or epigenetic alterations, influences the biological behavior of tumor cell clones and their interaction with the immune system. 1,2 It would be useful to identify key factors and biomarkers for metastatic progression and for predicting the outcome of therapeutic intervention.3,4 One of these factors is tumor MHC-I expression, which is associated with T/NK-cell mediated antitumor immunity and plays an important role in the interaction between the expression of tumor suppression genes and cancer immunogenicity.5-9 MHC-I loss has been reported in up to 90% of certain types of human cancers and is a mechanism widely used by tumor cells to evade T cell-mediated recognition and destruction. 10,11 The molecular alterations underlying MHC-I loss can be divided between reversible ("soft") and irreversible structural ("hard") defects, both of which have been described in solid tumors, cancer cell lines, and metastatic lesions. The likelihood of inducing tumor rejection by the recovery of MHC-I antigens appears to be strongly influenced by the soft or hard nature of the molecular defect. 12-15The frequency and molecular mechanisms of MHC-I loss have been amply studied in various types of malignancy over recent years. Nevertheless, it has not been fully elucidated how MHC-I loss variants are generated in the prim...

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Section: Mhc‐i Heterogeneity In Primary Tumor: Its Role In Intrinsic supporting

confidence: 71%

Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype

Garrido

Romero

Aptsiauri

et al. 2014

Intl Journal of Cancer

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“…These alterations are irreversible in nature and require restoration of a wild-type functional gene. LOH in chromosome 15 has been described in various types of tumour, including melanoma and head and neck cancer [28,29], and has been reported to correlate with the risk of metastatic progression [30]. Analysing primary tumours of various histological types we found that LOH in chromosome 15 could be detected in 40% of colon and laryngeal carcinomas [31] and in 50% of bladder carcinomas (unpublished data).…”

Section: Discussionmentioning

confidence: 68%

Efficient Recovery of HLA Class I Expression in Human Tumor Cells After Beta2‐Microglobulin Gene Transfer Using Adenoviral Vector: Implications for Cancer Immunotherapy

et al. 2009

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Here we report a successful use of a non‐replicating adenovirus expressing the wild‐type human β2m gene in recovery of normal human leucocyte antigen (HLA) class I expression in β2m‐null cancer cells. Total loss of HLA class I expression in these cell lines is caused by a mutation in β2m gene and a loss of heterozygosity in chromosome 15 carrying another copy of that gene. Normal HLA class I expression on the tumour cell surface is critical for the successful outcome of cancer immunotherapy as T cells can only recognize tumour‐derived peptides in a complex with self‐HLA class I molecules. In this report we characterize the newly generated adenoviral vector AdCMVβ2m and demonstrate an efficient β2m gene transfer in tumour cell lines of different histological origin, including melanoma, prostate and colorectal carcinoma. The β2m re‐expression lasted for an extended period of time both in vitro and in vivo in human tumour xenograft transplants. We propose that in a subset of cancer patients with structural defect in β2m gene or chromosome 15, the adenoviral‐mediated recovery (or even increase) of HLA class I expression on tumour cells in combination with vaccination or adoptive T‐cell therapy can provide a complementary approach to improve the clinical efficacy of cancer immunotherapy.

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“…MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level [ 5 - 7 ] and miRNA dysregulation is frequently associated with cancer progression, including OC [ 8 - 12 ]. The microRNA miR-211 is localized on intron 6 of the Trpm1 gene at 15q13-q14, a locus that is frequently lost in neoplasms [ 13 - 16 ]. MiR-211 functions and the effect of loss-of-function have been described in normal and cancer cells and tissues.…”

Section: Introductionmentioning

confidence: 99%

miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6

et al. 2015

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BackgroundEpithelial ovarian cancer (EOC) is a significant cause of morbidity and mortality. MicroRNAs play important roles in cancer development and progression. The microRNA miR-211 is localized on intron 6 of the Trpm1 gene at 15q13-q14, a locus that is frequently lost in neoplasms. Its function and loss-of-function have been described in normal and cancer cells and tissues. miR-211 is known to be dysregulated in ovarian cancer: however, its function and the downstream effect of its loss-of-function in ovarian cancer have not been described before.MethodsWe analyzed miR-211 expression in clinical samples of primary EOC tissues compared to normal epithelial ovarian tissues and in the EOC cell lines: OVCAR3, Caov3, OVCA429, SKOV3 and A2780 compared to human ovarian surface epithelial cells. We then investigated the effect of miR-211 on EOC cell proliferation and apoptosis by counting cell numbers, MTT, colony formation, cell cycle, and PI/Annexin V staining assays. A luciferase reporter system was developed to assess miR-211 regulation of the predicted targets. Expression level of discovered targets and correlation with miR-211 expression were analyzed in EOC tissues. Finally, OVCAR3 stably expressing miR-211 or control cells were injected subcutaneously into mice to determine in vivo effect of miR-211 on tumorigenesis.ResultsWe found that the expression of miR-211 is downregulated in EOC tissues and cell lines compared to normal epithelial ovarian tissue and human ovarian surface epithelial cells, respectively. miR-211 was found to arrest cells in the G0/G1-phase, inhibit proliferation and induce apoptosis. Cyclin D1 and CDK6 were found to be direct targets of miR-211, and when overexpressed in miR-211-expressing EOC cells, could restore proliferative ability. Finally, in vitro investigation confirmed that miR-211 is a tumor suppressor that controls Cyclin D1 and CDK6 expression.ConclusionsOur results demonstrate that miR-211 is a tumor suppressor that controls expression of Cyclin D1 and CDK6, and that its downregulation results in overexpression of Cyclin D1 and CDK6 which increases proliferation ability of EOC cells to proliferate compared to normal cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0322-4) contains supplementary material, which is available to authorized users.

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Loss of heterozygosity at 15q21.3 correlates with occurrence of metastases in head and neck cancer

Cited by 16 publications

References 39 publications

Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype

Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype

Efficient Recovery of HLA Class I Expression in Human Tumor Cells After Beta2‐Microglobulin Gene Transfer Using Adenoviral Vector: Implications for Cancer Immunotherapy

miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6

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