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Gene expression profiling of primary canine insulinomas and their metastases

ABSTRACT: Insulinomas (INS) are rare pancreatic endocrine tumours (PETs), arising from tumoral beta-cells from the pancreatic islets of Langerhans. Canine INS are malignant in >95% of cases. This study aims to provide further insights on molecular pathways involved in INS pathogenesis and to identify prognostic genes. Canine specific cDNA microarray representing 20,313 genes was used to analyze expression profiles in a panel of ten primary INS and ten INS metastases. Eighty-four genes were found to be significantly down-regulated in the group of metastases in comparison to the group of primary INS. From the microarray analysis it also followed that primary INS, based on their gene expression profiles, can be divided into two groups, which differ in their malignancy potential. It was also demonstrated that canine INS have both endocrine and exocrine cell features. Furthermore, the present study has revealed pancreatic lipase and chymotrypsinogen B1 as candidate genes that can be followed up in prospective studies as prognostic markers for INS. Our findings add to the current knowledge of INS pathogenesis and tumor progression, which can be used for future therapeutic and prognostic strategies, for both dogs and humans.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE32934 | GEO | 2013/01/13

SECONDARY ACCESSION(S): PRJNA146565

REPOSITORIES: GEO

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Project description:Insulinomas (INS) are rare pancreatic endocrine tumours (PETs), arising from tumoral beta-cells from the pancreatic islets of Langerhans. Canine INS are malignant in >95% of cases. This study aims to provide further insights on molecular pathways involved in INS pathogenesis and to identify prognostic genes. Canine specific cDNA microarray representing 20,313 genes was used to analyze expression profiles in a panel of ten primary INS and ten INS metastases. Eighty-four genes were found to be significantly down-regulated in the group of metastases in comparison to the group of primary INS. From the microarray analysis it also followed that primary INS, based on their gene expression profiles, can be divided into two groups, which differ in their malignancy potential. It was also demonstrated that canine INS have both endocrine and exocrine cell features. Furthermore, the present study has revealed pancreatic lipase and chymotrypsinogen B1 as candidate genes that can be followed up in prospective studies as prognostic markers for INS. Our findings add to the current knowledge of INS pathogenesis and tumor progression, which can be used for future therapeutic and prognostic strategies, for both dogs and humans. From 1993 to 2009, ten histologically confirmed primary insulinomas (INS) and their accompanying metastases were obtained from dogs that were presented at the Department of Clinical Sciences of Companion Animals of the Faculty of Veterinary Medicine of Utrecht University. Tumors were resected by experienced surgeons, and fragments (5-15 mm diameter) for RNA extraction were carefully removed from the central portion of the tumors to avoid contamination with normal adjacent tissue. Tissue specimens collected for RNA isolation were snap-frozen in liquid nitrogen immediately after surgical removal and stored at 70oC. Various clinical and pathological parameters were evaluated retrospectively for the dogs included in this study. Half of both the primary insulinoma samples, as well as half of the metastasis samples was labelled with Cy3, while the other half of both groups was labelled with Cy5. A common reference cRNA pool consisting of equal quantity of cRNA from all 20 tumor samples was used to hybridize against each sample on the array.

Project description:[original title] Metastatic Canine Mammary Carcinomas can be Identified by a Gene Expression Profile that partly Overlaps with Human Breast Cancer Profiles. Introduction: Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent. Methods: Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer. Results: Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors. Conclusions: Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs are in some aspects suitable as a translational model for human breast tumors in order to identify prognostic molecular signatures and potential therapeutic targets. Thirteen simple mammary carcinomas with invasive growth and lymph node metastases at the time of tumor resection and 14 simple carcinomas without lymph node metastases were included in the study. None of the patients had radiographically detectable pulmonary metastases at the time of tumor resection. Distant metastases as the cause of death were determined postoperatively by radiographic detection of metastases or necropsy. Selection criteria for carcinomas without lymph node metastases included an invasive growth, a negative lymph node status, a histological grade III and a minimal tumor diameter above the average of the lymph node positive tumors (> 2.42 cm). All animals with non-metastatic carcinomas had a survival rate of over 24 months except animal no. 22 (2627) which developed radiographic detectable lung metastases 8 months after surgery. Tumor and lymph node histologies were evaluated independently by two board-certified pathologists, following the criteria of the WHO classification of canine mammary tumors and the Nottingham grading system. All 27 tumors were simple carcinomas and characterized by an invasive, mostly solid growth pattern, marked cellular pleomorphism, anisokaryosis and 3 or more mitotic figures per high power field.

Project description:The identification of novel tumor-specific markers may improve understanding of melanoma progression and prognostic accuracy. Whole genome expression profiling of 46 primary melanomas, 12 metastases, and 16 normal skin samples using Affymetrix U133 PLUS 2.0 array generated gene lists including both known and new melanoma genes. The molecular genetic alterations contributing to the pathogenesis of melanoma are incompletely defined and few independent prognostic features have been identified beyond the pathologic characteristics of the primary tumor. Early stage melanoma is frequently curable, in contrast to the inferior prognosis of melanomas with regional lymph nodes involvement and the incurability of distant metastatic disease. The identification of novel tumor-specific markers may improve our understanding of melanoma progression and prognostic accuracy. To find differentially expressed genes that can distinguish melanoma from normal tissue, we performed a whole genome expression profiling of 46 primary melanoma samples, 12 regional or distant metastases, and 16 normal skin samples using Affymetrix U133 2.0 Plus array. Our study generated lists of differentially expressed genes in melanoma and identified novel prognostic marker HMGA2. It is a novel, highly overexpressed melanoma gene associated with poor prognosis. The overexpression of HMGA2 is strongly associated with regional and distant metastases and serves as an independent predictor of disease-free survival and overall survival in melanoma. Melanoma samples were obtained through an IRB-approved protocol using informed consent at the University of Michigan Multidisciplinary Melanoma Clinic. A portion of pigmented lesions clinically suspicious for melanoma and known melanoma were sampled by punch biopsy at the time of excision. The punch biopsy was bisected; half was sent to for clinical diagnosis and the other half along with adjacent normal skin when available immediately snap-frozen in liquid nitrogen. Snap-frozen tissue was embedded in OCT (TissueTek) followed by frozen sectioning and H&E slide preparation. The slides were evaluated by dermatopathologist who identified areas with greater than 70% tumor cellularity, which were sampled for RNA extraction. Primary melanomas and melanoma metastases were derived from different patients. Metastatic samples included lymph nodes (n=8), subcutaneous soft tissue (n=2), spleen (n=1), and small intestine (n=1).

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Gene expression profiling of primary canine insulinomas and their metastases

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