Dataset Information

Whole genome and transcriptome analysis of medullary thyroid cancer

ABSTRACT: Medullary thyroid cancer is the neoplasm of the calcitonin-producing parafollicular cells of the thyroid gland. The hormone calcitonin acts to lower the blood calcium level, counteracting the effects of the parathyroid hormone; it can also serve as a biomarker for the presence or recurrence of medullary thyroid cancer. Surgery is the only curative treatment for this cancer. Targeted therapeutics vandetanib and cabozantinib are approved for the treatment of aggressive and metastatic tumors that are not amenable to surgery. The use of these multikinase inhibitors are supported by the observed overactivation of the RET oncoprotein in a large sub-population of medullary thyroid cancers; however, not all patients carry oncogenic alterations of this kinase. Hence, there is a need for molecular characterization of medullary tumors on the genomic scale with the aim of identifying targetable mutations. Here, we describe the genomic profiles of two medullary thyroid cancers and report the presence of a putative oncogenic BRAF fusion in one. Such alterations previously observed in other malignancies and known targets of available drugs, can benefit patients who currently have no therapy options.

PROVIDER: EGAS00001001473 | EGA |

REPOSITORIES: EGA

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Publications

Putative BRAF activating fusion in a medullary thyroid cancer.

Kasaian Katayoon K Wiseman Sam M SM Walker Blair A BA Schein Jacqueline E JE Hirst Martin M Moore Richard A RA Mungall Andrew J AJ Marra Marco A MA Jones Steven J M SJ

Cold Spring Harbor molecular case studies 20160301 2

Medullary thyroid cancer (MTC) is a malignancy of the calcitonin-producing parafollicular cells of the thyroid gland. Surgery is the only curative treatment for this cancer. External beam radiation therapy is reserved for adjuvant treatment of MTC with aggressive features. Targeted therapeutics vandetanib and cabozantinib are approved for the treatment of aggressive and metastatic tumors that are not amenable to surgery. The use of these multikinase inhibitors are supported by the observed overa ...[more]

PMID: 27148585

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Project description:Recurrent non-medullary thyroid carcinoma (NMTC) is a rare disease. We initially characterized 27 recurrent NMTC: 13 papillary thyroid cancers (PTC), 10 oncocytic follicular carcinomas (FTC-OV), and 4 non-oncocytic follicular carcinomas (FTC). A validation cohort composed of benign and malignant (both recurrent and non-recurrent) thyroid tumours was subsequently analysed (n = 20). Methods Data from genome-wide SNP arrays and flow cytometry were combined to determine the chromosomal dosage (allelic state) in these tumours, including mutation analysis of components of PIK3CA/AKT and MAPK pathways. Results All FTC-OVs showed a very distinct pattern of genomic alterations. Ten out of 10 FTC-OV cases showed near-haploidisation with or without subsequent genome endoreduplication. Near-haploidisation was seen in 5/10 as extensive chromosome-wide monosomy (allelic state [A]) with near-haploid DNA indices and retention of especially chromosome 7 (seen as a heterozygous allelic state [AB]). In the remaining 5/10 chromosomal allelic states AA with near diploid DNA indices were seen with allelic state AABB of chromosome 7, suggesting endoreduplication after preceding haploidisation. The latter was supported by the presence of both near-haploid and endoreduplicated tumour fractions in some of the cases. Results were confirmed using FISH analysis. Relatively to FTC-OV limited numbers of genomic alterations were identified in other types of recurrent NMTC studied, except for chromosome 22q which showed alterations in 6 of 13 PTCs. Only two HRAS, but no mutations of EGFR or BRAF were found in FTC-OV. The validation cohort showed two additional tumours with the distinct pattern of genomic alterations (both with oncocytic features and recurrent). Conclusions We demonstrate that recurrent FTC-OV is frequently characterised by genome-wide DNA haploidisation, heterozygous retention of chromosome 7, and endoreduplication of a near-haploid genome. Whether normal gene dosage on especially chromosome 7 (containing EGFR, BRAF, cMET) is crucial for FTC-OV tumour survival is an important topic for future research. 28 thyroid tumors from 27 patients were profiled by SNP array. Comparisons between different types were made.

Project description:Successful carcinogenesis involves the integration of both pro- and anti-oncogenic pathways. We postulated that genes critical for balancing these opposing pathways are likely to be precisely controlled in tumors, since even subtle alterations in their activity might cause substantial alterations in tumor growth and survival. Using a novel genomic approach, we identified a 48-gene âPoised Gene Cassetteâ (PGC) showing tight regulation specifically in human cancers but not in corresponding nonmalignant tissues. We show, using a wide variety of in vitro and in vivo approaches, that small alterations in PGC expression are consistently associated with significant differences in experimental metastasis and patient survival, and we demonstrate a direct functional role for five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6 and SKIP) in cancer invasion. Our findings support the existence of a novel class of ultrasensitive genes that may regulate various cancer-associated phenotypes such as metastasis. Such precisely controlled genes could represent appealing drug targets, since even partial alterations in their activity should prove sufficient to induce potent effects on tumors. Besides cancer, our analytical approach is quite generalizable and likely to be applicable to other disease conditions. Experiment Overall Design: Primary human tumor and adjacent normal tissues were obtained from the Tissue Repository of the National Cancer Centre of Singapore (NCCS). Appropriate institutional approvals were obtained from the NCCS Tissue Repository and Ethics Committees. In the operating theater, morphologically visible tumor and adjacent matched normal tissues were removed by surgery and examined by a surgical pathologist to confirm the presence of cancer cells by cryosections. The tissue samples were divided into discrete aliquots, flash frozen and subsequently stored in liquid nitrogen. The detailed information regarding samples is available in Supplementary Information S1. The training set used in this study comprises 341 samples (270 tumors and 71 matched normals) from patients with breast, colon, liver, lung, oesophagal and thyroid cancer (Tissue Type/Tumor/Normal : Lung/18/12, Thyroid/35/16, Liver/9/8, Oesophagus/16/13, Colon/9/9, Breast/183/13.)

Project description:Hydroxylated polychlorinated biphenyls are the metabolites produced from polychlorinated biphenyls (PCBs) by drug-metabolizing enzyme cytochrome P450 1A1. These compounds are bound to transthyretin, a major plasma thyroid hormone-binding protein in amphibian tadpoles. The compounds-transthyretin complexes are transferred into the brain across the blood brain barrier in mammals. Thus these compounds are suspected to disrupt neural development in brain. We studied about the effects of hydroxylated PCBs on the thyroid system in brain using metamorphosing tadpoles of African clawed toad, Xenopus laevis. The metamorphosis assay revealed that these compounds had inhibitory effects on the thyroid hormone-induced metamorphosis. This in vivo assay was a powerful tool to detect thyroid-disrupting activities, because we were not able to detect the inhibitory effects of these compounds using thyroid hormone-responsive reporter gene assay in a cultured Xenopus cell line. A genome-wide gene expression analysis in brain following short-term exposure to these compounds demonstrated that the delay of metamorphosis and the morphological thyroid-disrupting changes could be caused partially by disruption of the thyroid hormone-induced gene expression by hydroxylated PCBs. Furthermore, we associated functional ontology terms with the transcripts whose expression were altered by thyroid hormone alone, or thyroid hormone and hydroxylated PCBs. We suggested that these approachs using a technique of bioinformatics revealed molecular mechanism of thyroid-disrupting activities in vivo. Thyroid hormones induce amphibian metamorphosis and alter a lot of thyroid hormone-responsive gene expression. We studied about the effects of hydroxylated PCBs on TH-induced gene expression. Premetamorphic tadpoles were treated with 500 nM hydroxylated PCBs in the presence of 1 nM thyroid hormone for 4 days. After exposure period total RNA was extracted from brain. Study included at least three replicate of each treatment.

Dataset Information

Whole genome and transcriptome analysis of medullary thyroid cancer

Publications

Putative BRAF activating fusion in a medullary thyroid cancer.

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