Disease relevance of CCDC6

• Moreover, the transcript coded for by the fused gene was detected in an additional PTC-positive human papillary carcinoma for which mRNA was available [1].
• Somatic rearrangements of RET are involved in the aetiology of a variable proportion of papillary thyroid carcinomas (PTC), the most common type of thyroid tumour whose prevalence is increasing in areas heavily exposed to radioactive fallout after the Chernobyl accident of 1986 [2].
• Identification of a novel subtype of H4-RET rearrangement in a thyroid papillary carcinoma and lymph node metastasis [3].
• Retroviral transduction of H4/PDGFbetaR, but not a kinase-inactive mutant, conferred factor-independent growth to Ba/F3 cells and caused a T-cell lymphoblastic lymphoma in a murine bone marrow transplantation assay of transformation [4].
• Twenty-six % of informative benign tumors (four follicular adenomas and three Hürthle cell adenomas) and only 3 of 49 (6.1%) informative malignant tumors (one PTC, one follicular carcinoma, and one anaplastic carcinoma) showed evidence of hemizygous deletion of PTEN (P = 0.046) [5].

Psychiatry related information on CCDC6

• We investigated the accuracy of intraoperative tumour classification in papillary thyroid cancers (PTC) and its effect on intraoperative decision-making [6].

High impact information on CCDC6

• We designated this transforming gene PTC (for papillary thyroid carcinoma) [1].
• We have determined the nucleotide sequence of a continuous 2100 bp segment of DNA including both H3 and H4 coding sequences, the entire spacer DNA separating the genes and surrounding nonhistone DNA [7].
• We have cloned and characterized members of a small multigene family that encodes late-stage histone H3 and H4 mRNAs from the sea urchin Lytechinus pictus [7].
• Unlike their highly repetitive histone gene counterparts, which are expressed at an earlier developmental stage, late H3 and H4 histone genes are not present in tandem repeats [7].
• We have isolated five clones containing human histone genes from a human genomic DNA library, using a cloned X. laevis histone H4 cDNA probe (pX1ch4) [8].

Chemical compound and disease context of CCDC6

• RET/papillary thyroid carcinoma (PTC) oncogenes, generated by recombination of the tyrosine kinase-encoding domain of RET with different heterologous genes, are prevalent in papillary carcinomas of the thyroid [9].
• The transmembrane glycoprotein CD44v6 is overexpressed in most papillary thyroid carcinomas (PTC) [10].
• DESIGN AND PATIENTS: Thyroid tumours removed from 51 subjects were analysed, including 43 PTC and 8 non-PTC tumours [3 follicular adenomas (FA), 4 follicular carcinomas (FTC) and 1 anaplastic carcinoma (AC)] [11].
• A monoclonal antibody (H4) against tryptase purified from human pulmonary mast cells was prepared and used as an immunoreactive marker for the cellular localization of tryptase in normal human skin and in lesional skin from subjects with systemic mastocytosis [12].
• Fusion of H4/D10S170 to PDGFRbeta in a patient with chronic myelomonocytic leukemia and long-term responsiveness to imatinib [13].

Biological context of CCDC6

• RET and D10S170 have been mapped to contiguous regions of the long arm of chromosome 10: q11.2 and q21, respectively [14].
• To identify the mechanism leading to the generation of the oncogenic sequence RET/PTC, a combined cytogenetic and molecular analysis of several cases of papillary thyroid carcinomas was done [14].
• Here we describe a family whose siblings, affected by both PTC and MTC, carried a germ-line point mutation in the RET extracellular domain, converting cysteine 634 into serine [15].
• Characterization of the promoter region and oligomerization domain of H4 (D10S170), a gene frequently rearranged with the ret proto-oncogene [16].
• H4/PTEN is another example of recombination involving the H4 locus, and points to the high susceptibility of thyroid cells to intrachromosomal gene rearrangements [17].

Anatomical context of CCDC6

• Finally, we applied our FISH approach to determine the extent of deletion involving this locus (D10S170) in a papillary thyroid cancer cell line, TPC-1 [18].
• At least one pair of RET and H4 was juxtaposed in 35% of normal human thyroid cells and in 21% of peripheral blood lymphocytes, but only in 6% of normal mammary epithelial cells [19].
• A signaling pathway downstream of RET/ PTC leads to restructuring of the nuclear envelope and chromatin, and the signal does not depend entirely, if at all, on a RAS pathway [20].
• We tested a resulting prediction that RET/PTC expression in thyroid epithelium should be sufficient to cause the changes in nuclear morphology diagnostic of this tumor [20].
• Using an informative panel of human-mouse somatic cell hybrids and 'in situ' hybridization to human metaphase chromosomes, we localized the PTC gene at bands q11-q12 of chromosome 10 [21].

Associations of CCDC6 with chemical compounds

• In most cases the activation consisted of the fusion of its tyrosine-kinase domain with the 5'-terminal region of a gene designated H4 or D10S170 [22].
• Refined localization to contiguous regions on chromosome 10q of the two genes (H4 and RET) that form the oncogenic sequence PTC [23].
• Mutational analysis showed that the amino-terminal H4 leucine zipper domain (amino acids 55-93), as well as H4 amino acids 101 to 386, was required for efficient induction of factor-independent growth of Ba/F3 cells [4].
• ZD6474 prevented the growth of two human PTC cell lines that carry spontaneous RET/PTC1 rearrangements [9].
• Activating mutations in RAS genes were detected in 15% of FA, 33% of FTC and 7% of PTC [24].

Regulatory relationships of CCDC6

• Ninety per cent of ret/PTC-1-positive tumours failed to express H4, a phenomenon that has not been described previously and which may have considerable bearing on tumour morphology [25].

Other interactions of CCDC6

• New breakpoints in both the H4 and RET genes create a variant of PTC-1 in a post-Chernobyl papillary thyroid carcinoma [26].
• Sequencing revealed a transcript consisting of exon 1 and 2 of H4 fused with exons 3-6 of PTEN [17].
• BRAF mutation occurred in PTC at a significantly higher frequency in male patients than in female patients [27].
• One founder line developed compound MTC/PTC at low frequency (8%) and pancreatic cystadenocarcinoma [28].
• Regulation of protein kinase B tyrosine phosphorylation by thyroid-specific oncogenic RET/PTC kinases [29].

Analytical, diagnostic and therapeutic context of CCDC6

• Interestingly, protein sequence analysis indicated a potential coiled-coil domain in the N-terminal region of H4 [16].
• Here we show the detection by in situ hybridisation, of activated ret transcripts in human thyroid papillary neoplasms that were positive for PTC activation by Southern blot analysis [30].
• Nested RT-PCR with specific primers bracketing the breakpoints confirmed the H4/PTEN rearrangements in irradiated KAT-1 and KAT-50 cells [17].
• Sequence analysis of the new chimera showed that the original frames of H4 and RET were joint with the intronic sequence without disruption of the open reading frame (ORF) [26].
• We used two-color fluorescence in situ hybridization and three-dimensional microscopy to map the positions of the RET and H4 loci within interphase nuclei [19].

References