The Tasmanian devil, a marsupial carnivore, is endangered because of the emergence of a transmissible cancer known as devil facial tumor disease (DFTD). This fatal cancer is clonally derived and is an allograft transmitted between devils by biting. We performed a large-scale genetic analysis of DFTD with microsatellite genotyping, a mitochondrial genome analysis, and deep sequencing of the DFTD transcriptome and microRNAs. These studies confirm that DFTD is a monophyletic clonally transmissible tumor and suggest that the disease is of Schwann cell origin. On the basis of these results, we have generated a diagnostic marker for DFTD and identify a suite of genes relevant to DFTD pathology and transmission. We provide a genomic data set for the Tasmanian devil that is applicable to cancer diagnosis, disease evolution, and conservation biology. † To whom correspondence should be addressed. DFTD appears to be a clonal cell line, transmitted (by biting) as an allograft between devils (5,6) and may be similar in transmission to canine transmissible venereal tumor (CTVT) and a transmissible sarcoma affecting Syrian hamsters (7-9). The prevalence and biology of such somatic cell parasites is generally unknown (10).Studies of captive Tasmanian devils have suggested that the species is prone to developing tumors, particularly carcinomas (11,12). However, DFTD does not resemble previously described devil cancers (3,13), and determining its etiology is critical for developing management strategies for the disease. Cytologically, DFTD appears as a soft tissue neoplasm consisting of undifferentiated round to spindle-shaped cells with few defining ultrastructural features (3,13). Immunohistochemistry suggests that the tumor is derived from neuroectoderm (13).Clonal transmission of DFTD was proposed on the basis of karyotypic evidence (5) and was supported by genetic analysis of DFTD tumors at microsatellite and major histocompatibility complex loci (6). We genotyped at 14 micro-satellite loci 25 paired tumor and host samples, as well as 10 samples from DFTD-unaffected devils from 16 locations in Tasmania (14) (figs. S1 and S2 and table S1). All DFTD tumors shared a similar genotype across all loci, regardless of location, sex, or age of the animal (P = 0.18, permutation test) (figs. S1 and S2). Furthermore, the tumor genotype was distinct from that of both the hosts and unaffected devils (P < 0.001, permutation test) (figs. S1 and S2). These data were consistent with previous studies (5,6) and support the supposition that DFTD is a single clonal cell line propagated as a tumor allograft.To further assess the clonal origin of DFTD, we sequenced a 1180-base pair fragment of the mitochondrial locus control region (LCR) from 14 tumors, 14 hosts, and 9 DFTD-unaffected devils (table S2). We found that all devils and tumors shared a single LCR haplotype in this region, except for one single-nucleotide polymorphism at position 15,711, which supported the idea that the tumors are clonal. Furthermore, this nucleotide variant was...
We isolated and analyzed, at single-nucleotide resolution, cancer-associated neochromosomes from well- and/or dedifferentiated liposarcomas. Neochromosomes, which can exceed 600 Mb in size, initially arise as circular structures following chromothripsis involving chromosome 12. The core of the neochromosome is amplified, rearranged, and corroded through hundreds of breakage-fusion-bridge cycles. Under selective pressure, amplified oncogenes are overexpressed, while coamplified passenger genes may be silenced epigenetically. New material may be captured during punctuated chromothriptic events. Centromeric corrosion leads to crisis, which is resolved through neocentromere formation or native centromere capture. Finally, amplification terminates, and the neochromosome core is stabilized in linear form by telomere capture. This study investigates the dynamic mutational processes underlying the life history of a special form of cancer mutation.
ObjectiveAlthough counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full.DesignHere, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells.ResultsOur CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both in vitro and in vivo. Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds.ConclusionsTaken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine.Clinical Trial RegistrationClinicalTrial.gov NCT01577511.
BackgroundWe present the genome sequence of the tammar wallaby, Macropus eugenii, which is a member of the kangaroo family and the first representative of the iconic hopping mammals that symbolize Australia to be sequenced. The tammar has many unusual biological characteristics, including the longest period of embryonic diapause of any mammal, extremely synchronized seasonal breeding and prolonged and sophisticated lactation within a well-defined pouch. Like other marsupials, it gives birth to highly altricial young, and has a small number of very large chromosomes, making it a valuable model for genomics, reproduction and development.ResultsThe genome has been sequenced to 2 × coverage using Sanger sequencing, enhanced with additional next generation sequencing and the integration of extensive physical and linkage maps to build the genome assembly. We also sequenced the tammar transcriptome across many tissues and developmental time points. Our analyses of these data shed light on mammalian reproduction, development and genome evolution: there is innovation in reproductive and lactational genes, rapid evolution of germ cell genes, and incomplete, locus-specific X inactivation. We also observe novel retrotransposons and a highly rearranged major histocompatibility complex, with many class I genes located outside the complex. Novel microRNAs in the tammar HOX clusters uncover new potential mammalian HOX regulatory elements.ConclusionsAnalyses of these resources enhance our understanding of marsupial gene evolution, identify marsupial-specific conserved non-coding elements and critical genes across a range of biological systems, including reproduction, development and immunity, and provide new insight into marsupial and mammalian biology and genome evolution.
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