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A Second Transmissible Cancer in Tasmanian Devils

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A Second Transmissible Cancer in Tasmanian Devils A second transmissible cancer in Tasmanian devils Ruth J. Pyea, David Pembertonb, Cesar Tovara, Jose M. C. Tubioc, Karen A. Dund, Samantha Foxb, Jocelyn Darbya, Dane Hayese, Graeme W. Knowlese, Alexandre Kreissa, Hannah V. T. Siddlef, Kate Swifte, A. Bruce Lyonsg, Elizabeth P. Murchisonc,1,2, and Gregory M. Woodsa,1,2 aMenzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia; bSave the Tasmanian Devil Program, Tasmanian Department of Primary Industries, Parks, Water and the Environment, Hobart, TAS 7000, Australia; cDepartment of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, United Kingdom; dDepartment of Cytogenetics, Royal Hobart Hospital, Hobart, TAS 7000, Australia; eMount Pleasant Laboratories, Tasmanian Department of Primary Industries, Parks, Water and the Environment, Prospect, TAS 7250, Australia; fCentre for Biological Science, University of Southampton, Highfield Campus, Southampton SO17 1BJ, United Kingdom; and gSchool of Medicine, University of Tasmania, Hobart, TAS 7000, Australia Edited by Stephen P. Goff, Columbia University College of Physicians and Surgeons, New York, NY, and approved November 30, 2015 (received for review October 9, 2015) Clonally transmissible cancers are somatic cell lineages that are DFTD has been associated with a single cancer clone that is spread between individuals via the transfer of living cancer cells. genetically distinct from its hosts (9). This DFTD lineage carries There are only three known naturally occurring transmissible a distinctive aneuploid karyotype notable for the presence of four cancers, and these affect dogs, soft-shell clams, and Tasmanian rearranged marker chromosomes (9). DFTD tumors share iden- devils, respectively. The Tasmanian devil transmissible facial cancer tical alleles at major histocompatibility complex (MHC) loci (10), was first observed in 1996, and is threatening its host species with and the survival of this lineage as an allogeneic graft in MHC- extinction. Until now, this disease has been consistently associated discordant hosts is at least partly mediated by down-regulation of with a single aneuploid cancer cell lineage that we refer to as DFT1. cell surface MHC molecules (11). DFTD tumors collected from Here we describe a second transmissible cancer, DFT2, in five devils different geographical locations in Tasmania share identical alleles located in southern Tasmania in 2014 and 2015. DFT2 causes facial at microsatellite loci (10, 12) and the whole genome sequences of tumors that are grossly indistinguishable but histologically distinct two distantly located DFTD tumors were found to share the from those caused by DFT1. DFT2 bears no detectable cytogenetic majority of their genetic variation (13). The DFTD clone has similarity to DFT1 and carries a Y chromosome, which contrasts been closely monitored during its epidemic sweep through Tas- with the female origin of DFT1. DFT2 shows different alleles to mania (Fig. 1A) (13–16). both its hosts and DFT1 at microsatellite, structural variant, and Here we report the discovery of a second transmissible cancer major histocompatibility complex (MHC) loci, confirming that it is a in Tasmanian devils. This second cancer, DFT2, manifests as second cancer that can be transmitted between devils as an allogeneic, facial tumors that are grossly indistinguishable from those caused MHC-discordant graft. These findings indicate that Tasmanian by the original DFTD clone, now designated DFT1. However, devils have spawned at least two distinct transmissible cancer DFT2 bears no detectable genetic or cytogenetic similarity to lineages and suggest that transmissible cancers may arise more DFT1 and the tumors that it causes are histologically distinct. frequently in nature than previously considered. The discovery of This finding indicates that DFTD tumors can be caused by at DFT2 presents important challenges for the conservation of Tasmanian least two distinct transmissible cancer clones. Given the rarity of devils and raises the possibility that this species is particularly prone to known transmissible cancer clones, it is remarkable that a second the emergence of transmissible cancers. More generally, our findings highlight the potential for cancer cells to depart from their hosts and Significance become dangerous transmissible pathogens. Transmissible cancers are somatic cell lineages that are spread transmissible cancer | contagious cancer | Tasmanian devil facial tumor between individuals via the transfer of living cancer cells. Only disease | Tasmanian devil three transmissible cancers have been reported in nature, suggesting that such diseases emerge rarely. One of the known lonally transmissible cancers are somatic cell lineages that transmissible cancers affects Tasmanian devils, and is threat- Care contagious between individuals via the transfer of living ening this species with extinction. Here we report the discov- cancer cells. Only three transmissible cancers have been observed ery of a second transmissible cancer in Tasmanian devils. This in nature, and these cause Tasmanian devil facial tumor disease cancer causes facial tumors that are grossly indistinguishable (DFTD), canine transmissible venereal tumor (CTVT), and soft- from those caused by the first-described transmissible cancer in shell clam disseminated neoplasia, respectively (1, 2). Each of this species; however, tumors derived from this second clone these clones originated in a “founder animal” whose somatic cells are genetically distinct. These findings indicate that Tasmanian acquired changes that drove carcinogenesis as well as adaptations devils have spawned at least two different transmissible can- for transmission and long-term survival (3). The rarity of trans- cers, and suggest that transmissible cancers may arise more missible cancer lineages in nature, despite the ubiquity of cancers frequently in nature than previously considered. that remain in one individual, suggests that the emergence of such clones is extraordinarily improbable. Author contributions: R.J.P., D.P., E.P.M., and G.M.W. designed research; R.J.P., C.T., J.M.C.T., Tasmanian devils (Sarcophilus harrisii) are iconic marsupial car- K.A.D., S.F., J.D., D.H., G.W.K., A.K., K.S., and E.P.M. performed research; R.J.P., D.P., C.T., J.M.C.T., K.A.D., S.F., G.W.K., A.K., H.V.T.S., K.S., A.B.L., E.P.M., and G.M.W. analyzed data; nivores endemic to the Australian island state of Tasmania. DFTD and E.P.M. wrote the paper. is spread between Tasmanian devils by biting and causes tumors The authors declare no conflict of interest. usually on the face or inside the mouth (Fig. 1) (4, 5). DFTD readily This article is a PNAS Direct Submission. metastasises, and the disease usually causes death of affected ani- Data deposition: The sequences reported in this paper have been deposited in the Gen- mals within months of the appearance of symptoms (4, 5). Since it Bank database (accession nos. KT188437 and KT188438). was first observed in 1996 in northeast Tasmania, DFTD has spread 1E.P.M. and G.M.W. contributed equally to this work. through most of Tasmania and has triggered widespread devil 2To whom correspondence may be addressed. Email: [email protected] or G.M.Woods@ population declines (Fig. 1A) (4, 6, 7). The species was listed as utas.edu.au. endangered by the International Union for Conservation of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. Nature in 2008 (8). 1073/pnas.1519691113/-/DCSupplemental. 374–379 | PNAS | January 12, 2016 | vol. 113 | no. 2 www.pnas.org/cgi/doi/10.1073/pnas.1519691113 Downloaded by guest on September 28, 2021 Fig. 1. Geographical location and gross appearance of DFT2 tumors. (A) Locations of confirmed DFT1 and DFT2 tumors in Tasmania (Left) and the Channel Peninsula (Right). Each DFT1 location is represented with a single dot regardless of the number of tumors identified at this location. Tumor diagnosis was performed by histopathology, cytogenetics, and/or genetic analysis. (B) Gross appearance of two DFT1 tumors (Left) and four DFT2 tumors (Right). Tumors were identified in Tasmanian devils in the Channel region between 2012 and 2015. Further information about animals is available in Table S1. clone has emerged in Tasmanian devils. These findings suggest in these animals were suggestive and typical of DFTD associated that Tasmanian devils may be particularly prone to this type of with the first described DFTD clone, DFT1. disease, or alternatively, that transmissible cancers are generally Initial histological assessment of two of the Channel DFTD more common than previously detected. The discovery of DFT2 cases from 2014, RV and SN, revealed that tumors from these changes our perception of transmissible cancers as exceptionally animals presented atypical features. DFTD tumors associated rare and bizarre natural occurrences, and challenges our un- with the DFT1 clone are generally composed of pleomorphic derstanding of the processes that cause somatic cells to depart round cells arranged in distinct bundles, cords or packets (5). In from their hosts and become transmissible cancer lineages. contrast, the tumors from RV and SN were characterized by sheets of pleomorphic (amorphic to stellate and fusiform) cells Results arranged in a solid pattern (Fig. 2). Furthermore, tumors from Gross and Histological Characteristics of DFT2. DFTD was first ob- RV and SN were negative for periaxin (PRX), an immunohis- served in northeast Tasmania in 1996, and rapidly
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