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Topic:Cancer

Cancer in horses encompasses a range of neoplastic diseases that affect various tissues and organs in equine species. These conditions involve the uncontrolled growth of abnormal cells, which can form tumors and potentially spread to other parts of the body. Common types of cancer in horses include sarcoids, squamous cell carcinoma, and melanoma, each with distinct characteristics and clinical presentations. Diagnosis often involves a combination of physical examination, imaging techniques, and histopathological analysis. Treatment options vary based on the type and stage of cancer and may include surgical intervention, chemotherapy, and radiation therapy. This page compiles peer-reviewed research studies and scholarly articles that explore the epidemiology, pathophysiology, diagnostic methods, and treatment strategies for cancer in horses.
Altered expression of collagen gene family members and its epigenetic background in equine Sarcoids.
Research in veterinary science    April 21, 2025   Volume 190 105656 doi: 10.1016/j.rvsc.2025.105656
Pawlina-Tyszko K, Semik-Gurgul E, Podstawski P, Herc W, Witkowski M, Ropka-Molik K.Alterations in the genes involved in the creation of the extracellular matrix (ECM) were observed in our earlier transcriptome studies of sarcoids and their cell culture model. For a complete characterization of the underlying molecular pathways, it is imperative to comprehend the involvement of ECM modifications in the oncogenic transformation of sarcoid fibroblasts. Thus, the aim of this investigation was to describe the expression patterns of a set of genes that are essential for the rearrangements of the extracellular matrix, namely collagen genes, and elucidate possible mechanisms underly...
Intratumoural tigilanol tiglate in the multicentre treatment of equine sarcoids and cutaneous melanomas.
Equine veterinary journal    April 2, 2025   doi: 10.1111/evj.14502
Labens R, Saba C, Williams J, Hollis A, Ensink J, José-Cunilleras ELV, Jordana-Garcia M, Bergvall K, Ruppin M, Condon F, Spelta C, Elce Y....Intralesional chemotherapeutic administration represents an important treatment option for equine cutaneous neoplasia. Tigilanol-tiglate (TT), a novel molecule extracted from Fontainea picrosperma, an Australian rainforest plant, is registered for intratumoural treatment of canine MCT, leading to rapid oncosis and tumour slough. Evidence from horses is limited but suggests that efficacy may be similar. Objective: To evaluate the response to intratumoural TT treatment in horses with sarcoids (fibroblastic/nodular) and cutaneous melanomas. Methods: Two noncontrolled prospective multicentre clini...
Papillary Renal Cell Carcinoma With Widespread Metastases in an Arabian Mare.
Veterinary medicine and science    April 2, 2025   Volume 11, Issue 3 e70281 doi: 10.1002/vms3.70281
Azari O, Ghamsari SM, Roustaei A, Golchin D, Baharloo F, Javaheri M, Valizadeh N.This report describes a case of massive renal cell carcinoma (RCC) causing mild chronic colic in a 20-day-postpartum Arabian mare. The mare presented with deteriorating abdominal pain following normal parturition. Clinical examination revealed tachycardia, tachypnoea, weak intestinal motility and pale mucosal membranes. Rectal examination identified a very large mass in the caudal part of the abdominal cavity, and abdominal ultrasound examination revealed a huge space-occupying mass with renal architecture. During midline exploratory laparotomy, a massive tumour was observed in the anatomical ...
Studying the Impact of the DDB2 T338M Missense Mutation on the Development of Equine Squamous Cell Carcinoma and Sarcoid.
Animals : an open access journal from MDPI    March 22, 2025   Volume 15, Issue 7 doi: 10.3390/ani15070911
Quatember H, Nell B, Richter B, Rigler D, Dolezal M, Sykora S, Wallner B.A missense mutation in damage-specific DNA binding protein 2 (DDB2 c.1013 C>T; p.Thr338Met) has been described as a risk factor for ocular squamous cell carcinoma (OSCC) in the Haflinger breed. Here, we examined the impact of DDB2 C>T allele status on the development of OSCC, squamous cell carcinoma (SCC) at other localisations, or equine sarcoid (ES) in Haflingers and other breeds with a high incidence of these tumour types. We genotyped affected Haflinger, Noriker, Warmblood, and Icelandic horses. Results based on 56 Haflingers confirmed the significantly higher risk for OSCC in DDB2-T...
Electrochemotherapy with bleomycin for bilateral ocular squamous cell carcinoma in a horse.
Veterinary ophthalmology    December 16, 2024   doi: 10.1111/vop.13310
Larsen MME, Eriksson A, Impellizeri JA.To describe the procedure and outcome of electrochemotherapy (ECT) with bleomycin as a first-line treatment for bilateral ocular surface squamous neoplasia (OSSN) in the eye of a horse. Methods: A client-owned 5-year-old Haflinger gelding with limbal-conjunctival squamous cell carcinoma. Methods: During general and local anesthesia, injection of bleomycin in the ocular tumor was followed by electroporation, applied with a 15 mm needle electrode, needles held parallel to the ocular surface. Results: Treatment with ECT resulted in therapeutic electric pulses and complete tumor response with no...
Electrochemotherapy with bleomycin for bilateral ocular squamous cell carcinoma in a horse.
Veterinary ophthalmology    December 16, 2024   doi: 10.1111/vop.13310
Larsen MME, Eriksson A, Impellizeri JA.To describe the procedure and outcome of electrochemotherapy (ECT) with bleomycin as a first-line treatment for bilateral ocular surface squamous neoplasia (OSSN) in the eye of a horse. Methods: A client-owned 5-year-old Haflinger gelding with limbal-conjunctival squamous cell carcinoma. Methods: During general and local anesthesia, injection of bleomycin in the ocular tumor was followed by electroporation, applied with a 15 mm needle electrode, needles held parallel to the ocular surface. Results: Treatment with ECT resulted in therapeutic electric pulses and complete tumor response with no...
[Retrospective study of the effectiveness of human tyrosinase vaccination in eight horses].
Schweizer Archiv fur Tierheilkunde    December 3, 2024   Volume 166, Issue 12 648-656 doi: 10.17236/sat00340
Brunner S, Fürst AE, Jackson MA.Dermal melanoma is a common neoplastic disease in horses, which occurs particularly in gray horses. There are various local and systemic therapeutic approaches to treat this skin tumor. Vaccination with human tyrosinase, ONCEPT ® vaccine, is a newer type of systemic melanoma therapy. In this study, the effectiveness of this ONCEPT ® vaccine was retrospectively examined in eight treated horses. In half of the horses (4) a positive change in tumor growth in the sense of retardation, stagnation and, in one of these horses, even reduction in the size of the melanomas was observed. Of the rem...
Overexpression of the key metabolic protein Carnitine Palmitoyl Transferase 1A (CPT1A) in equine sarcoid.
Journal of equine veterinary science    October 2, 2024   Volume 143 105205 doi: 10.1016/j.jevs.2024.105205
Martano M, Power K, Cuccaro B, Razzuoli E, Maiolino P, Restucci B.The equine sarcoid is the most common skin neoplasia of fibroblastic origin in horses, characterized by an excessive accumulation of extracellular matrix produced by sarcoid fibroblasts under hypoxic condition. Neoplastic cells can adapt to hypoxia by using alternative energy sources, particularly those that arise from fatty acid oxidation (FAO). The Carnitine Palmitoyl Transferase 1A (CPT1A) belongs to Carnitine System (CS) and promotes the entrance of fatty acids into the mitochondria for β-oxidation. In this study, CPT1A expression was comparatively addressed in 25 equine sarcoids and 5 no...
Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma.
bioRxiv : the preprint server for biology    September 27, 2024   2024.09.25.615007 doi: 10.1101/2024.09.25.615007
Kader T, Lin JR, Hug C, Coy S, Chen YA, de Bruijn I, Shih N, Jung E, Pelletier RJ, Leon ML, Mingo G, Omran DK, Lee JS, Yapp C, Satravada BA, Kundra R....High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling...
Disseminated pleomorphic rhabdomyosarcoma in a horse. Carpenter AL, Townsend KS, Johnson PJ, Kim DY.An 8-y-old National Show Horse mare was presented for evaluation of pneumonia and laminitis. Harsh bronchovesicular sounds were auscultated throughout both lung fields, and the mare had signs of moderately painful laminitis. Thoracic ultrasonography revealed lung consolidation throughout the dorsal aspect of both lungs, and radiography revealed an extensive diffuse-to-patchy bronchointerstitial lung pattern. The mare's clinical condition rapidly deteriorated, and euthanasia was elected. On postmortem examination, the lungs, omentum, spleen, liver, adrenal glands, kidneys, and femur contained 0...
Equine Melanoma Updates.
The Veterinary clinics of North America. Equine practice    September 11, 2024   Volume 40, Issue 3 431-439 doi: 10.1016/j.cveq.2024.07.008
Hollis AR.Melanomas are very common in older gray horses, with 80% of gray horses having at least 1 melanoma by 15 years of age. Historically considered a benign disease, it is now known that up to 66% of lesions will eventually metastasize. Melanomas may also cause local problems due to abscessation, ulceration, and interference with function of the affected areas. Treatment can be limited by size and location, but surgical resection, where possible, is likely to be the treatment of choice.
Diagnosis and Staging of Equine Neoplasia.
The Veterinary clinics of North America. Equine practice    September 11, 2024   S0749-0739(24)00051-8 doi: 10.1016/j.cveq.2024.07.002
Johns I, Bryan J.The diagnosis of neoplasia in the horse is both simple and extremely challenging, depending on the type of neoplasm and its location. Obtaining an accurate diagnosis of a neoplastic condition is key to formulating an appropriate treatment plan if possible or developing a palliative plan if curative treatment options do not exist. A combination of historical features, clinical examination findings, and diagnostic testing typically allow a working diagnosis of neoplasia to be made, with a definitive diagnosis requiring the identification of neoplastic cells in a sample or tissue.
An intronic copy number variation in Syntaxin 17 determines speed of greying and melanoma incidence in Grey horses.
Nature communications    August 29, 2024   Volume 15, Issue 1 7510 doi: 10.1038/s41467-024-51898-2
Rubin CJ, Hodge M, Naboulsi R, Beckman M, Bellone RR, Kallenberg A, J'Usrey S, Ohmura H, Seki K, Furukawa R, Ohnuma A, Davis BW, Tozaki T, Lindgren G....The Greying with age phenotype in horses involves loss of hair pigmentation whereas skin pigmentation is not reduced, and a predisposition to melanoma. The causal mutation was initially reported as a duplication of a 4.6 kb intronic sequence in Syntaxin 17. The speed of greying varies considerably among Grey horses. Here we demonstrate the presence of two different Grey alleles, G2 carrying two tandem copies of the duplicated sequence and G3 carrying three. The latter is by far the most common allele, probably due to strong selection for the striking white phenotype. Our results reveal a rem...
Exploring the Dissolution, Solid-state Properties, and Long-term Storage Stability of Cryoprotectant-free Fenbendazole Nanoparticles.
AAPS PharmSciTech    August 28, 2024   Volume 25, Issue 7 199 doi: 10.1208/s12249-024-02921-8
Bedogni G, Michelena LV, Seremeta K, Okulik N, Salomon C.Fenbendazole is an antiparasitic drug widely used in veterinary medicine to treat parasitic infections caused in animals like cattle, horses, sheep, and dogs. Recently, it has been repositioned as a potential alternative for cancer treatment. However, it is a highly hydrophobic molecule (0.9 ug/mL), which can compromise its dissolution rate and absorption. Thus, this work aimed to apply a nanotechnological approach to improve drug solubility and dissolution performance. Fenbendazole nanoparticles stabilized by different poloxamers were obtained by lyophilization without cryoprotectants. The be...
Principles of Tumor Biology.
The Veterinary clinics of North America. Equine practice    August 24, 2024   Volume 40, Issue 3 341-350 doi: 10.1016/j.cveq.2024.07.001
Murphy S.Cancer is disease of the genome. The Hallmarks of cancer are a way of thinking of cancer to help rationalize what occurs in this disease process. A solid tumor is a complex of normal and neoplastic cells, arising through an evolutionary process to survive and grow. By understanding how normal cellular mechanisms are subverted to promote cancer we can refine our approach to improve outcomes. It gives us opportunities to prevent some cancers and allowing earlier diagnosis. We can refine conventional diagnostic tools and give more accurate prognoses. It offers novel targets to improve treatment o...
Radiotherapy in Equine Practice.
The Veterinary clinics of North America. Equine practice    August 20, 2024   S0749-0739(24)00054-3 doi: 10.1016/j.cveq.2024.07.005
Mudge MC, Green E.Radiotherapy is a valuable treatment option for equine tumors that have a high rate of recurrence or where complete surgical resection may damage vital structures. Teletherapy, brachytherapy, and plesiotherapy have been used successfully for the treatment of a variety of tumors and locations in the horse. Radiobiology, treatment protocols, side effects, and patient management are reviewed, with a focus on linear accelerator-based teletherapy. There is evidence of good success rates for treatment of periocular sarcoids and squamous cell carcinoma but teletherapy treatment is often limited to tu...
Paraneoplastic Syndromes in Horses.
The Veterinary clinics of North America. Equine practice    August 20, 2024   S0749-0739(24)00074-9 doi: 10.1016/j.cveq.2024.07.015
Johns I.This article discusses the reported paraneoplastic syndromes (PNSs) in horses, including the possible pathogenesis, diagnostic methods, and any treatment options. The more commonly reported PNSs in horses include cancer anorexia and cachexia, fever and increased acute phase protein concentrations, and hypercalcemia and monoclonal gammopathy. As these conditions can often be more commonly diagnosed in non-neoplastic conditions, the diagnosis of a PNS and the accompanying neoplasia can be challenging. As signs of a PNS may precede signs of the underlying neoplasia, it is important that the clini...
Squamous Cell Carcinomas in Horses: An Update of the Aetiopathogenesis and Treatment Options.
The Veterinary clinics of North America. Equine practice    August 20, 2024   S0749-0739(24)00056-7 doi: 10.1016/j.cveq.2024.07.007
Hollis AR.Squamous cell carcinomas are a very common tumor type in horses, and are found in a variety of dermatologic and non-dermatologic locations. Metastasis is common, even at the first presentation of the disease, and a full staging workup is therefore strongly recommended to direct treatment and assist with prognostication. Wide surgical excision remains the treatment of choice in most cases, but recurrence is common, and adjunctive therapy may be indicated to improve the long-term prognosis.
Chemotherapeutics in Equine Practice.
The Veterinary clinics of North America. Equine practice    August 17, 2024   Volume 40, Issue 3 387-395 doi: 10.1016/j.cveq.2024.07.004
Malalana F.Chemotherapy is the treatment of cancerous cells through the use of cytotoxic drugs. Whilst the use of systemic (intravenous) chemotherapy in equine practice is generally limited to the management of lymphoma, cytotoxic drugs are commonly used in the treatment of accessible skin tumors, either by topical application in the form of ointments or injected intralesionally. These drugs should be employed with caution due to the risk of serious adverse effects. In addition, extreme caution should be followed when preparing, handling, administering, and disposing them, due to their carcinogenic, muta...
DNA Methylation and Its Effects on TRIM29 Gene Expression in the Equine Sarcoid Tissue.
Veterinary and comparative oncology    July 10, 2024   doi: 10.1111/vco.12994
Ewelina SG, Anna Z, Rafał P, Maciej W.Sarcoids are the most frequently diagnosed dermatological tumour in horses. It is a disease that can affect various species of equids, such as donkeys, mules and zebras. This type of tumour can develop in all horse breeds, regardless of age and gender. Treatment options depend on many factors, such as the type of lesion, location, extent, owner preference and financial considerations. In the present study, we investigated the TRIM29 expression, the methylation status of its first exon and its involvement in the formation of equine sarcoids. Bisulfite sequencing PCR (BSP) was used to determine ...
Programmed-cell death ligand 1 (PD-L1) expression in equine sarcoids and squamous cell carcinoma.
Open veterinary journal    June 30, 2024   Volume 14, Issue 6 1476-1482 doi: 10.5455/OVJ.2024.v14.i6.16
Pimenta J, Prada J, Pires I, Cotovio M.Sarcoids and squamous cell carcinomas (SCCs) are the most concerning equine oncological diseases. Both tumors are challenging to manage due to their invasive behavior and high prevalence of recurrences. Furthermore, SCCs have a propensity to metastasize. Programed cell-death ligand 1 (PD-L1) has been one of the main therapeutic targets for immunotherapy in various human tumors. PD-L1 research in equine tumors is scarce and more efforts are necessary to understand the potential of this biomarker as a therapeutical target. Unassigned: Evaluate the immunohistochemical expression of PD-L1 in equin...
Equus Caballus Papillomavirus Type 7 is A Rare Cause Of Equine Penile Squamous Cell Carcinomas.
Veterinary journal (London, England : 1997)    June 3, 2024   106155 doi: 10.1016/j.tvjl.2024.106155
Munday JS, Knight CG, Bodaan CJ, Codaccioni C, Hardcastle MR.Penile squamous cell carcinomas (SCCs) are common, potentially life-threatening neoplasms of horses. They are well-recognized to be caused by Equus caballus papillomavirus (EcPV) type 2, although EcPV2 cannot be detected in all cases. A 23-year-old standardbred gelding developed multiple penile in situ and invasive SCCs that contained histological evidence of PV infection. By using both consensus and specific PCR primers, these lesions were found to contain EcPV7 DNA, but not DNA from EcPV2 or any other PV type. To determine how frequently EcPV7 is present in equine penile SCCs, specific prime...
Deregulation of Metalloproteinase Expression in Gray Horse Melanoma Ex Vivo and In Vitro.
Cells    May 31, 2024   Volume 13, Issue 11 doi: 10.3390/cells13110956
Brodesser DM, Kummer S, Eichberger JA, Schlangen K, Corteggio A, Borzacchiello G, Bertram CA, Brandt S, Pratscher B.The ability of human melanoma cells to switch from an epithelial to a mesenchymal phenotype contributes to the metastatic potential of disease. Metalloproteinases (MPs) are crucially involved in this process by promoting the detachment of tumor cells from the primary lesion and their migration to the vasculature. In gray horse melanoma, epithelial-mesenchymal transition (EMT) is poorly understood, prompting us to address MP expression in lesions versus intact skin by transcriptome analyses and the immunofluorescence staining (IF) of gray horse tumor tissue and primary melanoma cells. RNAseq re...
A case of equine multicentric lymphoma: Clinical, microscopical, and molecular findings.
Open veterinary journal    May 31, 2024   Volume 14, Issue 5 1294-1301 doi: 10.5455/OVJ.2024.v14.i5.24
Silva GF, Ribeiro TE, Cunha R, Salas PB, Guimarães T, Ribeiro MR, Barros G, Carvalho F, Mesquita JR, Amorim I.Although relatively uncommon, lymphoma is the most prevalent haematopoietic neoplasia in horses, and multicentric lymphoma remains the most common presentation of the disease. The pathogenesis of equine lymphoma is still poorly understood and the diagnosis is usually confirmed at an advanced stage of the disease, compromising the prognosis. This study investigated the clinical, pathological, and molecular features of a case of equine multicentric lymphoma. Unassigned: An apparently healthy 5-year-old crossbreed mare hospitalized at the Centre of Animal Reproduction of Vairão, Portugal, sudden...
Operational Radiation Safety Considerations During Equine Superficial Radiation Treatment Using Portable X-Ray Devices.
Health physics    May 26, 2024   Volume 127, Issue 5 625-632 doi: 10.1097/HP.0000000000001841
Singh A, Johnson T, Wotman K, Leary D.Veterinary personnel exposure due to scattered x rays, when present during superficial radiation treatment (SRT), was evaluated. Veterinary personnel presence is needed during SRT to minimize the degree of required aesthesia to horses. Animal treatment was simulated, and exposure rates determined for 50, 70, and 100 kV x rays using eight different SRT applicators. Exposure rates at the surface of a solid water phantom (SWP) phantom ranged from 3.9 mR h-1 to 396 mR h-1 for 50 kV, from 41 mR h-1 to 2,880 mR h-1 for 70 kV, and from 235 mR h-1 to 7,500 mR h-1, for 100 kV, respectively. A horse pha...
Potent drug delivery enhancement of betulinic acid and NVX-207 into equine skin in vitro – a comparison between a novel oxygen flow-assisted transdermal application device and microemulsion gels.
BMC veterinary research    May 16, 2024   Volume 20, Issue 1 202 doi: 10.1186/s12917-024-04064-1
Zscherpe P, Kalbitz J, Weber LA, Paschke R, Mäder K, von Rechenberg B, Cavalleri JV, Meißner J, Klein K.Gray horses are predisposed to equine malignant melanoma (EMM) with advancing age. Depending on the tumor's location and size, they can cause severe problems (e.g., defaecation, urination, feeding). A feasible therapy for EMM has not yet been established and surgical excision can be difficult depending on the location of the melanoma. Thus, an effective and safe therapy is needed. Naturally occurring betulinic acid (BA), a pentacyclic triterpene and its synthetic derivate, NVX-207 (3-acetyl-betulinic acid-2-amino-3-hydroxy-2-hydroxymethyl-propanoate) are known for their cytotoxic properties ag...
Encapsulation of copper phenanthroline within horse spleen apoferritin: characterisation, cytotoxic activity and ability to retain temozolomide.
RSC advances    April 29, 2024   Volume 14, Issue 20 14008-14016 doi: 10.1039/d3ra07430g
Cassioli ML, Fay M, Turyanska L, Bradshaw TD, Thomas NR, Pordea A.Protein capsules are promising drug delivery vehicles for cancer research therapies. Apoferritin (AFt) is a self-assembling 12 nm diameter hollow nanocage with many desirable features for drug delivery, however, control of drug retention inside the protein cage remains challenging. Here we report the encapsulation of copper(ii)-1,10-phenanthroline (Cu(phen)) within the horse spleen AFt (HSAFt) nanocage, by diffusion of the metal through the pores between the protein subunits. Transmission electron microscopy revealed the formation of organised copper adducts inside HSAFt, without affecting pro...
Effects of tamoxifen on the immune response phenotype in equine peripheral blood mononuclear cells.
Frontiers in veterinary science    April 10, 2024   Volume 11 1381162 doi: 10.3389/fvets.2024.1381162
Rodríguez M, Quiroga J, Cortés B, Morán G, Henríquez C.Tamoxifen (TAM) is widely utilized in the prevention and treatment of human breast cancer and has demonstrated the potential to modulate the immune response. It has been proposed as a therapeutic tool for immune-mediated diseases. TAM has been investigated as a possible treatment for asthma-like conditions in horses, revealing specific impacts on the innate immune system. While the effects of TAM on equine neutrophils are well-documented, its influence on lymphocytes and the modulation of the immune response polarization remains unclear. This study employed peripheral blood mononuclear cells ...
Impact of Equine Ocular Surface Squamous Neoplasia on Interactions between Ocular Transcriptome and Microbiome.
Veterinary sciences    April 7, 2024   Volume 11, Issue 4 167 doi: 10.3390/vetsci11040167
Chow L, Flaherty E, Pezzanite L, Williams M, Dow S, Wotman K.Ocular surface squamous neoplasia (OSSN) represents the most common conjunctival tumor in horses and frequently results in vision loss and surgical removal of the affected globe. Multiple etiologic factors have been identified as contributing to OSSN progression, including solar radiation exposure, genetic mutations, and a lack of periocular pigmentation. Response to conventional treatments has been highly variable, though our recent work indicates that these tumors are highly responsive to local immunotherapy. In the present study, we extended our investigation of OSSN in horses to better und...
White horses – non-coding sequences drive premature hair greying and predisposition to melanoma.
Upsala journal of medical sciences    April 2, 2024   Volume 129 doi: 10.48101/ujms.v129.10626
Andersson L.The Grey allele in horses is causing premature hair greying and susceptibility to melanoma. The causal mutation is a 4.6 kb tandem duplication in intron 6 of the Syntaxin 17 gene. A recent study demonstrated that the most common allele at the Grey locus (G3) involves three tandem copies of this sequence, whilst a more rare allele (G2) has two tandem copies and the wild-type allele (G1) only one copy. The G3 allele is causing fast greying and high incidence of skin melanoma, whereas the G2 allele is causing slow greying and no obvious increase in melanoma incidence. Further somatic copy number ...