In other species: domestic cat

Categories: Neoplasm

Single-gene trait/disorder: unknown

Mode of inheritance: Somatic mutation

Disease-related: yes

Species summary: see also OMIA:001356-9796 : Coat colour, grey/gray in Equus caballus as gray horses have an increased risk of developing melanomas

Molecular basis: Wong et al. (2019) performed "a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. ... As the gray phenotype, associated with progressive silvering of colored hair, has been linked to melanoma development in horses, we obtained a coat color phenotype for each case from clinical records ... . In the cutaneous melanomas, samples with a higher mutational load were generally from horses without the gray coat phenotype, suggesting a different path to melanoma development in these cases ... . Although the gray phenotype is known to predispose to melanomas in and around mucosal sites, a definitive association between this coat color phenotype and mutational load was not evident for mucocutaneous/mucosal-like cases." The authors identified somatic mutations in several driver genes: " The most prominent driver genes were NRAS ... and TP53 ... , while two cases had mutations in BRAF. Mutations were also observed in PTEN ... , KIT ... , and RB1 ... , with 14% of samples carrying a mutation in at least one of these genes ... . Intriguingly, we also found C>T missense mutations in the KNSTRN gene ... , in 1 cutaneous melanoma ... and two mucosal-like samples with a high mutation rate and UV signature ... . ... As noted above, as a comparator to our sequencing of equine melanomas from in and around mucosal sites, we sequenced 32 cases of equine cutaneous melanoma ... . With the exception of one NRAS Q61R mutation, these tumors lacked point or indel mutations in known melanoma driver genes ... , suggesting a distinct clinical entity or an alternative path to melanoma development." The authors also investigated DNA copy number profiles in equine melanomas: "frequent gain of chromosome 25 and loss of chromosome 31 was observed in tumors from mucosal-like or mucocutaneous sites."
Druml et al. (2022): "Several studies have documented a genetic melanoma predisposition which is referred to the 4.6 kb duplication in intron 6 of STX17 and its surrounding haplotype. However, the genetic background and mechanisms responsible for differences in etiopathogenesis of equine dermal melanomatosis still remain unknown. In the current study, we performed a genome wide association analysis in 141 Lipizzan horses and subsequently identified one candidate gene on chromosome 24 putatively involved in melanoma pathogenesis in gray horses. The associated SNP was located in the intronic region of DPF3, a gene which is involved in humans in cell growth, proliferation, apoptosis and motility of cancer cells. The replication study in 1210 horses from seven breeds demonstrated, that the G/G genotype of the DPF3 associated SNP exhibits putative melanoma suppression effects."