Genetic determinants of cutaneous malignant melanoma in Sinclair swine

Abstract

Summary The role of genetic factors involved in the determination of risk of cutaneous malignant melanoma (CMM) in humans remains unclear owing to genetic heterogeneity and reliance on simplistic models of inheritance. Here, we report a statistical genetic analysis of cutaneous malignant melanoma in Sinclair swine (SSCM), a unique animal model for human CMM. Using complex segregation analysis a two-locus model involving an unknown major locus and a second locus that lies within or close to the swine leucocytic antigen (SLA) complex jointly determine risk of SSCM in pedigreed animals. These loci also influence severity of affection, accounting for approximately 20% of the phenotypic variation in quantitative tumour burden.

The porcine Major Histocompatibility Complex and related paralogous regions: a review

“…Segregation analyses of the occurrence of melanocytic lesions in the American miniature pig Sinclair line were consistent with a two-loci model involving an as yet undefined major initiator gene and a second locus belonging to the SLA region [4]. One particular SLA haplotype appeared to be necessary for the tumour initiator locus to be fully penetrant.…”

Congenital and hereditary tumours in domestic animals. 2. Pigs. A review

“…Familial aggregation of benign and malignant melanocytic skin tumours has been described, particularly in purebred miniature swine such as Sinclair (7,36,48), and Hormel swine (26), but also in Duroc-Jersey swine (35,39). Among the several crosses involved are Duroc x Slovak pigs (47), Munich-Troll x German Landrace (60) and Duroc x Iberian swine (23).…”

“…Since Sinclair swine melanoma is an inherited neoplasm and as selective breeding increases the incidence of pigmented tumours, this animal model provides an unique opportunity yo determine the mode of inheritance (54,57). Although two loci being involved in the expression of melanomas in swine were discovered, the complete mode of inheritance has not yet been elucidated (7,73). The few reports on congenital papillomatosis (69,76,81) are intriguing because of the question concerning transmaternal transmission of a papilloma-virus (76).…”

Modeling Inheritance of Malignant Melanoma With DNA Markers in Sinclair Swine

“…Interval mapping for a tumor initiator locus with full lethality of homozygotes: To test the hypothesis of lethality in utero of homozygotes for the tumor initiator allele, T (Blangero et al 1996), the above model of interval mapping can be generalized. Consider that selection coefficient Blangero et al (1996), is LBGð f T ; C Tt j r 1 ; r 2 ; c; MM 9; Mm; 9mM 9; mm9Þ…”

“…A second locus may lie within or close to the swine leukocytic antigen (SLA) complex on swine chromosome 7 (SSC7), and a third, as yet unidentified locus, affects the penetrance of the initiator locus. It has been hypothesized that the tumor initiator locus was a homozygous lethal in utero (Blangero et al 1996) but this has not been verified. The complex inheritance of this disease, involving several loci with different penetrance and possibly different modes of gene action, makes resolving the mode of inheritance of this disease difficult just by phenotypic recording of crosses and tumor susceptibility in the offspring.…”