Modeling Inheritance of Malignant Melanoma With DNA Markers in Sinclair Swine

Gomez‐Raya, Luis; Okomo-Adhiambo, Margaret; Beattie, Craig W.; Osborne, Karen A.; Rink, Anette; Rauw, W. M.

doi:10.1534/genetics.106.070268

Cited by 5 publications

(4 citation statements)

References 22 publications

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“…Since the incidence of nevi is often associated with an increased risk of melanoma, determining the genetic loci responsible for nevus formation as well as melanoma is of great interest. The quantitative trait loci (QTLs) can interact in a non‐additive manner, thus the knowledge of their interactions with one another and their effect on the disease will help understand how all these loci impact the disease jointly . Using animal models like this one can be of great value, to help understand and uncover candidate genes to be studied in humans .…”

Section: Discussionmentioning

confidence: 99%

A murine model for the development of melanocytic nevi and their progression to melanoma

et al. 2015

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Acquired melanocytic nevi are commonly found in sun exposed and unexposed human skin, but the potential for their transformation into invasive melanoma is not clear. Therefore, a mouse model of nevus initiation and progression was developed in C3H/HeN mice using a modified chemical carcinogenesis protocol. Nevi develop due to DNA damage initiated by dimethylbenz(a) anthracene (DMBA) followed by chronic promotion with 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA). Dysplastic pigmented skin lesions appeared in 7–9 wk with 100% penetrance. Nests of melanocytic cells appeared in a subset of skin draining lymph nodes (dLN) by 25 wk, but not in age matched controls. Immunohistochemistry, real‐time PCR, and flow cytometric analyses confirmed their melanocytic origin. Transformed cells were present in a subset of nevi and dLNs, which exhibited anchorage‐independent growth, tumor development, and metastasis in nude mice. Approximately 50% of the cell lines contained H‐Ras mutations and lost tumor suppressor p16Ink4a expression. While most studies of melanoma focus on tumor progression in transgenic mouse models where the mutations are present from birth, our model permits investigation of acquired mutations at the earliest stages of nevus initiation and promotion of nevus cell transformation. This robust nevus/melanoma model may prove useful for identifying genetic loci associated with nevus formation, novel oncogenic pathways, tumor targets for immune‐prevention, screening therapeutics, and elucidating mechanisms of immune surveillance and immune evasion. © 2015 The Authors. Molecular Carcinogenesis, published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

A murine model for the development of melanocytic nevi and their progression to melanoma

et al. 2015

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“…Melanoma in Sinclair swine usually develops in utero or within the first 6 weeks of life (Gomez-Raya et al, 2007), with lesions varying from benign flat nevi to large, deeply invasive, exophytic tumors possessing characteristics of malignant tumors (Das Gupta et al, 1989) as well as some in vitro characteristics of benign neoplastic cells found in childhood tumors such as retinoblastoma or neuroblastoma that are of neural or neural crest tissue origin as are melanocytes. Cutaneous malignant melanoma in Sinclair swine may have multiple primary sites and usually disseminates in the lymph nodes and visceral organs (Das Gupta et al, 1989;Greene et al, 1994;Greene et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Gene expression in Sinclair swine with malignant melanoma

Okomo-Adhiambo

Rink

Rauw

et al. 2012

Animal

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Sinclair swine develop an aggressive form of melanoma, which, in many cases, spontaneously regresses after a complete metastatic phase. We used Affymetrix GeneChip R Porcine Genome Arrays consisting of 24 123 probe sets to compare gene expression in white blood cells (WBCs) and various tissues including the liver, lungs, inguinal lymph nodes and spleen harvested from a Sinclair piglet afflicted by melanoma at birth and exhibiting metastatic lesions at weaning (6 weeks) with those from a full-sibling piglet that showed no incidence of melanoma at birth and weaning. The highest number (3489; ,14%) of significantly upregulated transcripts (fold change in gene expression >2.0 and t-test P-value r0.05) was observed in the liver, while the spleen exhibited the lowest number of upregulated transcripts (528; ,2%). Among significantly downregulated genes, the highest numbers were observed in the inguinal lymph nodes (3651; ,15%) and the least in WBCs (730; ,3%). Differentially expressed transcripts included genes involved in melanoma pathogenesis including SILV, TYR and RAB28. SILV was over-expressed 784-, 430-and 164-fold, while TYR was over-expressed 138-, 81-and 28-fold in the liver, lungs and inguinal lymph nodes, respectively. Quantitative real-time RT-PCR (qRT-PCR) confirmed the microarray data of 12 selected differentially expressed sequences. These results suggest that significant changes in gene expression occur during metastasis of malignant melanoma in the Sinclair swine model. In addition, qRT-PCR analysis of the above 12 differentially expressed sequences was carried out on liver samples collected from 22 pigs (12 of which had melanoma during the first 6 weeks of life), and an ANOVA test contrasting absolute RNA expression between pigs with regressing, progressing and without tumors was significant for TYR, TACSTD1, MATP, GPNMB and CYP4A22, with P-values of 0.034, 0.015, 0.007, 0.050 and 0.022, respectively.

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“…Natural selection acting against the disease should be incorporated into mapping methods to uncover the mode of inheritance of this disease. Recently, Gomez‐Raya et al. (2007) proposed linkage analysis methods to discriminate between a tumour initiator locus (with alleles needed to develop the disease) and other loci increasing penetrance (number of tumours).…”

Section: Discussionmentioning

confidence: 99%

“…Natural selection acting against the disease should be incorporated into mapping methods to uncover the mode of inheritance of this disease. Recently, Gomez-Raya et al (2007) proposed linkage analysis methods to discriminate between a tumour initiator locus (with alleles needed to develop the disease) and other loci increasing penetrance (number of tumours). Their approach was first to search for loci needed for expression of the disease and, second, to search for loci affecting the aggressiveness (once the animal suffers the disease).…”

Section: Number Of Tumuorsmentioning

confidence: 99%

Role of selection and inbreeding on the incidence of cutaneous malignant melanoma in Sinclair swine

Gomez‐Raya

Amoss

et al. 2009

J Animal Breeding Genetics

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This paper reports the quantitative analysis of the historical database of a herd of Sinclair swine affected by cutaneous malignant melanoma. The herd was under partial and non-systematic selection for melanoma susceptibility (animals having at least one tumour during the first 6 weeks of life). Weighted selection differentials for the number of tumours at birth and the number of tumours at 6 weeks were generally positive and between -0.43 and 4.76 tumours for the number of tumours at 6 weeks. Estimates of the heritability for number of tumours at birth and at 6 weeks using 1934 animals were 0.27 (+/-0.03) and 0.25 (+/-0.03), respectively. The estimate of the genetic correlation between these two traits was 0.95 (+/-0.03). Genetic trends were positive for the number of tumours at birth and at 6 weeks. In spite of positive selection differentials and a moderate heritability, there was a negative phenotypic trend in the number of tumours. Natural selection might be acting in a direction opposite to artificial selection in the Sinclair herd. The slopes of the regression of the number of tumours at birth, at 6 weeks, and melanoma susceptibility on individual inbreeding coefficients were non-significant, indicating no evidence of dominance. The number of live-born pigs was lower in litters from parents susceptible to the disease (p < 0.01).

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Modeling Inheritance of Malignant Melanoma With DNA Markers in Sinclair Swine

Cited by 5 publications

References 22 publications

A murine model for the development of melanocytic nevi and their progression to melanoma

A murine model for the development of melanocytic nevi and their progression to melanoma

Gene expression in Sinclair swine with malignant melanoma

Role of selection and inbreeding on the incidence of cutaneous malignant melanoma in Sinclair swine

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