Molecular screening for somatic mutations in corticotropic adenomas of dogs with pituitary-dependent hyperadrenocorticism

Abstract

Pituitary tumorigenesis is now generally regarded as a multistep process of genomic damage leading to uncoupling of interdependent systems that control cell proliferation and differentiation. The alterations include mutations in genes encoding for proteins involved in signal transduction pathways, such as G-proteins and the p21 protein encoded for by the ras genes. Apart from their excessive secretion of ACTH, corticotropic adenomas are characterized by decreased sensitivity to inhibition by glucocorticoids. Therefore, mutations in the glucocorticoid receptor leading to decreased sensitivity to glucocorticoids may contribute to corticotropic tumor formation. In this study, 16 corticotropic adenomas of dogs with pituitary-dependent hyperadrenocorticism were screened for mutations in the Gs alpha, H-, K-, N-ras genes and the coding region of the DNA-binding domain of the glucocorticoid receptor. The cDNA fragment of the Gs alpha gene encompassed codons 159-240. The K-, and N-ras fragments spanned codons 1-71. The H-ras gene was only screened for mutations in codons 12/13 by direct sequencing of the PCR product. The cDNA fragment of the DNA-binding domain of the glucocorticoid receptor encompassed codons 410-500. The Gs alpha, K-ras, N-ras genes and the DNA-binding domain of the glucocorticoid receptor were screened by single-strand conformation polymorphism analysis. No mutations were found in the Gs alpha gene, the ras genes and the DNA-binding domain of the glucocorticoid receptor. It is concluded that mutations in the Gs alpha gene (codons 159-240), the K- and N-ras genes (codons 1-71), the H-ras gene (codons 12/13) and mutations in the DNA-binding domain of the glucocorticoid receptor do not play a role in the tumorigenesis of canine corticotropic adenomas.

Epidemiological, clinical, and laboratory aspects in a case series of canine hyperadrenocorticism: 115 cases (2010-2014)

“…This hypothesis would justify the greater frequency of ACTH-dependent HAC. However, new evidence discredits this possibility (van Wijk et al 2014). Despite significant improvement in the biomolecular techniques applied to endocrinology; etiopathogenesis and triggering factors of the mutations involved in HAC occurrence remain uncertain (Teshima et al 2009, Kool et al 2013.…”

Epidemiology of hyperadrenocorticism among 210,824 dogs attending primary‐care veterinary practices in the UK from 2009 to 2014

“…This study reports the estimated prevalence of diagnosis with canine hyperadrenocorticism in the UK as 0·28%, suggesting hyperadrenocorticism is the third most prevalent endocrinopathy of dogs behind hypothyroidism (0·87%, Dixon et al 1999 ) and diabetes mellitus (0·34%, Mattin et al 2014 ), although methodological differences between the various studies complicate direct prevalence comparisons. Despite several molecular studies that investigated aetiopathogenesis, the exact cause of hyperadrenocorticism in most dogs remains unknown (Teshima et al 2009, Hanson et al 2010, van Rijn et al 2010, Kool et al 2013, van Wijk et al 2014. Access to clinical health data on the large population of dogs in VetCompass offers the intriguing prospect of aetiological and epidemiological research across a range of disorders such as hyperadrenocorticism and of linking these with primary-care diagnosis and health management (Kearsley-Fleet et al 2012, O ' Neill et al 2013, Mattin et al 2014, Taylor-Brown et al 2015.…”

“…Despite several molecular studies that investigated its aetiopathogenesis, the exact cause of hyperadrenocorticism in most dogs remains unknown (Hanson et al, 2010, Kool et al, 2013, Teshima et al, 2009, van Rijn et al, 2010, van Wijk et al, 2014. Access to clinical health data on the large population of dogs in VetCompass offers the intriguing prospect of aetiological and epidemiological research across a range of disorders such as hyperadrenocorticism and of linking these with primary-care diagnosis and health management (Mattin et al, 2014, Kearsley-Fleet et al, 2012, Taylor-Brown et al, 2015, Mattin et al, 2015, O'Neill et al, 2013.…”