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tvpjournal.com | November/December 2015 | ToDay's VeTeriNary PracTice caNiNe PiTuiTary DePeNDeNT HyPeraDreNocorTicism series Peer reviewed 41 Monoclonal Theory The main evidence against the hypothalamic theory is presence of tumor clonality in the majority of the adenomas studied in humans. 9,22 The monoclonal theory argues that the adenoma occurs in the pituitary outside of other infuences and arises through the somatic mutation of a corticotroph cell, resulting in a tumor clone. This mutation precedes the clonal expansion of the tumor. 23 Unknown are which mutation(s) result in the development of a tumor. Taking into account microadenomas and macroadenomas, the existence of a variety of corticotrophinomas is suggested. The majority of microadenomas in dogs do not progress to become macroadenomas. Macroadenomas can display a variety of behaviors, from limited growth and indolent course to more aggressive behavior as seen in human patients with Nelson's syndrome in which the pituitary tumor grows rapidly following bilateral adrenalectomy or suppressive medical therapy. 24 Gene Origin. In humans with functional ACTH- PAs, studies have identifed 43 genes and 22 proteins as overexpressed and 58 genes and 15 proteins as underexpressed compared with normal pituitary tissue (Table 2). 2 In dogs, we are just beginning to learn more about genes and protein expression in patients with PDH. The recent demonstration of expression of somatostatin receptor subtypes and dopamine receptor subtype 2 (D 2 ) in canine corticotroph adenomas offers the possibility for novel medical treatment of PDH with somatostatin analogs and dopamine agonists (see Part 3 of this series in a future issue of Today's Veterinary Practice). 19 Cancer Stem Cell Origin. Another possible origin of pituitary adenomas is found in cancer stem cells. In a recent study in dogs, the expression of melanotroph specifc transcription factor paired box protein 7 (Pax7) and stem cell marker and reprogramming factor sex determining region Y-box 2 (Sox2) was determined and correlated to parameters, such as tumor size. This study suggested that Pax7 and Sox2 remain interesting targets for molecular investigations into their roles in pituitary tumorigenesis, but were unsuitable as clinical prognosticators in dogs. 25 Pituitary Size & Proliferation Markers The ratio between pituitary height and area of the brain (P/B) has been used to evaluate pituitary size: • A P/B ratio > 0.31 indicates an enlarged pituitary • A P/B ratio ≤ 0.31 indicates a nonenlarged pituitary. A recent study investigated the expression of proliferation markers Ki-67 and minichromosome maintenance-7 (MCM7) in canine corticotroph adenomas in enlarged and nonenlarged pituitaries, and evaluated their relation to the size of canine pituitary corticotroph adenomas: 26 • Canine corticotroph adenomas in enlarged pituitaries showed greater proliferation potential compared with adenomas in nonenlarged pituitaries. • MCM7 expression was significantly greater than Ki-67 expression in canine pituitary corticotroph adenomas. Thus, MCM7 may be superior to Ki-67 as a proliferation marker in canine pituitary tumors. Table 2. Genes & Proteins Expressed in Pituitary Tissue in Humans with Functional ACTH-PAs 2 GENES NEUROD1 + hPTTG1 Overexpressed in 3 studies HIGD1B + HSD11B2 Overexpressed in 2 studies CDKN1B Underexpressed in 4 studies CDKN2A Underexpressed in 2 studies let-7 Underexpressed in 2 studies PROTEINS c-myc Overexpressed in 2 studies p27Kip1 Underexpressed in 4 studies p16 Underexpressed in 2 studies A polymorphism is a DNA sequence variation that is common in the population, and no single allele is regarded as the standard sequence. Instead, there are 2 or more equally acceptable alternatives. In contrast, a mutation is defned as any change in a DNA sequence away from normal, implying that there is a normal allele prevalent in the population and the mutation changes this to a rare and abnormal variant. The cut-off point between a mutation and polymorphism is 1%: To be classifed as a polymorphism, the least common allele must have a frequency of 1% or greater in the population. Once the frequency is less than 1%, the allele is regarded as a mutation. A missense mutation or polymorphism (compared to a nonsense mutation or polymorphism) is a single nucleotide change that results in a code for a different amino acid, leading to disease. Polymorphism Versus Mutation