Ept7, a quantitative trait locus that controls estrogen-induced pituitary lactotroph hyperplasia in rat, is orthologous to a locus in humans that has been associated with numerous cancer types and common diseases.

Kirsten L Dennison,Maureen Peters Hickman,Quincy Eckert Harenda,Aaron C Chack,James D Shull,Robert Daniel Blank

doi:10.1371/journal.pone.0204727

Abstract

Pituitary adenoma is a common intracranial neoplasm that is observed in approximately 10% of unselected individuals at autopsy. Prolactin-producing adenomas, i.e., prolactinomas, comprise approximately 50% of all pituitary adenomas and represent the most common class of pituitary tumor. Multiple observations suggest that estrogens may contribute to development of prolactinoma; however, direct evidence for a causal role of estrogens in prolactinoma etiology is lacking. Rat models of estrogen-induced prolactinoma have been utilized extensively to identify the factors, pathways and processes that are involved in pituitary tumor development. The objective of this study was to localize to high resolution Ept7 (Estrogen-induced pituitary tumor), a quantitative trait locus (QTL) that controls lactotroph responsiveness to estrogens and was mapped to rat chromosome 7 (RNO7) in an intercross between BN and ACI rats. Data presented and discussed herein localize the Ept7 causal variant(s) to a 1.91 Mb interval of RNO7 that contains two protein coding genes, A1bg and Myc, and Pvt1, which yields multiple non-protein coding transcripts of unknown function. The Ept7 orthologous region in humans is located at 8q24.21 and has been linked in genome wide association studies to risk of 8 distinct epithelial cancers, including breast, ovarian, and endometrial cancers; 3 distinct types of B cell lymphoma; multiple inflammatory and autoimmune diseases; and orofacial cleft defects. In addition, the Ept7 locus in humans has been associated with variation in normal hematologic and development phenotypes, including height. Functional characterization of Ept7 should ultimately enhance our understanding of the genetic etiology of prolactinoma and these other diseases.

Highlights

Pituitary adenoma is a common intracranial neoplasm that is observed in approximately 10% of unselected individuals examined at autopsy [1,2,3]
In order to further localize the Ept7 and Emca4 causal variants we generated and characterized multiple congenic rat strains, each of which is homozygous for Brown Norway (BN) alleles across a unique segment of RNO7 introgressed onto the ACI genetic background (S1 Table)
We evaluated survival of E2 treated rats from each congenic strain as a function of morbidities that are known to result from lactotroph hyperplasia/adenoma and gross pituitary enlargement (Table 1)

Summary

Introduction

Pituitary adenoma is a common intracranial neoplasm that is observed in approximately 10% of unselected individuals examined at autopsy [1,2,3]. Mutations in a small number of genes are known to underlie distinct genetic syndromes in which pituitary adenoma is observed. Examples of pituitary adenoma associated genes and syndromes include: MEN1, multiple endocrine neoplasia type I; CDKN1B, multiple endocrine neoplasia type IV; and PRKAR1A, Carney complex type 1 [4]. Non-syndromic forms of familial pituitary adenoma are becoming recognized. One such class of familial isolated pituitary adenoma results from mutations in AIP [5]. The majority of pituitary adenomas appear to be sporadic in origin, suggesting that acquired somatic mutations and/or common germline variants acting with low penetrance may contribute to development of these tumors

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