Genetic background influences tumour development in heterozygous Men1 knockout mice

Area of Science:

• Endocrinology
• Genetics
• Oncology

Background:

• Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by MEN1 germline mutations, leading to parathyroid, pancreatic, and pituitary tumors.
• Familial Isolated Primary Hyperparathyroidism (FIHP) is a milder form caused by identical mutations, suggesting genetic modifiers influence tumor phenotype.
• Adult Men1+/- mice develop tumors in multiple endocrine glands, serving as a model for studying genetic influences.

Purpose of the Study:

• To investigate the impact of genetic background on tumor development in Men1+/- mice.
• To identify potential genetic modifiers that alter the phenotypic expression of MEN1-related tumors.

Main Methods:

• Backcrossing Men1+/- mice to C57BL/6 and 129S6/SvEv strains to create congenic lines.
• Macroscopic study of 275 Men1+/- mice (aged 5-26 months) to assess tumor development.
• Whole genome sequencing and qRT-PCR analysis to identify genetic variants and gene expression differences.

Main Results:

• Genetic background significantly influenced pituitary, adrenal, and ovarian tumor development in Men1+/- mice.
• Tumor onset and frequency varied between C57BL/6 and 129S6/SvEv strains, with specific patterns observed in males and females.
• Whole genome sequencing identified numerous genetic variants, with Kras showing significantly higher expression in the pituitaries of male 129S6/SvEv mice.

Conclusions:

• Genetic background plays a crucial role in modulating tumor development in MEN1.
• Genes such as Kras are potential candidates for genetic modifiers of Men1, influencing tumor phenotype and progression.