Atypical pituitary adenoma with MEN1 somatic mutation associated with abnormalities of DNA mismatch repair genes; MLH1 germline mutation and MSH6 somatic mutation.

The mechanism of pituitary tumorigenesis remains largely unknown. Lynch syndrome is an autosomal, dominantly inherited syndrome caused by a defective mismatch repair (MMR) mechanism involved in the development of various tumors at an early age. In this case study, we showed the occurrence of pituitary tumors associated with Lynch syndrome for the first time and performed genetic and immunohistochemical analysis to evaluate the genetic aberrations that might be related to the tumorigenesis and proliferation. A 68-year-old female patient with Lynch syndrome due to mutL homolog 1 (MLH1) gene mutation suffered from hypersecretion of adrenocorticotrophic hormone (ACTH), hypercortisolism and a rapidly progressive pituitary tumor. We performed genetic analysis by whole genome sequencing with genomic DNA of the pituitary tumor and peripheral blood leukocytes, as well as immunohistochemical analysis of MMR proteins. Genetic analysis revealed that the tumor had homozygous gene mutation of MEN1 associated with pituitary tumorigenesis and mutS homolog 6 (MSH6) gene. Furthermore, immunohistochemical analysis showed that MLH1 and MSH6 immunoexpression were negative. We reveal for the first time that MMR abnormality could cause somatic mutation of MEN1 and pituitary tumor occurrence is associated with Lynch syndrome. We suggest that the identified gene mutations, especially those of MSH6 and MLH1 genes, may be involved in the pathogenesis and proliferation of pituitary tumor. The knowledge obtained from our case study is important to elucidate the pathogenesis and proliferation mechanisms of pituitary tumors.