New Insights from the Expression of the Mismatch Repair System in Pituitary Neuroendocrine Tumors

Although defects in the mismatch repair (MMR) system have been occasionally reported in aggressive/metastatic pituitary neuroendocrine tumors (PitNETs), the potential role of MMR dysregulation in pituitary tumorigenesis is largely unknown. This study aimed to evaluate the expression of the four key MMR components in a large series of PitNETs. MMR gene expression was studied by RT-qPCR in 127 tumors (54 PIT1, 51 SF1, 22 TPIT), and semi-quantitative immunohistochemistry (score 0-12) in selected cases (n=46). MSH2/6 and MLH1 promoters methylation was studied in 96 tumors. Except for MLH1, tumor lineage of origin was the most significant factor influencing MMR transcripts (P=0.005, <0.001 and 0.039 for MSH2/6 and PMS2, respectively), the highest levels being observed in SF1 tumors. Within subgroups, MMR transcripts were significantly lower in large/invasive PIT1 and in functioning TPIT tumors. MSH2 promoter methylation was occasionally associated with reduced MSH2 expression. Global loss of MSH6 (score 0), defining MMR deficiency, was observed in a single silent lactotroph PitNET, unrelated to the Lynch's syndrome. Near global loss involving MSH6, MSH2 or PMS2 (score 1) was observed in 5 tumors (1 lactotroph, 1 SF1, 3 TPIT). MMR mutations were excluded in 4/5 cases but 2 had LOH at MSH2/MSH6 loci. Heterogeneous immunostaining for any MMR (score 2-4) was also observed in 15 cases. In conclusion, MMR deficiency was rarely observed (2.2%) but reduced MMR expression could be found, especially in functioning corticotroph and invasive lactotroph tumors. The molecular mechanisms and prognostic significance of such findings would deserve further investigation.