Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors

Objective/Purpose: The aryl hydrocarbon receptor (AHR) pathway plays a critical role inthe biology of Growth Hormone (GH)-secreting pituitary tumor (somatotropinoma).Germline rs2066853 AHR variant was found to be more frequent among acromegalypatients and associated with a more severe disease with larger invasive somatropinoma,and with resistance to somatostatin analogs treatment in patients living in polluted areas.However, no somatic changes in AHR gene have been reported so far in acromegalypatients. On that basis, the aim of the study was to assess at the somatic level the AHRgene status encompassing exon 10 region, also because of the high rate of variants foundin this genomic region.Methods: A cohort of 13 patients aged 20-76 years with biochemical, clinical andhistological diagnosis of somatotropinoma was studied. DNA and RNA from pituitarytumor histological samples have been extracted and analyzed by PCR and directsequencing for AHR gene variants, and compared with corresponding patients'germline DNA as well as normal pituitary tissue as reference control.Results: A degenerated letter codes in the region corresponding to AHR exon 10(c.1239-c.2056) was detected in somatotropinomas-derived DNA but not in that ofmatched germline and pituitary normal tissue. By multiple PCR and sequencing analysis,we observed amplification only before codon 1246 and after codon 1254, confirming thepresence of a tumor-restricted somatic deletion in the 5' upstream region of AHR exon 10.Analysis of PCR-amplified cDNA revealed a wildtype sequence of exon 9 and 10 in normalpituitary tissue, and a wildtype sequence of exon 9 and 10 up to codon 1246 and nosequence after the deletion region (c.1246-c.1254) in 6 out of 9 tumor samples. Patientscarrying the germline rs2066853 AHR variant showed no somatic LOH at thecorresponding genetic locus.Conclusion: This is the first demonstration of a recurrent somatic deletion in the exon 10of the AHR gene in somatotropinomas. The functional impact of this genetic finding needsto be clarified.