ABSTRACT
Acromegaly is a rare disease due to chronic excess growth hormone (GH) and IGF-1. Aryl hydrocarbon receptor interacting protein (AIP) mutations are associated with an aggressive, inheritable form of acromegaly that responds poorly to SST2-specific somatostatin analogs (SSA). The role of pasireotide, an SSA with affinity for multiple SSTs, in patients with AIP mutations has not been reported. We studied two AIP mutation positive acromegaly patients with early-onset, invasive macroadenomas and inoperable residues after neurosurgery. Patient 1 came from a FIPA kindred and had uncontrolled GH/IGF-1 throughout 10 years of octreotide/lanreotide treatment. When switched to pasireotide LAR, he rapidly experienced hormonal control which was associated with marked regression of his tumor residue. Pasireotide LAR was stopped after >10 years due to low IGF-1 and he maintained hormonal control without tumor regrowth for >18 months off pasireotide LAR. Patient 2 had a pituitary adenoma diagnosed when aged 17 that was not cured by surgery. Chronic pasireotide LAR therapy produced hormonal control and marked tumor shrinkage but control was lost when switched to octreotide. Tumor immunohistochemistry showed absent AIP and SST2 staining and positive SST5. Her AIP mutation positive sister developed a 2.5 cm follicular thyroid carcinoma aged 21 with tumoral loss of heterozygosity at the AIP locus and absent AIP staining. Patients 1 and 2 required multi-modal therapy to control diabetes. On stopping pasireotide LAR after >10 years of treatment, Patient 1's glucose metabolism returned to baseline levels. Long-term pasireotide LAR therapy can be beneficial in some AIP mutation positive acromegaly patients that are resistant to first-generation SSA.
ABSTRACT
Recent advances in population genomics have triggered great interest in the genomic landscape of divergence in taxa with 'porous' species boundaries. One important obstable of previous studies of this topic was the low genomic coverage achieved. This issue can now be overcome by the use of 'next generation' or short-read DNA-sequencing approaches capable of assaying many thousands of single nucleotide polymorphisms (SNPs) in divergent species. We have scanned the 'porous' genomes of Populus alba and Populus tremula, two ecologically divergent hybridizing forest trees, using >38,000 SNPs assayed by restriction site associated DNA (RAD) sequencing. Windowed analyses indicate great variation in genetic divergence (e.g. the proportion of fixed SNPs) between species, and these results are unlikely to be strongly biased by genomic features of the Populus trichocarpa reference genome used for SNP calling. Divergence estimates were significantly autocorrelated (P < 0.01; Moran's I up to 0.6) along 11 of 19 chromosomes. Many of these autocorrelations involved low divergence blocks, thus suggesting that allele sharing was caused by recurrent gene flow rather than shared ancestral polymorphism. A conspicuous low divergence block of three megabases was detected on chromosome XIX, recently put forward as an incipient sex chromosome in Populus, and was largely congruent with introgression of mapped microsatellites in two natural hybrid zones (N > 400). Our results help explain the origin of the 'genomic mosaic' seen in these taxa with 'porous' genomes and suggest rampant introgression or extensive among-species conservation of an incipient plant sex chromosome. RAD sequencing holds great promise for detecting patterns of divergence and gene flow in highly divergent hybridizing species.
