Investigating Somatic Mutations in Pulmonary Lesions of Patients With Hereditary Pulmonary Arterial Hypertension and Hereditary Hemorrhagic Telangiectasia

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Abstract Introduction Hereditarypulmonary arterial hypertension (HPAH) and hereditary hemorrhagic telangiectasia(HHT) are two rare genetic diseases affecting the pulmonary vasculature. Theyare both characterized by haploinsufficiency in different components of the bonemorphogenetic protein receptor type 2 (BMPR2) pathway. Despite shared genetics, the vascular phenotype differs. HPAH causes plexiform lesions, convolutes ofvascular channels that are considered a pathological hallmark of PAH. Incontrast, HHT can lead to pulmonary arteriovenous malformations (pAVMs), directconnections between arteries and veins. The pathobiology of both plexiformlesions and pAVMs is incompletely understood. In HHT-associated vascularmalformations in the skin and some solid organs, there is evidence that loss ofheterozygosity caused by somatic loss-of-function mutations in the functionalallele of the HHT gene results in clonally expanding endothelial cells. Inplexiform lesions, clonal vascular expansion has been described as well. Wetherefore aimed at detecting somatic mutations in pulmonary vascular lesions ofpatients with HPAH and a patient with HHT and PAH (HHT/PAH). Methods Genomic DNA wasextracted from vascular lesions of 2 patients with HPAH and 1 patient with HHT/PAH.Whole exome sequencing was performed on 2 plexiform lesions of the HPAHpatients. A targeted deep sequencing panel including 3 HHT causing genes, and 11VM associated genes was applied to 4 pAVMs and 14 plexiform lesions of thepatient with HHT/PAH. Results Germline variants in BMPR2 andSMAD9 were confirmed in the 2 HPAH patients, and a germline variant in Endoglinin the HHT/PAH patient. Interestingly, a somatic mutation in BMPR2 was found in theplexiform lesion of the patient with HPAH due to haploinsufficiency in BMPR2, whereas a somatic mutationin SMAD9 was present in the plexiformlesion of the SMAD9 patient. In the HHT/PAH patient, somatic mutations in VMassociated genes occurred in 4 out of 14 plexiform lesions. These included asomatic activating mutation in Phosphatidylinositol-4,5-Bisphosphate 3-KinaseCatalytic Alpha (PIK3CA) that was previously described in breast cancer andfunctionally validated as a moderately potent oncogenic mutation. Furthermore, no somatic mutations were found in pAVMs of this patient. Conclusions We identified localsomatic mutations in PAH causing genes in plexiform lesions of HPAH patientsand a somatic activating mutation in PIK3CA in a plexiform lesion of an HHT/PAHpatient. Both events likely result inaltered signaling that might contribute to changed endothelial cell behaviorand excessive proliferation in plexiform lesions.

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