Identification of a novelRASD1somatic mutation in aUSP8-mutated corticotroph adenoma

Abstract

Cushing's disease (CD) is caused by pituitary corticotroph adenomas that secrete excess adrenocorticotropic hormone (ACTH). In these tumors, somatic mutations in the gene USP8 have been identified as recurrent and pathogenic and are the sole known molecular driver for CD. Although other somatic mutations were reported in these studies, their contribution to the pathogenesis of CD remains unexplored. No molecular drivers have been established for a large proportion of CD cases and tumor heterogeneity has not yet been investigated using genomics methods. Also, even in USP8-mutant tumors, a possibility may exist of additional contributing mutations, following a paradigm from other neoplasm types where multiple somatic alterations contribute to neoplastic transformation. The current study utilizes whole-exome discovery sequencing on the Illumina platform, followed by targeted amplicon-validation sequencing on the Pacific Biosciences platform, to interrogate the somatic mutation landscape in a corticotroph adenoma resected from a CD patient. In this USP8-mutated tumor, we identified an interesting somatic mutation in the gene RASD1, which is a component of the corticotropin-releasing hormone receptor signaling system. This finding may provide insight into a novel mechanism involving loss of feedback control to the corticotropin-releasing hormone receptor and subsequent deregulation of ACTH production in corticotroph tumors.

A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer

“…The remaining variants were first manually reviewed by examining the raw sequence reads to exclude false positives from automated WES variant calling algorithms. In addition, each variant was independently assessed by a Pacific Biosciences sequencing platform for orthogonal validation using targeted amplicon circular consensus sequencing, as previously described ( 47 , 50 ). Using this method, we confirmed the presence of each variant except for SMARCA4 , which was inconclusive strictly because of technical reasons and was included in our final selection of variants for building the Drosophila model.…”

Somatic variants in new candidate genes identified in focal cortical dysplasia type II

“…Recently, combining WES with amplicon sequencing has become an effective strategy for detecting somatic mutations in tumors, psychiatric disorders, and FCDII . To avoid false‐positive results in the WES data, we applied strict screening strategies, and we performed site‐specific amplicon sequencing for the validation.…”

Recent advances in understanding corticotroph pituitary tumor initiation and progression

“…So far, apart from mutated USP8, no other recurrent mutations have been found in CAs 4 , 23 , 38 . Thus, more than half of the CA cases may have a variable genetic background and may be associated with mutations of different single genes or may be caused by epigenetic mechanisms (see below).…”