Consistent copy number changes and recurrent PRKAR1A mutations distinguish Melanotic Schwannomas from Melanomas: SNP‐array and next generation sequencing analysis

Abstract

Melanotic Schwannomas (MS) are rare tumors that share histological features with melanocytic tumors and schwannomas. However, their genetics are poorly understood. To elucidate the genetic characteristics of MS, we performed genome-wide studies in a series of cases. Twelve MS cases were available for the study. Genomic DNAs extracted from formalin-fixed paraffin embedded tumor tissues were subjected to copy number (CN) and allelic imbalance (AI) analysis by Single Nucleotide Polymorphism (SNP)-array and screened for mutations in coding exons of 341 key cancer-associated genes using a hybrid capture-based next-generation sequencing (NGS) assay. Sanger sequencing was used to further verify recurrent mutations detected by NGS study. SNP-array analysis revealed remarkably stereotypic chromosomal abnormalities in MS. Hypodiploidy was common, typically involving monosomies of chromosomes 1, 2, and 17. All 12 samples showed mutations in PRKAR1A gene, including 2 cases with 2 mutations each. The 14 mutations were scattered across PRKAR1A, and most were inactivating mutations. AI on 17q, presenting as loss of heterozygosity with or without CN losses, combined with a PRKAR1A mutation was observed in 9/12 MS cases. The remaining 3 cases included the two samples harboring two mutations in PRKAR1A. MS exhibits a stereotypic pattern of chromosomal losses. In contrast, melanomas are typically characterized by the presence of multiple CN aberrations, without demonstrable differences in the frequency of losses and gains. Inactivation of both alleles of PRKAR1A by "two hits" observed in almost all cases underscores the central role of PRKAR1A in the pathogenesis of this neoplasm. © 2015 Wiley Periodicals, Inc.

Myxoid fibroadenomas differ from conventional fibroadenomas: a hypothesis‐generating study

“…PRKAR1A encodes the cAMP‐dependent protein kinase type I‐α regulatory subunit, and its inactivation induces protein kinase A activation and tumorigenesis . As PRKAR1A is a tumour suppressor gene, biallelic inactivation of PRKAR1A has been documented in tumours of the Carney complex . It has been suggested, however, that PRKAR1A may be haploinsufficient, given that no loss of heterozygosity (LOH) was found in an eyelid myxoma occurring in a patient known to be heterozygous for a common PRKAR1A germline mutation .…”

“…3 Somatic PRKAR1A mutations may contribute to~30% of tumours of the Carney complex spectrum occurring in patients without other features of Carney complex and without a germline inactivating mutation in PRKAR1A. 6,37 For instance, recurrent somatic PRKAR1A mutations have been described in cardiac myxomas 38 and melanotic schwannomas, 39 which are tumour types observed in Carney complex patients. 7,39,40 PRKAR1A encodes the cAMP-dependent protein kinase type I-a regulatory subunit, and its inactivation induces protein kinase A activation and tumorigenesis.…”

“…6,37 For instance, recurrent somatic PRKAR1A mutations have been described in cardiac myxomas 38 and melanotic schwannomas, 39 which are tumour types observed in Carney complex patients. 7,39,40 PRKAR1A encodes the cAMP-dependent protein kinase type I-a regulatory subunit, and its inactivation induces protein kinase A activation and tumorigenesis. 6,7,41 As PRKAR1A is a tumour suppressor gene, biallelic inactivation of PRKAR1A has been documented in tumours of the Carney complex.…”

“…6,7,41 As PRKAR1A is a tumour suppressor gene, biallelic inactivation of PRKAR1A has been documented in tumours of the Carney complex. 39 It has been suggested, however, that PRKAR1A may be haploinsufficient, given that no loss of heterozygosity (LOH) was found in an eyelid myxoma occurring in a patient known to be heterozygous for a common PRKAR1A germline mutation. 42 Our findings of a PRKAR1A mutation with a low mutant allele fraction (Table S2) in a breast myxoma are consistent with a heterozygous mutation, and the lack of coupled LOH further supports the notion that loss of one copy of PRKAR1A may be sufficient for myxomagenesis.…”

Sporadic melanotic schwannoma with overlapping features of melanocytoma bearing a GNA11 mutation in an adolescent girl

“…The genetic characteristics of sporadic MSs are largely unknown. Studies have shown genomic losses of chromosomes 1, 2, 17, 21, and 22 . On the other hand, PMSs in the context of CNC are due to germline mutations in the PRKAR1A gene .…”