Differences in genetic and epigenetic alterations between von Hippel–Lindau disease–related and sporadic hemangioblastomas of the central nervous system

Abstract

<div class="section"> <a class="named-anchor" id="d6741516e223"> <!-- named anchor --> </a> <h5 class="section-title" id="d6741516e224">Background</h5> <p id="d6741516e226">Although inactivation of the von Hippel–Lindau gene ( <i>VHL</i>), located on chromosome 3p25, is considered to be a major cause of hemangioblastomas (HBs), the incidence of biallelic inactivation of <i>VHL</i> is reportedly low. The aim of this study was to determine the prevalence of <i>VHL</i> alterations in HBs, as well as to identify additional molecular aberrations. </p> </div><div class="section"> <a class="named-anchor" id="d6741516e237"> <!-- named anchor --> </a> <h5 class="section-title" id="d6741516e238">Methods</h5> <p id="d6741516e240">Genetic and epigenetic alterations were comprehensively and comparatively analyzed in 11 VHL-related and 21 sporadic HBs. </p> </div><div class="section"> <a class="named-anchor" id="d6741516e242"> <!-- named anchor --> </a> <h5 class="section-title" id="d6741516e243">Results</h5> <p id="d6741516e245"> <i>VHL</i> alterations detected by sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were more frequent in VHL-related HBs than in sporadic HBs (100% vs 62%; <i>P</i> = 0.029). <i>VHL</i> alterations were found only in 4 sporadic HBs by direct sequencing; however, targeted deep sequencing detected 9 additional alterations. Loss of heterozygosity (LOH) on chromosome 3 was found in 64% and 57% of VHL-related and sporadic HBs, respectively, by single nucleotide polymorphism (SNP) array analysis. Among 19 tumors with chromosome 3 LOH, 5 were classified as copy-neutral LOH. <i>VHL</i> promoter hypermethylation was detected only in sporadic HBs (33%), indicating that epigenetic suppression of <i>VHL</i> is a common mechanism in sporadic HBs. The rate of biallelic <i>VHL</i> inactivation among VHL-related and sporadic HBs was 64% and 52%, respectively. LOH on either chromosome 6 or 10 was detected only in sporadic HBs (43%). </p> </div><div class="section"> <a class="named-anchor" id="d6741516e266"> <!-- named anchor --> </a> <h5 class="section-title" id="d6741516e267">Conclusion</h5> <p id="d6741516e269">Although biallelic inactivation of <i>VHL</i> is a dominant mechanistic cause of the pathogenesis of HB, other unknown mechanisms may also be involved, and such mechanisms may be different between VHL-related and sporadic HB. </p> </div>