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CONSTITUTIONAL AND SOMATIC METHYLATION STATUS OF DMRH19 AND KVDMR IN WILMS TUMOR PATIENTS
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Abstract
The most frequent epigenetic alterations in Wilms tumor (WT) occur at WT2, assigned to 11p15. WT2 consists of two
domains: telomeric domain 1 (DMRH19) that contains the IGF2 gene and an imprinted maternally expressed transcript
(H19) and centromeric domain 2 (KvDMR) that contains the genes KCNQ1, KCNQ1OT1 and CDKN1C. In this
work, we used pyrosequencing and MS-MLPA to compare the methylation patterns of DMRH19/KvDMR in blood
and tumor samples from 40 WT patients. Normal constitutional KvDMR methylation indicated that most of the
epigenetic alterations in WT occur at DMRH19. Constitutional DMRH19 hypermethylation (HM DMRH19) was observed
in two patients with Beckwith-Wiedemann syndrome. Pyrosequencing and MS-MLPA showed HM DMRH19
in 28/34 tumor samples: 16/34 with isolated HM DMRH19 and 12/34 with concomitant HM DMRH19 and KvDMR
hypomethylation, indicating paternal uniparental disomy. With the exception of one blood sample, the MS-MLPA and
pyrosequencing findings were concordant. Diffuse or focal anaplasia was present in five tumor samples and was associated
with isolated somatic HM DMRH19 in four of them. Constitutional 11p15 methylation abnormalities were
present in 5% of the samples and somatic abnormalities in the majority of tumors. Combined analysis of
DMRH19/KvDMR by pyrosequencing and MS-MLPA is beneficial for characterizing epigenetic anomalies in WT,
and MS-MLPA is useful and reliable for estimation of DNA methylation in a clinical setting.
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