Bilateral Retinoblastoma in a Male Patient with an X;13 Translocation: Evidence for Silencing of the RB1 Gene by the Spreading of X Inactivation

Jones, Carrie K.; Booth, Carol; Rita, D; Jazmines, Lydia; Brandt, Birgit; Newlan, Anna; Horsthemke, Bernhard

doi:10.1086/523996

Cited by 7 publications

(9 citation statements)

References 11 publications

(20 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In all cases where blood was screened with a negative result, we have checked for promoter methylation. Again, none was found in this cohort although we have subsequently seen promoter methylation in one patient carrying an X;13 translocation (unpublished data) as previously reported by Jones et al 39. Of the 27 tumours found to be methylated, 13 had LOH (48%) while 14 (52%) did not.…”

Section: Discussionsupporting

confidence: 84%

Spectrum ofRB1mutations identified in 403 retinoblastoma patients

Price

Kolkiewicz

et al. 2013

J Med Genet

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 84%

Spectrum ofRB1mutations identified in 403 retinoblastoma patients

Price

Kolkiewicz

et al. 2013

J Med Genet

View full text Add to dashboard Cite

show abstract

“…In cases of X;autosome translocation the X inactivation signal may spread variably into an attached autosomal segment, with the translocated portion of autosome adopting features of the adjacent inactivated X chromatin (Jones et al 1997;Keitges and Palmer 1986). Many studies have shown that such translocated autosomal material can become delayed in its replication timing, and this feature is commonly used as a marker to define the extent of spread of X inactivation in such cases.…”

Section: Introductionmentioning

confidence: 99%

Absence of correlation between late-replication and spreading of X inactivation in an X;autosome translocation

2001

View full text Add to dashboard Cite

We have analysed the spread of X inactivation in an individual with an unbalanced 46,X,der(X)t(X;10)(q26.3;q23.3) karyotype. Despite being trisomic for the region 10q23.3-qter, both the proband and her aunt with the same karyotype presented only with secondary amenorrhoea and lacked any features normally associated with trisomy of distal 10q. Cytogenetic and molecular studies showed that the derivative X;10 chromosome was exclusively inactive. Transcribed polymorphisms were identified in five genes contained within the translocated region of chromosome 10 and were used to perform allele-specific transcription studies. We showed that four of the genes studied are inactive on the derivative chromosome, directly demonstrating the spread of X inactivation over some 30 Mb of autosomal DNA. However, the most distal gene examined remained active, indicating that this spreading was incomplete. In contrast to the gene expression data, replication timing studies showed no spreading of late replication into the translocated portion of 10q. We conclude that silencing of autosomal genes by X inactivation can occur without a delay in the replication timing of the surrounding chromatin. Our findings support the hypothesis that autosomal chromatin lacks certain features present on the X chromosome that are required for the effective spread and/or maintenance of X inactivation.

show abstract

“…In RB tissues, methylation of a CpG island (CpG106) encompassing the promoter region of RB1 is a quite frequent mechanism inactivating one copy of the gene (13%) but the same event in patients’ nontumor cells has been rarely described (Greger et al., ). In 1997, a first report provided evidence that RB can develop in the context of a X;13 translocation spreading X inactivation to chromosome 13 and producing functional monosomy for genes on proximal 13q including RB1 (Jones et al., ). A more recent study reported a possible constitutional methylation of the RB1 promoter as cause of hereditary RB; however such results have been questioned by Sloane and colleagues, in a subsequent letter on the same journal, given the lack of all the criteria necessary to demonstrate the presence of an epimutation (Quinonez‐Silva et al., ; Sloane, Ward, & Hesson, ).…”

mentioning

confidence: 99%

Evidence of predisposing epimutation in retinoblastoma

et al. 2018

View full text Add to dashboard Cite

Retinoblastoma (RB), which represents the most common childhood eye cancer, is caused by biallelic inactivation of RB1 gene. Promoter hypermethylation is quite frequent in RB tissues but conclusive evidence of soma‐wide predisposing epimutations is currently scant. Here, 50 patients who tested negative for RB1 germline sequence alterations were screened for aberrant promoter methylation using methylation‐specific MLPA. The assay, performed on blood, identified a sporadic patient with methylation of CpG106, absent in parents’ DNA. Bisulfite pyrosequencing accurately quantified CpG methylation in blood DNA (mean ∼49%) and also confirmed the aberration in DNA isolated from oral mucosa although at lower levels (mean ∼34%). Using a tag‐SNP, methylation was demonstrated to affect the maternal allele. Real‐time qPCR demonstrated RB1 transcriptional silencing. In conclusion, we documented that promoter methylation can act as the first “hit” in Knudson's model. This mosaic epimutation mimics the effect of an inactivating mutation and phenocopies RB onset.

show abstract

Bilateral Retinoblastoma in a Male Patient with an X;13 Translocation: Evidence for Silencing of the RB1 Gene by the Spreading of X Inactivation

Abstract: HH, et al. (1995)

Cited by 7 publications

References 11 publications

Spectrum ofRB1mutations identified in 403 retinoblastoma patients

Spectrum ofRB1mutations identified in 403 retinoblastoma patients

Absence of correlation between late-replication and spreading of X inactivation in an X;autosome translocation

Evidence of predisposing epimutation in retinoblastoma

Contact Info

Product

Resources

About