Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor.
Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor. We explored their possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.
Scott
Richard H
RH
Section of Cancer Genetics, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, SM2 5NG, UK.
Douglas
Jenny
J
Baskcomb
Linda
L
Huxter
Nikki
N
Barker
Karen
K
Hanks
Sandra
S
Craft
Alan
A
Gerrard
Mary
M
Kohler
Janice A
JA
Levitt
Gill A
GA
Picton
Sue
S
Pizer
Barry
B
Ronghe
Milind D
MD
Williams
Denise
D
Cook
Jackie A
JA
Pujol
Pascal
P
Maher
Eamonn R
ER
Birch
Jillian M
JM
Stiller
Charles A
CA
Pritchard-Jones
Kathy
K
Rahman
Nazneen
N
D001824:Body Constitution / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D017384:Sequence Deletion; D009396:Wilms Tumor / Q000235:genetics*
C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated