1A). Accordingly, cancers may arise either di-
rectly in isolation through LOH of 11p15, or
indirectly via clonal nephrogenesis with per-
turbation of 11p15 by hypermethylation ofH19.
Our findings show that clonal expansions in
histologically normal tissue are an atypical out-
come of renal development that commonly an-
tedates Wilms tumor. We demonstrated a direct
phylogenetic link between clonal expansions,
H19hypermethylation, and the formation of
cancer, thus identifyingclonal nephrogenesis
as an epigenetic progenitor of cancer compris-
ing“neoplasia-ready cells”( 12 ). In contrast to
precursors of adult cancer, clonal nephrogene-
sis generated histologically and functionally
normal tissues, which in the most pronounced
cases occupied the bulk of renal tissues. If
future work shows that the extent of clonal
nephrogenesis is a marker of malignant po-
tential and risk of cancer recurrence, this in-
formation potentially could be used to guide
treatment and surveillance of patients with
Wilms tumor. Moreover, if we were able to
manipulate the neoplastic potential of clonal
nephrogenesis, prevention of Wilms tumor
could become feasible. Collectively, our findings
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background of a premalignant tissue bed, rather
than a clearly demarcated neoplasm in an other-
wise normal polyclonal kidney. We speculate
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ACKNOWLEDGMENTS
We thank the research nursing staff at Cambridge University
Hospitals, the Royal Hospital for Sick Children (Edinburgh), and
the Royal Hospital for Children (Glasgow) as well as all IMPORT
investigators. We thank M. Gerstung and A. J. Lawson for critical
review of the manuscript. We are indebted to our little and older
patients and their families for participating in our research.Funding:
This project was principally funded by the Little Princess Trust,
the St. Baldrick’s Foundation (Robert J. Arceci International Award
to S.B.), and Wellcome (fellowship to S.B.; Sanger core funding).
Additional funding was received from CRUK (IMPORT study;
fellowship to T.J.M.; Cambridge Centre), NIHR (Biomedical
Research Centre Great Ormond Street; Cambridge Human
Research Tissue Bank; Oxford Biomedical Research Centre;
fellowship to T.R.W.O.), the Royal College of Surgeons of
England (fellowship to T.J.M.), Wellcome (fellowship to T.H.H.C.
and K.S.), Great Ormond Street Hospital Children’sCharityCoorenset al.,Science 366 , 1247–1251 (2019) 6 December 2019 4of5
Fig. 3. Phylogenies of bilateral and multifocal
Wilms tumor.(A,C,E, andG) For each tumor,
the phylogeny of shared mutations is shown
including de novo germline mutations, embryonic
mutations, mutations demarcating clonal neph-
rogenesis, and tumor mutations. Numbers refer
to the number of substitutions defining each
developmental trunk. Truncal driver events are
detailed. (B) Heat map showing the contribution
of a mutation to the sample PD40735 shown in
(A). The pattern of shared mutations reveals a
split between
left and right kidney, which is obeyed
by both tumor and normal samples.
(D) As revealed by the pattern of shared
mutations, in patient PD36159 the left
tumor is more closely related to the right branch
of clonal nephrogenesis than to
the left branch. (F) Two mutations indicate the
independent emergence of tumors
at different time points from the nephrogenic
clone in patient PD40641. As shown in (G),
tumor and nephrogenic rest in patient PD36165
both originated from clonal
nephrogenesis despite being situated
at opposing kidney poles.
RESEARCH | REPORT
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