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Wilms tumor and constitutional epigenetic defects
© 2008 Nature Publishing Group http://www.nature.com/naturegenetics
Andrea Riccio Constitutional epigenetic defects affecting the 11p15.5 imprinted region cause a number of syndromic conditions involving birth defects. Now, an analysis of a large cohort of individuals with nonsyndromic Wilms tumor demonstrates the presence of known and newly identified constitutional IGF2-H19 imprinting defects, extending the phenotype associated with soma-wide 11p15.5 imprinting disorders. Constitutional defects affecting the imprinted gene cluster located at chromosome 11p15.5 cause a variety of syndromes characterized by congenital growth disorders, either growth enhancement or growth retardation1,2. Among these conditions, an increased risk of developing pediatric cancer is associated with the overgrowth disorders, of which the best characterized is the Beckwith-Wiedemann syndrome (BWS)2. A new study shows that 11p15.5 imprinting abnormalities including two newly identified mutations of the IGF2-H19 imprinting center are present in the blood lymphocytes of individuals with Wilms tumor and no overgrowth or other syndromic features3. These cases include one familial pedigree but also a significant fraction (3%) of sporadic Wilms tumor cases, many of which were bilateral. This observation is relevant because it demonstrates that recurrence risks of nonsyndromic Wilms tumor can, at least in part, be estimated with a simple blood test, in both the probands and their families.
BWS molecular defects can be found at lower frequency in individuals with only some of its clinical features, such as those affected by isolated hemihyperplasia5. Somatic defects at 11p15.5 have also been found in several tumors, including Wilms tumor6. Loss of IGF2 imprinting has been detected in the lymphocytes of individuals with colorectal cancer7 and IGF2-H19 imprinting defects have been found in the normal kidney cells surrounding nonsyndromic Wilms tumor8,9. Through the analysis of more than 400 affected individuals with a newly developed methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) method, Scott et al.3 now find that 11p15.5 imprinting alterations are soma-wide in a subset of nonsyndromic sporadic and familial Wilms tumor cases, indicating that these lesions are either germline or originate very early during development.
The 11p15.5 imprinted locus and its defects The 11p15.5 imprinted gene cluster includes more than ten imprinted genes organized in two domains, each controlled by a separate imprinting center (IC1 and IC2)4. The IGF2 and H19 genes are in domain 1, and genes such as CDKN1C and KCNQ1OT1 are in domain 2. Individuals with BWS have heterogeneous molecular defects affecting one or both domains of the cluster, including paternal uniparental disomy (UPD) or duplication, CDKN1C mutations and IC epimutations and microdeletions2. Phenotypic expression of BWS is variable and includes features such as macroglossia, gigantism, abdominal wall defects and predisposition to embryonal tumors, particularly Wilms tumor. Typical
11p15.5 paternal UPD P and M
Andrea Riccio is at the Department of Environmental Science, Second University of Naples, Caserta 81100, Italy and at the Institute of Genetics and Biophysics “A. BuzzatiTraverso”, CNR, Naples 80131, Italy. e-mail:
[email protected]
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The molecular abnormalities include cases of UPD and IC1 hypermethylation, a newly identified IC1 microdeletion and an IC1 microinsertion. The IGF2-H19 domain The imprinting of the paternally expressed IGF2 and maternally expressed H19 is controlled by IC1, which is located upstream of the H19 transcription start site4. On the maternal chromosome, IC1 binds the zincfinger protein CTCF that, by inducing higherorder chromatin structures, insulates IGF2 from the effects of downstream enhancers. On the paternal chromosome, the insulator function of IC1 is inactivated by DNA methylation that inhibits CTCF binding. In BWS, aberrant IGF2 activation and H19 silencing result from paternal UPD or heterogeneous molecular defects that
Table 1 Constitutional defects of the 11p15.5 imprinted locus and associated phenotypes Genetic abnormality
Affected allelea Epigenetic abnormality
Phenotypeb
Paternal epigenotype duplicated/ BWS, IH, WT maternal epigenotype lost
Risk of recurrencec Low
11p15.5 duplication
P
Paternal epigenotype duplicated BWS
High
11p15.5 duplication
M
Maternal epigenotype duplicated SRS
High
None
M
IC1 hypermethylation
BWS, IH, WT
Low
None
P
IC1 hypomethylation
SRS
Low Low
None
M
IC2 hypomethylation
BWS, IH
None
M
Biallelic IGF2 expression7
Colorectal cancer Undefined
IC1 microdeletion
M
IC1 hypermethylation
BWS
High
M
None
BWS
High, but lower than that of the other IC1 microdeletions
M
IC1 hypermethylation
BWS, WT
High
M
IC1 hypermethylation
WT
High
(CTSs 2-3 or CTS 4)12 IC1 microdeletion (CTSs 3-5)11
IC1 microdeletion (CTSs 1-6)3 IC1 microinsertion (+ 2 CTSs)3 IC2 microdeletion15
M
CDKN1C silencing
BWS
High
Translocations with breakpoint in KCNQ1
M
Undefined
BWS
High
CDKN1C mutation
M or P
None
BWS
High
aM,
maternal allele; P, paternal allele. bBWS, Beckwith-Wiedemann syndrome; SRS, Silver-Russell syndrome; IH, isolated hemihyperplasia; WT, nonsyndromic Wilms tumor. cRecurrence risk of a given abnormality is assumed, in some cases, rather than derived from a significant amount of data. When not otherwise indicated, see refs. 1, 2 and 6 for references on molecular defects. Red text indicates new findings reported by Scott et al.3.
volume 40 | number 11 | november 2008 | nature genetics
© 2008 Nature Publishing Group http://www.nature.com/naturegenetics
news and views presumably inactivate the maternal IC1. BWS cases with domain 1 alterations or UPD have a higher risk of developing Wilms tumor than cases with other molecular abnormalities10. The defects reported by Scott et al.3 mainly affect domain 1 and confirm the role that the IGF2 and H19 genes have in the pathogenesis of Wilms tumor. One of the mutations found by Scott et al. is a deletion removing most of the CTCF binding sites (CTS) of IC1 (ref. 3). Intriguingly, the other defect is a microinsertion resulting in the addition of two further CTSs and at first glance does not resemble an inactivating mutation. This lesion, however, is associated with abnormal methylation when maternally transmitted. The microdeletions found in BWS suggest that alterations of the CTS spacing result in gain of IC1 methylation and this seems to be critical for the penetrance of the phenotype11,12. By interrupting the two CTS clusters present in the wild-type IC1, the microinsertion found by Scott et al. strongly supports this hypothesis3. Such a mutation probably abolishes the IC1 insulator activity by inducing de novo methylation. Mouse studies indicate that deficient CTCF binding results in gain of methylation of its target sites in early embryogenesis13. Whether IC1 mutations cause hypermethylation because they interfere with CTCF binding or with
other properties of this regulatory region remains to be seen. Clinical heterogeneity The study of Scott et al.3 further expands the list of molecular defects and phenotypes derived from constitutional 11p15.5 defects (Table 1). The clinical heterogeneity derives only in part from the presence of different alleles. Scott et al. clearly show that the same constitutional 11p15.5 alterations can result in a spectrum of phenotypes ranging from BWS to isolated Wilms tumor3. As a notable example of this, in the case of two siblings who inherited the same IC1 microdeletion, one showed features of BWS and the other had nonsyndromic Wilms tumor. The reason for this heterogeneity likely resides in the epigenetic nature of the causative defect, as variegated phenotypes are typical features of epigenetic phenomena14. The origin of this variation may be stochastic or due to environmental factors or other genes. The IC1 epimutations (including those associated with mutations) are generally mosaic, consistent with the proposal that they originate postzygotically3,12. Different degrees of mosaicism may be a possible explanation for the phenotypic variability (although in this study the authors did not find differences in the level of IC1 hypermethylation in the tis-
sues of the affected individuals analyzed 3). Functional polymorphisms in genes interacting with IGF2-H19 may also be implicated. Further investigation of constitutional epigenetic abnormalities in nonsyndromic cancer is needed to identify at-risk individuals and ultimately to improve cancer prevention. 1. Rossignol, S., Netchine, I., Le Bouc, Y. & Gicquel, C. Best Pract. Res. Clin. Endocrinol. Metab. 22, 403–414 (2008). 2. Weksberg, R., Shuman, C. & Smith, A.C. Am. J. Med. Genet. C. Semin. Med. Genet. 137, 12–23 (2005). 3. Scott, R.H. et al. Nat. Genet. 40, 1329–1334 (2008). 4. Ideraabdullah, F.Y., Vigneau, S. & Bartolomei, M.S. Mutat. Res. advance online publication, doi: 10.1016/j.mrfmmm.2008.08.008 (20 August 2008). 5. Martin, R.A., Grange, D.K., Zehnbauer, B. & Debaun, M.R. Am. J. Med. Genet. A. 134A, 129–131 (2005). 6. Feinberg, A.P. & Tycko, B. Nat. Rev. Cancer 4, 143– 153 (2004). 7. Cui, H. et al. Science 299, 1753–1755 (2003). 8. Moulton, T. et al. Nat. Genet. 7, 440–447 (1994). 9. Okamoto, K. et al. Proc. Natl. Acad. Sci. USA 94, 5367–5371 (1997). 10. Cooper, W.N. et al. Eur. J. Hum. Genet. 13, 1025– 1032 (2005). 11. Prawitt, D. et al. Proc. Natl. Acad. Sci. USA 102, 4085–4090 (2005). 12. Sparago, A. et al. Hum. Mol. Genet. 16, 254–264 (2007). 13. Schoenherr, C.J., Levorse, J.M. & Tilghman, S.M. Nat. Genet. 33, 66–69 (2003). 14. Morgan, H.D., Sutherland, H.G., Martin, D.I. & Whitelaw, E. Nat. Genet. 23, 314–318 (1999). 15. Niemitz, E.L. et al. Am. J. Hum. Genet. 75, 844–849 (2004).
Rice, rising Yonghong Wang & Jiayang Li Two new studies identify PROG1, a gene underlying a quantitative trait locus that regulates rice tiller angle and that has likely been a target for artificial selection during rice domestication. Genetic manipulation of PROG1 has the potential to promote agronomically valuable traits. Rice (Oryza sativa L.) is one of the most important staple food crops that feed more than half of the world’s population. To meet increasing demand for rice production, new elite varieties with ideal plant architecture that can produce much higher grain yields need to be developed, following up on the ‘green revolution’ in which grain yields have been increased significantly by growing semi-dwarf varieties of wheat and rice1. Rice plant architecture is Yonghong Wang and Jiayang Li are in the State Key Laboratory of Plant Genomics and National Center for Plant Gene Research, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China. e-mail:
[email protected]
to a large extent determined by tiller number and tiller angle, and the selection of plants with ideal tiller angle and number is one of the most critical events in rice domestication. The transition from the characteristic architecture of wild rice to that of cultivars allows for effective high-yield production. However, the molecular basis of rice plant architecture and its selection remain elusive. On pages 1360 and 1365 of this issue2,3, two groups report a quantitative trait locus (QTL), PROG1 (PROSTRATE GROWTH 1), that regulates rice tiller angle and shows evidence of having been a target for artificial selection during rice domestication. These papers present a breakthrough toward the elucidation of molecular mechanisms underlying rice tiller angle. The authors not only advance our
nature genetics | volume 40 | number 11 | november 2008
understanding of how rice tiller angle is controlled, but also provide an example of how a domestication-selected gene can be genetically manipulated to increase agronomic value. Tiller angle, then and now Tiller angle of cereal crops is an important agronomic trait that contributes to grain production, and it has long attracted the attention of breeders aiming for ideal plant architecture to improve grain yield and developmental biologists attempting to understand the control of plant morphology. In practice, neither the extreme-spreading nor the compact plant type is beneficial to rice grain production. Spreading rice plants may escape from some diseases but occupy too much space, and the
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