Wilms tumor

Digital cases

 Case 54 (HPC:54) : Post-chemotherapy Wilms tumor in Beckwith-Wiedemann syndrome

Localization

 kidney (renal Wilms tumor)
 extrarenal Wilms tumor

• ovarian Wilms tumor (11782005)
• testicular Wilm tumor (7529549)

• Wilms tumor in testicular germ cell tumor (15105660)

Macroscopical variants

 solid Wilms tumor
 cystic Wilms tumor
 botryoid Wilms tumor
 post-chemotherapy Wilms tumor

Microscopical variants

 anaplastic Wilms tumor (anaplasia in Wilms tumor)
 Wilms tumor with teratomatous cysts

Epidemiological variants

 Wilms tumor arising in a germ cell tumor (15105660)
 bilateral Wilms tumor (multiple Wilms tumor)
 adult Wilms tumor

Associations

 juxtaposed cystic nephroma and Wilms tumor (10594137)

Predisposition syndrome

 aniridia, WAGR syndrome (WT1 locus at 11p13)
 Drash syndrome (WT1 locus at 11p13)
 Beckwith-Wiedemann syndrome (BWS) (11p15.5)
 trisomy 18 (7700182, 12900902)
 monosomy X (Turner syndrome) (7700182)
 constitutional translocation t(1;7)(q42;p15)

• with skeletal anomalies (bilateral radial aplasia) (8946193, 1651392)

 constitutional translocation t(7;19)(q11.2;q13.3)

• with thick corpus callosum, enlarged cisterna magna, normal vermis, thick corpus callosum, micrognathia, small and low-set ears (16193462)

 Fanconi syndrome +/- BRCA2 biallelic mutations (14670928)

Cytogenetics

• target regions: 1q21, 1q42, 2p25, 5q21, 6q21, 7p13, 7p15, 7q11, 7q36, 11p11, 11p13, 11p15, 12q13, 13q13, 15q21, 16q13, 19q13, Chr.X, Chr.20, 22q12

 constitutional 6q21 rearrangements

• constitutional t(6;15)(q21;q21) (11566349)
• constitutional t(5;6)(q21;q21) (12606127, 9138163)

 constitutional t(7;19)(q11;q13) (16193462)
 constitutional t(7;13)(q36;q13) (6321191)

• facial dysmorphism with hydrocephaly and mental retardation (6321191)

 7p15 rearrangements (PTHB locus)

• i(7)q
• constitutional t(1;7)(q42;p15) (8946193, 12618763)
• interruption of PTHB1

 11p13 rearrangements (WAGR)

• constitutional t(2;11)(p25;p13) (12845852)
• constitutional t(5;11)(q11;p13) (2838157)
• constitutional t(11;22)(p13;q12) (3754537)
• del(11)(p11p13) (2550862)
• aniridia and genitourinary abnormalities

 miscellaneous tumoral translocations

• target regions: 1q21, 7p13, 11p11, 11p15, 12q13, 16q13, Chr.X, Chr.20
• tumoral t(1;16)(q21;q13) (8614388)
• tumoral t(7;7)(p13;q21) (8397065)
• tumoral t(11;12)(p11;q13) (2550862)
• tumoral t(X;20) (2154323)
• tumoral t(11;11)(p13;p15) (2838157)

CGH

 Gain of 1q is associated with adverse outcome in favorable histology Wilms’ tumors (11159177)

Allelotyping (LOH)

 Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology wilms tumor (16129848)

Genic mutations

 germline and somatic mutations of WT1 at 11p13 (mutational inactivation) (10-20% of sporadic tumors)
 somatic mutations of CTNNB1 coding for beta-catenin at 3p22-21 (mutational activation) (14% of sporadic tumors) (10463574, 11103785)

WNT/beta-catenin pathway deregulation (17691963)

Beta-catenin gain-of-function mutations are strongly linked to WT1 loss-of-function mutations in syndromic Wilms tumors, and Wnt/beta-catenin signaling increases androgen receptor mRNA expression and blocks apoptosis in prostate cancers.

Novel downstream target genes activated by Wnt/beta-catenin signaling are emerging from expression profiling in genetically defined classes of Wilms tumors

The WNT/beta-catenin pathway is involved in numerous human cancers. Somatic mutations of the CTNNB1 (beta-catenin) gene have also been detected in a subset of pediatric Wilms tumor.

 CTNNB1 somatic mutations

• Activation of beta-catenin is a late event in the pathogenesis of nephroblastomas and rarely correlated with genetic changes of the APC gene. (22081130)
• The strong representation of muscle-related genes in the expression profile of CTNNB1-mutated Wilms tumors corresponded to histologically detectable areas of myomatous cells in these tumors that displayed intense and preferential nuclear beta-catenin antibody staining. (16575872)

 PITX2, APCDD1, and two members of the endothelin axis (EDN3 and EDNRA) are directly activated downstream targets of the WNT/beta-catenin pathway that may enhance proliferation of these tumor cells. (16575872)

 Several upstream inhibitors of WNT/beta-catenin signaling like WIF1 and PRDC were also strongly up-regulated in the CTNNB1-mutated Wilms tumors. (16575872)

 Deregulated genes have been detected in both the retinoic acid and the RAS pathways, such as ATX/ENPP2 and RIS1, suggesting an association between these two pathways with that of WNT. (16575872)

References

 Activation of beta-catenin is a late event in the pathogenesis of nephroblastomas and rarely correlated with genetic changes of the APC gene. Grill C, Sunitsch S, Hatz M, Hauser-Kronberger C, Leuschner I, Hoefler G, Guertl B. Pathology. 2011 Dec;43(7):702-706. PMID: 22081130

 Tamimi Y, Ziebart K, Desaulniers N, Dietrich K, Grundy P. Identification of a minimal region of loss on the short arm of chromosome 1 in Wilms tumor. Genes Chromosomes Cancer. 2007 Jan 22;46(4):327-335. PMID: 17243164

 Wittmann S, Zirn B, Alkassar M, Ambros P, Graf N, Gessler M. Loss of 11q and 16q in Wilms tumors is associated with anaplasia, tumor recurrence, and poor prognosis. Genes Chromosomes Cancer. 2007 Feb;46(2):163-70. PMID: 17099873

 Zirn B, Samans B, Wittmann S, Pietsch T, Leuschner I, Graf N, Gessler M. Target genes of the WNT/beta-catenin pathway in Wilms tumors. Genes Chromosomes Cancer. 2006 Jun;45(6):565-74. PMID: 16575872

 Watanabe N, Nakadate H, Haruta M, Sugawara W, Sasaki F, Tsunematsu Y, Kikuta A, Fukuzawa M, Okita H, Hata J, Soejima H, Kaneko Y. Association of 11q loss, trisomy 12, and possible 16q loss with loss of imprinting of insulin-like growth factor-II in Wilms tumor. Genes Chromosomes Cancer. 2006 Jun;45(6):592-601. PMID: 16518847

Reviews

 Tycko B, Li CM, Buttyan R. The Wnt/beta-catenin pathway in Wilms tumors and prostate cancers. Curr Mol Med. 2007 Aug;7(5):479-89. Review. PMID: 17691963

 Rivera MN, Haber DA. Wilms’ tumour: connecting tumorigenesis and organ development in the kidney. Nat Rev Cancer. 2005 Sep;5(9):699-712. PMID: 16110318

 Dome JS, Coppes MJ. Recent advances in Wilms tumor genetics. Curr Opin Pediatr. 2002 Feb;14(1):5-11. PMID: 11880727