FaCD Online Syndrome Fact Sheet

Last updated: 30 Mar 2008

Name: Familial Wilms' tumor

Mode of Inheritance: AD?/ multifact?

Genes

FWT1/WT4#, mapped to 17q12-q21
FWT2#, mapped to 19q13.3-q13.4
WT1, mapped to 11p13

Tumor features

Wilms' tumor (nephroblastoma)

Comment

Wilms' tumor (nephroblastoma) is the most common renal tumor in children. Approximately 0.5-2.5 % of cases are familial[1-4]. The proportion of bilateral cases is higher in familial than in sporadic cases (20 % versus 3 %)[2]. No clear evidence for cancer prone families, i.e. families with an increased risk to develop cancer in general, was found in the French Wilms' tumor study, which looked at relatives of 501 patients[4]. Site-specific familial Wilms' tumor has been reported and is genetically heterogenous[5,21,23]. Rare familial extra-renal Wilms' tumor have been reported as well[22].

Although germline Wilms Tumor 1 gene (WT1) mutations have been observed in familial Wilms' tumor[6-8], the vast majority of familial Wilms' tumor does not appear to be caused by these mutations[9-13]. Loci on 17q[14;15] and 19q[16] have been suggested by linkage analysis. Other regions of interest were suggested by loss of heterozygosity (LOH) studies (1p, 16q, 4q, 9p, 20p, 3q)[11] and Rapley et al.[17] strongly suggested that more genes are involved in familial Wilms tumor than just WT1, FWT1 and FWT2, on the basis of their linkage analysis in familial WT.

Because LOH on the FWT1 17q locus is rare in sporadic Wilms tumors, Rahman et al.[18] have suggested that FWT1 is not a tumor suppressor gene. There is some evidence to suggest that FWT1 linked Wilms tumors present at a later age (average age at diagnosis 5.5 years, in a small series) and a more advanced stage than familial Wilms' tumors not linked to FWT1 (average age 0.6 years) or non-familial Wilms' tumors[19].The risk of Wilms tumor conferred by (postulated) FWT1 mutations has been estimated between 15 and 26%[20].

Links

Risk Factors for Wilms tumor, American Cancer Society 24 1 08

References

[1] Breslow NE, Beckwith JB. Epidemiological features of Wilms'tumor: results of the national Wilms'tumor study. JNCI 1982; 68(3):429-436.
[2] Matsunaga E. Genetics of Wilms' tumor. Hum Genet 1981; 57:231-246.
[3] Pastore G, CArli M, Lemerle J, Tournade MF, Voute PA, Rey A, Burgers JMV, Zucker JM, Burger D, de Kraker J, Delemarre JFM. Epidemiological features of Wilms'tumor: results of studies by the international society of Peadiatric Oncology(SIOP). Med Pediatr Oncol 1988; 16:7-11.
[4] Bonaiti-Pellie C, Chompret A, Tournade MF, Hochez J, Moutou C, Zucker JM, Steschenko D, Brunat-Mentigny M, Roche H, Tron P, Frappaz D, Munzer M, Bachelot C, Dusol F, Sommelet-Olive D, Lemerle J. Genetics and epidemiology of Wilms' tumor: The French Wilms'tumor study. Med Pediatr Oncol 1992; 20:284-291.
[5] Huff V. Wilms tumor genetics. Am J Med Genet 79[4], 260-267. 1998.
[6] Pelletier J, Bruening W, Li FP, Haber DA, Glaser T, Housman DE. WT1 mutations contribute to abnormal genital system development and hereditary Wilm's tumour. Nature 1991; 353:431-434.
[7] Kaplinsky C, Ghahremani M, Frishberg Y, Rechavi G, Pelletier J. Familial Wilms' tumor associated with a WT1 zinc finger mutation. Genomics 38[3], 451-453. 1996.
[8] Pritchard-Jones K, Rahman N, Gerrard M, Variend D, King-Underwood L. Familial Wilms tumour resulting from WT1 mutation:intronic polymorphism causing artefactual constitutional homozygosity. J Med Genet 2000; 37:377-379.
[9] Grundy P, Koufos A, Morgan K, Li FP, Meadows AT, Cavenee WK. Familial predisposition to Wilms'tumour does not map to the short arm of chromosome 11. Nature 1988; 336:374-376.
[10] Huff V, Compton DA, Chao LY, Strong LC, Geiser CF, Saunders GF. Lack of linkage of familial Wilms'tumour to chromosomal band 11p13. Nature 1988; 336:377-378.
[11] Altura RA, Valentine M, Li H, Boyett JM, Shearer P, Grundy P, Shapiro DN, Look AT. Identification of novel regions of deletion in familial Wilms' tumor by comparative genomic hybridization. Cancer Res 56[16], 3837-3841. 1996.
[12] Schwartz CE, Haber DA, Stanton VP, Strong LC, Skolnick MH, Housman DE. Familial predisposition to Wilms tumor does not segregate with the WT1 gene. Genomics 1991; 10:927-930.
[13] Huff V, Reeve AE, Leppert M, Strong LC, Douglass EC, Geiser CF, Li FP, Meadows A, Callen DF, Lenoir G, Saunders GF. Nonlinkage of 16q markers to familial predisposition to Wilm's tumor. Cancer Res 1992; 52:6117-6120.
[14] Rahman N, Arbour L, Tonin P, Renshaw J, Pelletier J, Baruchel S, Pritchard-Jones K, Stratton MR, Narod SA. Evidence for a familial Wilms'tumour gene (FWT1) on chromosome 17q12-q21. Nat Genet 1996; 13:461-463.
[15] Rahman N, Abidi F, Ford D, Arbour L, Rapley E, Tonin P, Barton D, Batcup G, Berry J, Cotter F, Davison V, Gerrard M, Gray E, Grundy R, Hanafy M, King D, Lewis I, Ridolfi Luthy A, Madlensky L, Mann J, O'Meara A, Oakhill T, Skolnick M, Strong L, Variend D, Narod S, Schwartz C, Pritchard-Jones K, Stratton MR. Confirmation of FWT1 as a Wilms' tumour susceptibility gene and phenotypic characteristics of Wilms' tumour attributable to FWT1. Hum Genet 103, 547-556. 1998.
[16] McDonald JM, Douglass EC, Fisher R, Geiser CF, Krill CE, Strong LC, Virshup D, Huff V. Linkage of familial Wilm's tumor predisposition to chromosome 19 annd a two-locus model for the etiology of familial tumors. Cancer Res 1998; 58:1387-1390.
[17] Rapley EA, Barfoot R, Bonaiti-Pellie C, Chompret A, Foulkes W, Perusinghe N, Reeve A, Royer-Pokora B, Schumacher V, Shelling A, Skeen J, de Tourreil S, Weirich A, Pritchard-Jones K, Stratton MR, Rahman N. Evidence for susceptibility genes to familial Wilms tumour in addition to WT1, FWT1 and FWT2. Br J Cancer 2000; 83(2):177-183.
[18] Rahman N, Arbour L, Tonin P, Baruchel S, Pritchard-Jones K, Narod SA, Stratton MR. The familial Wilms' tumour susceptibility gene, FWT1, may not be a tumour suppressor gene. Oncogene 14[25], 3099-3102. 1997.
[19] Rahman N, Arbour L, Tonin P, Schwartz C, Narod SA, Pritchard-Jones K, Stratton MR. Characterization of the familial Wilms tumour gene FWT1. Am J Hum Genet 1997; 61(4):A79.
[20] Rahman N, Arbour L, Houlston R, Bonaiti Pellie C, Abidi F, Tranchemontagne J, Ford D, Narod S, Pritchard-Jones K, Foulkes WD, Schwartz C, Stratton MR. Penetrance of mutations in the familial Wilms tumor gene FWT1. J Natl Cancer Inst 2000; 92(8):650-652.
[21] Ruteshouser EC, Huff V. Familial Wilms tumor. American journal of medical genetics. Part C, Seminars in medical genetics 2004; 129(1):29-34.
[22] Houben CH, Tong JH, Chan AW, Chik KW, Lee KH, Sihoe JD, Tam YH, Yeung CK. Familial extrarenal Wilms tumor. Journal of pediatric surgery 2007; 42(11):1826-30.
[23] Scott RH, Stiller CA, Walker L, Rahman N. Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. Journal of medical genetics 2006; 43(9):705-15.