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Wilms tumor is the most common renal malignancy of childhood. To identify common variants that confer susceptibility to Wilms tumor, we conducted a genome-wide association study in 757 individuals with Wilms tumor (cases) and 1,879 controls. We evaluated ten SNPs in regions significantly associated at P < 5 × 10?5 in two independent replication series from the UK (769 cases and 2,814 controls) and the United States (719 cases and 1,037 controls). We identified clear significant associations at 2p24 (rs3755132, P = 1.03 × 10?14; rs807624, P = 1.32 × 10?14) and 11q14 (rs790356, P = 4.25 × 10?15). Both regions contain genes that are plausibly related to Wilms tumorigenesis. We also identified candidate association signals at 5q14, 22q12 and Xp22. [ABSTRACT FROM AUTHOR]

Background Constitutional mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). Aim To investigate the contribution and phenotypic spectrum of constitutional and somatic mutations to cancer. Methods and results The authors sequenced in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli–Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli–Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli–Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from mutation-positive patients showed universal retention of the wild-type allele. truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations. Conclusion Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli–Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition ‘ syndrome’. Accession numbers The cDNA Genbank accession number for the sequence reported in this paper is NM_030621.2. [ABSTRACT FROM PUBLISHER]

Reports that mutations in the NSD1 gene cause Sotos syndrome and occur in some cases of Weaver syndrome. Rarity in other overgrowth phenotypes; Analysis of pertinent topics and relevant issues; Implications on human genetics.

PALB2 was recently identified as a nuclear binding partner of BRCA2. Biallelic BRCA2 mutations cause Fanconi anemia subtype FA-D1 and predispose to childhood malignancies. We identified pathogenic mutations in PALB2 (also known as FANCN) in seven families affected with Fanconi anemia and cancer in early childhood, demonstrating that biallelic PALB2 mutations cause a new subtype of Fanconi anemia, FA-N, and, similar to biallelic BRCA2 mutations, confer a high risk of childhood cancer. [ABSTRACT FROM AUTHOR]

A correction to the article "A Genome-Wide Association Study Identifies Susceptibility Loci for Wilms Tumor," published in the online edition of the periodical on April 29, 2012.

Juvenile hyaline fibromatosis (JHF) is an autosomal recessive condition characterized by multiple subcutaneous nodular tumors, gingival fibromatosis, flexion contractures of the joints, and an accumulation of hyaline in the dermis. We performed a genomewide linkage search in two families with JHF from the same region of the Indian state of Gujarat and identified a region of homozygosity on chromosome 4q21. Dense microsatellite analyses within this interval in five families with JHF who were from diverse origins demonstrate that all are compatible with linkage to chromosome 4q21 (multipoint LOD score 5.5). Meiotic recombinants place the gene for JHF within a 7-cM interval bounded by D4S2393 and D4S395. [ABSTRACT FROM AUTHOR]