To identify risk variants for childhood acute lymphoblastic leukemia (ALL) we conducted a genome-wide association study of 2 case-control series, analyzing the genotypes of 291,423 tagging SNP genotypes in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601; OR = 1.69, P = 1.20 x 10-19), 10q21.2 (ARIDB5, rs7089424; OR = 1.65, P = 6.69 x 10-19) and 14q11.2 (CEBPE, rs2239633; OR = 1.34, P = 2.88 x 10-7). The 10q21.2 (ARIDB5) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide novel insight into disease causation of this hematological cancer; notably all 3 risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors.

Biallelic, truncating mutations of the hSNF5/INI1 gene have recently been documented in malignant rhabdoid tumor (MRT), one of the most aggressive human cancers. This finding suggests that hSNF5/INI1 is a new tumor-suppressor gene for which germline mutations might predispose to cancer. We now report the presence of loss-of-function mutations of this gene in the constitutional DNA from affected members but not from healthy relatives in cancer-prone families. Furthermore, a constitutional mutation is documented in a patient with two successive primary cancers. In agreement with the two-hit model, the wild-type hSNF5/INI1 allele is deleted in the tumor DNA from mutation carriers. In all tested cases, DNA from parents demonstrated normal hSNF5/INI1 sequences, therefore indicating the de novo occurrence of the mutation, which was shown to involve the maternal allele in one case and the paternal allele in two other cases. These data indicate that constitutional mutation of the hSNF5/INI1 gene defines a new hereditary syndrome predisposing to renal or extrarenal MRT and to a variety of tumors of the CNS, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumor. This condition, which we propose to term "rhabdoid predisposition syndrome," may account for previous observations of familial and multifocal cases of the aforementioned tumor types. It could also provide the molecular basis for cases of Li-Fraumeni syndrome without p53 germline mutations.

Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we analyzed 824 ALL cases and 2398 controls genotyped for 292 200 tagging SNPs. Across the genome, cumulative distribution of ROH was not significantly different between cases and controls. Four common ROH at 10p11.2-10q11.21, 1p31.1, 19p13.2-3, and 20q11.1-23 were, however, associated with ALL risk at P less than .01 (including 1 ROH to which the erythropoietin receptor [EPOR] gene maps, P ‫؍‬ .005) but were nonsignificant after adjusting for multiple testing. Our findings make it unlikely that levels of measured homozygosity, caused by autozygosity, uniparental isodisomy, or hemizygosity, play a major role in defining BCP-ALL risk in predominantly outbred populations. IntroductionAlthough acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy, accounting for approximately 80% of leukemia in the pediatric age group, its etiology is largely unknown. 1 B-cell precursor (BCP)-ALL is the major form of the disease, accounting for approximately 85% of all pediatric ALL.Two recent genome-wide association (GWA) studies of ALL identified several common single nucleotide polymorphisms (SNPs) at 7p12.2 (IKZF1), 10q21.2 (ARID5B), and 14q11.2 (CEBPE) that influence the risk of BCP-ALL. 2,3 The variants so far identified by these GWA studies are common in the general population (minor allele frequency, Ͼ 5%), but have, individually, small effects on disease risk, 2,3 with odds ratios typically less than 1.6. Despite the relatively small predisposing effects conferred, the variants identified provide important and novel insights into the disease biology. Specifically, these risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors, suggesting dysfunctional B-cell pathway gene expression as an etiologic basis for BCP-ALL development.The majority of cancer predisposition genes that have been identified to date through GWA studies act in a codominant fashion, and studies have found no good evidence for recessively acting disease loci. Although this may be reflective of the biology, it may also be a consequence of GWA studies having suboptimal ability to detect recessively acting disease alleles. Clues that tumor susceptibility may have a recessive basis come from reports of an increased incidence associated with consanguinity and in populations characterized by a high degree of inbreeding. [4][5][6][7][8][9] Further evidence for the role of homozygosity in cancer predisposition is provided by experimental animal inbreeding (eg, backcrossing mice) increasing tumor incidence. 10 Specific situations of homozygosity have also been directly associated with cancer, such as uniparental disomy through altered imprinting. 11 Common regions of homozyg...

No abstract

A BS TRACT: Background and Objective: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders.Methods: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed