Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R) and 20 older children (MLL-R cases) with leukemia. Our data demonstrated infant MLL-R ALL to have one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite the paucity of mutations, activating mutations in kinase/PI3K/RAS signaling pathways were detected in 47%. Surprisingly, however, these mutations were often sub-clonal and frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (a mean of 6.5/case versus 1.3/case, P=7.15×10−5) and contained frequent mutations (45%) in epigenetic regulators, a category of genes that with the exception of MLL was rarely mutated in infant MLL-R ALL.

No abstract

GST-based metabolism, cytokine MCP-1 and TNFR-1, and TGF-beta3 signaling pathways, and some helix-loop-helix nuclear proteins could be potentially important in organ-confined prostate cancer and deserve further investigation.

Introduction: Screening is an effective means for colorectal cancer prevention and early detection. Family history is strongly associated with colorectal cancer risk. We describe the rationale, evidence and recommendations for colorectal cancer screening by family history for people without a genetic syndrome, as reported in the 2017 revised Australian guidelines. Main recommendations: Based on 10‐year risks of colorectal cancer, people at near average risk due to no or weak family history (category 1) are recommended screening by immunochemical faecal occult blood test (iFOBT) every 2 years from age 50 to 74 years. Individuals with moderate risk due to their family history (category 2) are recommended biennial iFOBT from age 40 to 49 years, then colonoscopy every 5 years from age 50 to 74 years. People with a high risk due to their family history (category 3) are recommended biennial iFOBT from age 35 to 44 years, then colonoscopy every 5 years from age 45 to 74 years. Changes in management as a result of the guidelines: By 2019, the National Bowel Cancer Screening Program will offer all Australians free biennial iFOBT screening from age 50 to 74 years, consistent with the recommendations in these guidelines for category 1. Compared with the 2005 guidelines, there are some minor changes in the family history inclusion criteria for categories 1 and 2; the genetic syndromes have been removed from category 3 and, as a consequence, colonoscopy screening is now every 5 years; and for categories 2 and 3, screening begins with iFOBT for people aged 40 and 35 years, respectively, before transitioning to colonoscopy after 10 years.

A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P = 0.0002, summary odds ratio = 2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative b-catenin binding sites. Expression of Fat, Catnb (b-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P = 0.027), and Catnb and Enah were significantly upregulated (P = 0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P = 0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

These genes are involved in a diverse range of biological functions, including maintaining metal ion homeostasis and chemical/electrical gradients across membranes, regulating RNA polymerase II, protein degradation, and G-protein-coupled signal transduction. These results indicate that lithium can regulate a large number of different cellular pathways in the brain. Understanding the molecular and cellular mechanisms by which lithium achieves its therapeutic action represents a valuable step in clarifying the pathophysiology of bipolar disorder.

These results suggest that transcriptional regulation of ion channels, crucial for neurotransmission, may play a role in mediating antipsychotic drug effects.

Our results indicate that MSX1 may be associated with the invasion capacity of Wilms tumors. RIN1 is a downstream effector of RAS and Bcl2A1 functions as an anti-apoptotic protein. EphB2 is an ephrin receptor and is up-regulated in invasive tumors but its role needs to be confirmed in further cases of Wilms tumors.