Previous research has proposed that genomic instability contributes to cancer progression, with its initiation linked to tetraploid cell formation (Duesberg, P., and R. Li. 2003. Cell Cycle. 2:202–210; Ganem, N.J., Z. Storchova, and D. Pellman. 2007. Curr. Opin. Genet. Dev. 17:157–162). However, there is little direct evidence linking cancer-causing mutations with such events, and it remains controversial whether genomic instability is a cause or an effect of cancer. In this study, we show that adenomatous polyposis coli (APC) mutations found in human colorectal cancers dominantly inhibit cytokinesis by preventing mitotic spindle anchoring at the anaphase cortex and, thus, blocking initiation of the cytokinetic furrow. We find that dividing crypt cells in the small intestines of APCMin/+ mice exhibit similar mitotic defects, including misoriented spindles and misaligned chromosomes. These defects are observed in normal crypt cells with wild-type levels of β-catenin and, importantly, are associated with tetraploid genotypes. We provide direct evidence that the dominant activity of APC mutants induces aneuploidy in vivo. Our data support a model whereby tetraploid cells represent a first step in the onset of genomic instability and colorectal cancer.

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BackgroundThe course of depression is poorer in clinical settings than in the general population. Several predictors have been studied and there is growing evidence that a history of childhood maltreatment consistently predicts a poorer course of depression.MethodsBetween 2008 and 2012, we assessed 238 individuals suffering from a current episode of major depression. Fifty percent of these (N = 119) participated in a follow-up study conducted between 2012 and 2014 that assessed sociodemographic and clinical variables, the history of childhood abuse and neglect (using the Adverse Childhood Experience questionnaire), and the course of depression between baseline and follow-up interview (using the Life Chart method). The Structured Clinical Interview for DSM-IV-TR was used to assess diagnosis at baseline and follow-up interview. Statistical analyses used the life table survival method and Cox proportional hazard regression tests.ResultsAmong 119 participants, 45.4% did not recover or remit during the follow-up period. The median time to remission or recovery was 28.9 months and the median time to the first recurrence was 25.7 months. Not being married, a chronic index depressive episode, comorbidity with an anxiety disorder, and a childhood history of physical neglect independently predicted a slower time to remission or recovery. The presence of three or more previous depression episodes and a childhood history of emotional neglect were independent predictors of depressive recurrences.ConclusionsChildhood emotional and physical neglect predict a less favorable course of depression. The effect of childhood neglect on the course of depression was independent of sociodemographic and clinical variables.

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