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Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

© 2016 The Authors Longitudinal studies including brain measures acquired through magnetic resonance imaging (MRI) have enabled population models of human brain development, crucial for our understanding of typical development as well as neurodevelopmental disorders. Brain development in the first two decades generally involves early cortical grey matter volume (CGMV) increases followed by decreases, and monotonic increases in cerebral white matter volume (CWMV). However, inconsistencies regarding the precise developmental trajectories call into question the comparability of samples. This issue can be addressed by conducting a comprehensive study across multiple datasets from diverse populations. Here, we present replicable models for gross structural brain development between childhood and adulthood (ages 8–30 years) by repeating analyses in four separate longitudinal samples (391 participants; 852 scans). In addition, we address how accounting for global measures of cranial/brain size affect these developmental trajectories. First, we found evidence for continued development of both intracranial volume (ICV) and whole brain volume (WBV) through adolescence, albeit following distinct trajectories. Second, our results indicate that CGMV is at its highest in childhood, decreasing steadily through the second decade with deceleration in the third decade, while CWMV increases until mid-to-late adolescence before decelerating. Importantly, we show that accounting for cranial/brain size affects models of regional brain development, particularly with respect to sex differences. Our results increase confidence in our knowledge of the pattern of brain changes during adolescence, reduce concerns about discrepancies across samples, and suggest some best practices for statistical control of cranial volume and brain size in future studies.

Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology. © 2016 by The American Society of Hematology.

Purpose: Adolescence is a time of dramatic changes in a range of behaviours, which occur in tandem with changes in brain structure and function. These coincide with the physiological changes of puberty, but little research has focussed on the possible contributing role of puberty. One important behaviour emerging in adolescence is the increased propensity to make risky decisions. A prominent theory to explain this increased propensity for risk is the ‘dual systems’ model (Casey et al., 2008), where risky decisions result from a dissociation in the timing of the maturation of the limbic system and the prefrontal cortex, both regions involved in risky decision-making. The limbic system (incorporating the ventral striatum) is hypothesised to mature relatively early in adolescence, and is thought to be related to pubertal maturation. In contrast, the prefrontal cortex is thought to undergo more protracted development throughout adolescence. This study explores how developmental changes in brain function when performing a risk-taking fMRI (functional Magnetic Resonance Imaging) task are related to puberty, independently of chronological age.\ud \ud - Methods: Forty-five male participants aged 13-14 years underwent fMRI scanning whilst performing a risk-taking task (BART task, adapted from Lejuez et al., 2002). In this age range, there is normal variability in pubertal development, with individuals being at all stages of puberty from pre-puberty to having completed puberty. In the BART task, participants had to decide whether to inflate a virtual balloon on a screen. Successful inflation of the balloon resulted in the opportunity to earn more money, but risked the balloon popping and the money being lost. Stopping allowed the participants to save the money towards their final earnings. Participants completed four six-minute runs of the task. Pubertal stage was assessed using self-report measures including a pictorial Tanner stage and the Pubertal Developmental Scale (Petersen et al., 1988). Salivary hormone levels were collected to measure levels of Testosterone, Oestradiol and DHEA. Participants also completed validated self-report questionnaires of risk-taking, impulsivity and sensation-seeking.\ud \ud - Results: The analysis focused on a main effect, across the entire group, of active decision-making compared to the control condition in regions including the prefrontal cortex and limbic system, which are known to be involved in risky decision-making. We also investigated whether this activation was differentially related to puberty across regions, using both group-wise and regression analyses.\ud - Conclusions; This study investigated a role for puberty in the functional development of brain regions involved in risky decision-making in males, and further informs the usefulness of the dual systems model of risk taking during adolescence.

Previous studies have shown that taking into account another person's perspective to guide decisions is more difficult when their perspective is incongruent from one's own compared to when it is congruent. Here we used dynamic causal modelling (DCM) for functional magnetic resonance imaging (fMRI) to investigate effective connectivity between prefrontal and posterior brain regions in a task that requires participants to take into account another person's perspective in order to guide the selection of an action. Using a new procedure to score model evidence without computationally costly estimation, we conducted an exhaustive search for the best of all possible models. The results elucidate how the activity in the areas from our previously reported analysis (Dumontheil et al., 2010) are causally linked and how the connections are modulated by both the social as well as executive task demands of the task. We find that the social demands modulate the backward connections from the medial prefrontal cortex (MPFC) more strongly than the forward connections from the superior occipital gyrus (SOG) and the medial temporal gyrus (MTG) to the MPFC. This was also the case for the backward connection from the MTG to the SOG. Conversely, the executive task demands modulated the forward connections of the SOG and the MTG to the MPFC more strongly than the backward connections. We interpret the results in terms of hierarchical predictive coding.

Our everyday actions are often performed in the context of a social interaction. We previously showed that, in adults, selecting an action on the basis of either social or symbolic cues was associated with activations in the fronto-parietal cognitive control network, whereas the presence and use of social versus symbolic cues was in addition associated with activations in the temporal and medial prefrontal cortex (MPFC) social brain network. Here we investigated developmental changes in these two networks. Fourteen adults (21–30 years of age) and 14 adolescents (11–16 years) followed instructions to move objects in a set of shelves. Interpretation of the instructions was conditional on the point of view of a visible “director” or the meaning of a symbolic cue (Director Present vs. Director Absent) and the number of potential referent objects in the shelves (3-object vs. 1-object). 3-object trials elicited increased fronto-parietal and temporal activations, with greater left lateral prefrontal cortex and parietal activations in adults than adolescents. Social versus symbolic information led to activations in superior dorsal MPFC, precuneus, and along the superior/middle temporal sulci. Both dorsal MPFC and left temporal clusters exhibited a Director × Object interaction, with greater activation when participants needed to consider the directors' viewpoints. This effect differed with age in dorsal MPFC. Adolescents showed greater activation whenever social information was present, whereas adults showed greater activation only when the directors' viewpoints were relevant to task performance. This study thus shows developmental differences in domain-general and domain-specific PFC activations associated with action selection in a social interaction context.

Non-linear changes in behaviour and in brain activity during adolescent development have been reported in a variety of cognitive tasks. These developmental changes are often interpreted as being a consequence of changes in brain structure, including non-linear changes in grey matter volumes, which occur during adolescence. However, very few studies have attempted to combine behavioural, functional and structural data. This multi-method approach is the one we took in the current study, which was designed to investigate developmental changes in behaviour and brain activity during relational reasoning, the simultaneous integration of multiple relations. We used a relational reasoning task known to recruit rostrolateral prefrontal cortex (RLPFC), a region that undergoes substantial structural changes during adolescence. The task was administered to female participants in a behavioural (N = 178, 7–27 years) and an fMRI study (N = 37, 11–30 years). Non-linear changes in accuracy were observed, with poorer performance during mid-adolescence. fMRI and VBM results revealed a complex picture of linear and possibly non-linear changes with age. Performance and structural changes partly accounted for changes with age in RLPFC and medial superior frontal gyrus activity but not for a decrease in activation in the anterior insula/frontal operculum between mid-adolescence and adulthood. These functional changes might instead reflect the maturation of neurocognitive strategies.

The ability to select and manipulate self-generated (stimulus-independent, SI), as opposed to stimulus-oriented (SO), information, in a controlled and flexible way has previously only been studied in adults. This ability is thought to rely in part on the rostrolateral prefrontal cortex (RLPFC), which continues to mature anatomically during adolescence. We investigated (1) the development of this ability behaviorally, (2) the associated functional brain development, and (3) the link between functional and structural maturation. Participants classified according to their shape letters either presented visually (SO phases) or that they generated in their head by continuing the alphabet sequence (SI phases). SI phases were performed in the presence or absence of distracting letters. A total of 179 participants (7–27 years old) took part in a behavioral study. Resistance to visual distractors exhibited small improvements with age. SI thoughts manipulation and switching between SI and SO thoughts showed steeper performance improvements extending into late adolescence. Thirty-seven participants (11–30 years old) took part in a functional MRI (fMRI) study. SI thought manipulation and switching between SO and SI thought were each associated with brain regions consistently recruited across age. A single frontal brain region in each contrast exhibited decreased activity with age: left inferior frontal gyrus/anterior insula for SI thought manipulation, and right superior RLPFC for switching between SO and SI thoughts. By integrating structural and functional data, we demonstrated that the observed functional changes with age were not purely consequences of structural maturation and thus may reflect the maturation of neurocognitive strategies.

The development of theory of mind use was investigated by giving a computerized task to 177 female participants divided into five age groups: Child I (7.3–9.7 years); Child II (9.8–11.4); Adolescent I (11.5–13.9); Adolescent II (14.0–17.7); Adults (19.1–27.5). Participants viewed a set of shelves containing objects, which they were instructed to move by a ‘director’ who could see some but not all of the objects. Correct interpretation of critical instructions required participants to use the director’s perspective and only move objects that the director could see. In a control condition, participants were asked to ignore objects in slots with a grey background. Accuracy improved similarly in both conditions between Child I and Adolescent II. However, while performance of the Adolescent II and Adult groups did not differ in the control condition, the Adolescent II group made more errors than the adults in the experimental condition. These results suggest that theory of mind use improves between late adolescence and adulthood. Thus, while theory of mind tasks are passed by age 4, these data indicate that the interaction between theory of mind and executive functions continues to develop in late adolescence.