Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Adolescents at ultra-high risk of psychosis in Italian neuropsychiatry services: prevalence, psychopathology and transition rate

Studies in adolescents on ultra-high risk (UHR) and basic symptoms (BS) criteria for psychosis prediction are scarce. In Italy, early interventions in psychosis are less widespread than in other European countries. In the present study, we (1) assessed the clinical relevance of a UHR diagnosis [according to the comprehensive assessment of at-risk mental states (CAARMS) criteria] to promote the implementation of specific services for UHR adolescents into the Italian health care system; (2) described severity of positive, negative, general, and basic symptoms in UHR adolescents compared to adolescents with first-episode psychosis (FEP) and non-UHR adolescents (i.e., individuals who did not meet CAARMS criteria for UHR or FEP); and (3) investigated the predictive validity of UHR criteria in relation to BS criteria. Seventy-nine adolescents (aged 13-18 years) were assessed with the CAARMS, the positive and negative syndrome scale (PANSS), and the schizophrenia proneness instrument, child and youth version (SPI-CY). Both UHR (n = 25) and FEP (n = 11) had significantly higher PANSS subscale scores compared to non-UHR (n = 43). UHR had significantly lower PANSS-positive symptom scores than FEP, but similar global functioning and PANSS-negative symptoms and general psychopathology scores. Compared to non-UHR, both FEP and UHR had more severe thought and perception BS disturbances, and significantly more often met BS criteria. After 12 months, 2 of 20 (10%) UHR had transitioned to psychosis. They also met both BS criteria. Given the uncertain outcome of UHR adolescents, future research is needed to determine whether the combined assessment of BS with UHR symptoms can improve the accuracy of psychosis prediction in adolescence

The Italian Version of the Brief 21-Item Prodromal Questionnaire: Field Test, Psychometric Properties and Age-Sensitive Cut-Offs.

BACKGROUND: The Brief, 21-item version of the Prodromal Questionnaire (PQ-B) is a promising screener for psychosis-risk states that could be implemented in routine clinical practice. In this study, we assessed psychometric properties of the Italian version of the PQ-B (iPQ-B) in a sample of 243 help-seekers, aged 13-35 years. SAMPLING AND METHODS: After completing the iPQ-B, participants were assessed with the Comprehensive Assessment of At-Risk Mental States (CAARMS). Diagnostic accuracy (sensitivity, specificity, positive and negative predictive values [PPV and NPV], positive and negative likelihood ratios) and concurrent validity between PQ-B and CAARMS were determined using Cronbach's alpha and Cohen's kappa. We also tested the validity of the adopted PQ-B cut-offs through Receiver Operating Characteristic (ROC) curves plotted against CAARMS diagnoses and the predictive validity of the iPQ-B at 1-year follow-up. RESULTS: The iPQ-B showed high internal consistency (Cronbach's alpha = 0.868), acceptable diagnostic accuracy and concurrent validity (70% sensitivity, 67% specificity, 81% PPV, Cohen's kappa = 0.335). ROC analyses pointed to threshold of ≥20 on the PQ-B total distress score as best cut-off. After 12 months of follow-up, 11% of participants who scored ≥4 on the PQ-B distressing item total score and did not meet CAARMS psychosis criteria at baseline, developed a psychotic disorder. Interestingly, age had significant negative correlations with iPQ-B scores and adolescents (aged < 18 years) showed higher iPQ-B scores than young adults. CONCLUSIONS: Overall, the psychometric properties of the iPQ-B were satisfactory. As iPQ-B scores appeared inversely associated to age, age-tailored cut-off scores are recommended for screening purposes in child-adolescent cohorts

Screening for psychosis risk among help-seeking adolescents: application of the Italian version of the 16-item prodromal questionnaire (iPQ-16) in child and adolescent neuropsychiatry services

AIM: The 16-item Prodromal Questionnaire (PQ-16) is a versatile screen tool for routine screening of at-risk individuals. We wished to evaluate the psychometric properties of the Italian version of the PQ-16 (iPQ-16) in a sample of 72 help-seeking adolescents (age range 13-17 years) referred to child and adolescent neuropsychiatry services for diagnostic assessment. METHODS: Participants who completed iPQ-16 were subsequently interviewed with the Comprehensive Assessment of At-Risk Mental States (CAARMS) to confirm the psychosis high risk state. We then examined the diagnostic accuracy (sensitivity, specificity, positive and negative predictive values [PPV e NPV]) and concurrent validity between iPQ-16 and CAARMS using Cronbach's alpha and Cohen's kappa. We also tested the validity of the adopted iPQ-16 cut-offs through Receiver Operating Characteristic (ROC) curves plotted against CAARMS diagnoses and the 1-year predictive validity of the iPQ-16. RESULTS: Overall, the psychometric properties of the iPQ-16 were satisfactory. The iPQ-16 showed high internal consistency (Cronbach's alpha = .827) and acceptable diagnostic accuracy (77% sensitivity, 72% PPV) and concurrent validity (Cohen's k = 0.309). ROC analyses pointed to iPQ-16 total distress score of ≥10 as best cut-off. CONCLUSION: The iPQ-16 is a reliable and valid instrument for routine screening of at-risk individuals in Italian neuropsychiatry services

Validation of the "early detection Primary Care Checklist" in an Italian community help-seeking sample: The "checklist per la Valutazione dell'Esordio Psicotico"

BACKGROUND: To establish the concordant validity of the "Checklist per la Valutazione dell'Esordio Psicotico" (CVEP) in an Italian help-seeking population. The CVEP is the Italian adaptation of the "early detection Primary Care Checklist," a 20-item tool specifically designed to assist primary care practitioners in identifying young people in the early stages of psychosis. METHODS: The checklist was completed by the referring practitioners of 168 young people referred to the "Reggio Emilia At Risk Mental States" Project, an early detection infrastructure developed under the aegis of the Regional Project on Early Detection of Psychosis in the Reggio Emilia Department of Mental Health. The concordant validity of the CVEP was established by comparing screen results with the outcome of the "Comprehensive Assessment of At Risk Mental States" (CAARMS), a gold standard assessment for identifying young people who may be at risk of developing psychosis. RESULTS: The simple checklist as originally conceived had excellent sensitivity (98%), but lower specificity (58%). Using only a CVEP total score of 20 or above as cut-off, the tool showed a slightly lower sensitivity (93%) with a substantial improvement in specificity (87%). Simple cross-tabulations of the individual CVEP item scores against CAARMS outcome to identify the more discriminant item in terms of sensitivity and specificity were carried out. CONCLUSIONS: In comparison to other, much longer, screening tools, the CVEP performed well to identify young people in the early stages of psychosis. Therefore, the CVEP is well suited to optimize appropriate referrals to specialist services, building on the skills and knowledge already available in primary care settings