Attention-Deficit/Hyperactivity Disorder and Unhealthy Lifestyle in Adolescence: Unforeseen Role of Allostatic Overload and Psychological Well-Being.

Unhealthy lifestyle behaviors (ULBs) are common in early adolescence and could be worsened by Attention-Deficit/Hyperactivity Disorder (ADHD), as well as by specific psychosocial factors, such as stress and unbalanced (i.e., too high or low scores of) psychological well-being (PWB) dimensions. This multi-center study aimed to evaluate how interactions between ADHD symptoms and psychosocial factors associated with ULBs (i.e., Allostatic Overload and multidimensional Psychological Well-Being), considered as moderators, could affect the adoption of ULBs during adolescence. A total of 440 fourteen-year-old adolescents were recruited from six upper secondary schools in Bologna and Rome (Italy) and completed self-report questionnaires on ULBs, ADHD, and psychosocial factors. Relations between ADHD symptomatology and specific ULBs (i.e., impaired sleep, problematic Internet use) were moderated by variables deemed as "negative" (i.e., Allostatic Overload) or "positive" (i.e., PWB dimensions of Self-Acceptance, Personal Growth, Positive Relations, Purpose in Life, Environmental Mastery): when the "negative" moderator is absent and the levels of the "positive" moderators are higher, ULBs decrease among students with lower ADHD symptomatology but increase among students with more severe ADHD. Based on ADHD severity, interventions should aim at promoting a state of euthymia, which consists in balanced PWB dimensions and reflects the optimal level of well-being to fulfill one's own potential and self-realization.

Development of the acne-specific quality of life questionnaire Quality of Life Relevance-Acne.

Background: Participating members of the European Academy of Dermatology and Venereology Task Forces on quality of life (QoL) and Patient Oriented Outcomes and Acne, Rosacea and Hidradenitis Suppurativa initiated data collection in 9 European countries and formed the list of the most relevant topics for acne patients. Objective: The aim of this study was to develop a new acne-specific health-related QoL instrument based on the list of the most relevant topics for acne patients. Methods: After assessment by acne patients (n = 715) on how clear and relevant the items in the prototype questionnaire were, a group of experts on acne and QoL performed discussions on items inclusion, which resulted in a series of 21 items. Then another group of acne patients (n = 1502) filled in the new version of the instrument. A factor analysis was conducted on the 21-item version. Results: Three-factor model with 19 items indicated a satisfactory fit. The three dimensions were called: Socioemotional; Symptoms; Stigma and Suicidal thoughts. Limitations: Included patients and experts may not fully represent acne patients and health care professionals worldwide. Conclusion: A final 19-item version of the Quality of Life Relevance-Acne was developed.

Meta-analysis of the Difficulties in Emotion Regulation Scale and its short forms: A two-part study.

The Difficulties in Emotion Regulation Scale (DERS) is the most used self-report questionnaire to assess deficits in emotion regulation (ER), composed of 6 dimensions and 36 items. Many studies have evaluated its factor structure, not always confirming the original results, and proposed different factor models. A possible way to try to identify the dimensionality of the DERS could be through a meta-analysis with structural equation models (MASEM) of its factor structure. The MASEM indicated that a six-factor model with 32 items (DERS-32) was the most suitable to represent the dimensionality of the DERS (χ2 = 2095.96, df = 449, p < .001; root mean square error of approximation [RMSEA] = 0.024, 95% confidence interval [CI]: 0.023-0.025; comparative fit index [CFI] = 0.97; Tucker Lewis index [TLI] = 0.96; standardized root mean squared residual [SRMR] = 0.04). This result was also confirmed by a confirmatory factor analysis (χ2 = 3229.67, df = 449, p < 0.001; RMSEA = 0.075, 95% CI: 0.073-0.078; CFI = 0.94; TLI = 0.93; SRMR = 0.05) on a new sample (1092 participants; mean age: 28.28, SD = 5.82 years) recruited from the Italian population. Analyses and results from this sample are reported in the second study of this work. The DERS-32 showed satisfactory internal consistency (i.e., ordinal α, Molenaar Sijtsma statistic, and latent class reliability coefficient) for all its dimensions and correctly categorized individuals with probable borderline symptomatology. In conclusion, the DERS-32 has demonstrated to be the best model for the DERS among all the others considered in this work, as well as a reliable tool to assess deficits in ER.

Psychometric Properties of the Detachment and Compartmentalization Inventory (DCI) in an Italian Community Sample.

The Detachment and Compartmentalization Inventory (DCI) is a valid and reliable self-report instrument that assesses these two distinct forms of dissociative symptoms. However, there is limited research on the cross-cultural validation of the DCI. Therefore, this study aimed to develop an Italian translation of the DCI and examine its internal structure and psychometric properties (including internal consistency, convergent validity, and test-retest reliability) within an Italian-speaking community sample. The sample consisted of 1276 adults (887 females; mean age: 29.57 ± 10.96 years), who completed the DCI and other self-report measures evaluating dissociative experiences and childhood trauma. Confirmatory factor analyses supported the original two-factor model (χ2169 = 1312.80, RMSEA = 0.073, 95%CI 0.069-0.077; CFI = 0.94; TLI = 0.94; SRMR = 0.04). Additionally, the DCI exhibited good internal consistency, test-retest reliability, and convergent validity with another measure of dissociation. The study also confirmed the association between DCI scores and the severity of childhood trauma. Finally, a Receiver Operating Characteristic (ROC) curve analysis demonstrated that the DCI effectively distinguishes individuals who screened positively for dissociative disorders. Overall, these findings indicate that the Italian translation of the DCI possesses satisfactory psychometric properties, suggesting its utility as a screening tool for assessing detachment and compartmentalization experiences.

Behavioral Lifestyle Interventions for Weight Loss in Overweight or Obese Patients with Type 2 Diabetes: A Systematic Review of the Literature.

PURPOSE OF REVIEW: Around 80-90% of patients with type 2 diabetes mellitus (T2DM) are overweight or obese, presenting a greater risk for serious health complications and mortality. Thus, weight loss represents a main goal for T2DM management. Although behavioral lifestyle interventions (BLIs) could help promoting weight loss in T2DM patients with overweight or obesity, their effectiveness is still controversial. This systematic review offers an updated and comprehensive picture of BLIs according to Michie's classification in T2DM patients with overweight or obesity and identifies possible factors (related to both patients and interventions) associated with weight loss. The PRISMA guidelines were followed. The literature search till March 2023 indicated 31 studies involving 42 different BLIs. RECENT FINDINGS: Our findings suggest that structured BLIs, characterized by frequent feedback and support, can lead to a clinically meaningful 5% weight loss, regardless of specific behavioral, diet, and physical activity components. Further research should address methodological issues and heterogeneity of interventions, also considering the effect of pharmacological therapies on weight reduction. Lastly, more attention should be paid to the long-term effectiveness of behavioral lifestyle interventions and to the relationship between weight loss and diabetes.

Item-specific patterns of the Skindex-17 in individuals with different levels of Hidradenitis Suppurativa severity: a network analysis study.

Background: Recent studies are stressing the idea that the level of Hidradenitis Suppurativa (HS) severity does not always correspond to the same illness load. In fact, it was found that there was no significant association between Skindex-17 and clinical severity of HS, and that some items of the Skindex-17 might be more related to HS severity than others. Objective: The aim of the current study was to explore the associations between different levels of clinical severity of HS (mild, moderate, severe) and the Skindex-17 single-item responses in a large sample of adults patients. Methods: A cross-sectional study with a sample include 547 consecutive HS patients, approaching for the first time the specific dermatologic evaluation. Eligible criteria included age ≥ 18 years, HS diagnosis formulated contextually by the same expert clinician, and providing informed consent. All participants completed the Skindex-17 and were evaluated for the disease clinical severity with the International Hidradenitis Suppurativa Severity Score System. A Network Analysis was conducted, which represents a powerful methodological approach in clinical research. It allows to study specific patterns and the structure of complex system in order to better understand how the elements of the system interact with each-other. Three different Network Analyses were conducted for each group of HS clinical severity by including the items of the Skindex-17 as the nodes of each network. Results: Among 547 patients, 40% (219) were female and mean age was of 32.70 (±11.41). Different patterns among items of the Skindex-17 for the three clinical severity groups emerged, meaning that in each group different items are more crucial than others. The psychosocial subscale of the Skindex-17 is the most relevant when assessing the Quality of Life of individuals with different levels of HS severity, however, with the progression of the disease, individuals place attention also on two different aspects of the symptoms subscale of the Skindex-17, irritation and pain, which in turn perfectly reflect the severity of HS, from a clinical perspective. Conclusion: These results provide new insights on the association between levels of HS severity and related Quality of Life, measured with the Skindex-17.

Italian Validation of the Short Version of the Failure to Mentalize Trauma Questionnaire in Adults at Risk Due to Childhood Trauma.

The impact of recurrent traumatic experiences during childhood may impede the integration of mentalization abilities and lead to psychopathology. Recently, the Failure to Mentalize Trauma Questionnaire (FMTQ), a comprehensive 29-item self-report scale aimed at identifying deficits in mentalization arising from childhood trauma, was developed. However, the length of the FMTQ may render it impractical for epidemiological studies involving multiple variables and measures. Furthermore, the initial testing revealed inadequate factor reliabilities for the two first-order factors. Therefore, this study aimed to shorten and create a unidimensional version (FMTQ-s) and investigate its psychometric properties, including internal consistency and convergent and concurrent validity, in a non-clinical Italian adult sample. The factor analysis supported a 13-item unidimensional version of the FMTQ with acceptable internal consistency (ordinal alpha = 0.88) and satisfactory convergent and concurrent validity. The FMTQ-s obtained scalar invariance between individuals with and without self-reported childhood traumas. Overall, the FMTQ-s appears to be a feasible and reliable tool for assessing deficits in mentalization resulting from childhood trauma.

Interface Diffusion and Compatibility of (Ba,La)FeO3-δ Perovskite Electrodes in Contact with Barium Zirconate and Ceria.

Ba1-xLaxFeO3-δ perovskites (BLF) capable of conducting electrons, protons, and oxygen ions are promising oxygen electrodes for efficient solid oxide cells (fuel cells or electrolyzers), an integral part of prospected large-scale power-to-gas energy storage systems. We investigated the compatibility of BLF with lanthanum content between 5 and 50%, in contact with oxide-ion-conducting Ce0.8Gd0.2O2-δ and proton-conducting BaZr0.825Y0.175O3-δ electrolytes, annealing the electrode-electrolyte bilayers at high temperature to simulate thermal stresses of fabrication and prolonged operation. By employing both bulk X-ray diffraction and synchrotron X-ray microspectroscopy, we present a space-resolved picture of the interaction between electrode and electrolyte as what concerns cation interdiffusion, exsolution, and phase stability. We found that the phase stability of BLF in contact with other phases is correlated with the Goldschmidt tolerance factor, in turn determined by the La/Ba ratio, and appropriate doping strategies with oversized cations (Zn2+, Y3+) could improve structural stability. While extensive reactivity and/or interdiffusion was often observed, we put forward that most products of interfacial reactions, including proton-conducting Ba(Ce,Gd)O3-δ and mixed-conducting (Ba,La)(Fe,Zr,Y)O3-δ, may not be very detrimental for practical cell operation.

The EU-funded I3LUNG Project: Integrative Science, Intelligent Data Platform for Individualized LUNG Cancer Care With Immunotherapy.

Although immunotherapy (IO) has changed the paradigm for the treatment of patients with advanced non-small cell lung cancers (aNSCLC), only around 30% to 50% of treated patients experience a long-term benefit from IO. Furthermore, the identification of the 30 to 50% of patients who respond remains a major challenge, as programmed Death-Ligand 1 (PD-L1) is currently the only biomarker used to predict the outcome of IO in NSCLC patients despite its limited efficacy. Considering the dynamic complexity of the immune system-tumor microenvironment (TME) and its interaction with the host's and patient's behavior, it is unlikely that a single biomarker will accurately predict a patient's outcomes. In this scenario, Artificial Intelligence (AI) and Machine Learning (ML) are becoming essential to the development of powerful decision-making tools that are able to deal with this high-complexity and provide individualized predictions to better match treatments to individual patients and thus improve patient outcomes and reduce the economic burden of aNSCLC on healthcare systems. I3LUNG is an international, multicenter, retrospective and prospective, observational study of patients with aNSCLC treated with IO, entirely funded by European Union (EU) under the Horizon 2020 (H2020) program. Using AI-based tools, the aim of this study is to promote individualized treatment in aNSCLC, with the goals of improving survival and quality of life, minimizing or preventing undue toxicity and promoting efficient resource allocation. The final objective of the project is the construction of a novel, integrated, AI-assisted data storage and elaboration platform to guide IO administration in aNSCLC, ensuring easy access and cost-effective use by healthcare providers and patients.

Testing some psychometric properties of the Italian version of the Skin Cancer Index: A questionnaire for measuring quality of life in patients with non-melanoma skin cancer.

Objectives: Non-melanoma skin cancers (NMSC) include two main types: basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Generic Health-Related Quality of Life (HRQoL) instruments revealed little to no HRQoL impairment in NMSC patients. Instead, the use of specific skin disease HRQoL tools contradicted those observations. For example, the Skin Cancer Index (SCI) was suggested as a validated instrument for the evaluation of the impact of skin cancers on HRQoL, and has already been validated in several languages, but not in Italian. The aim of this study is to testing some psychometric properties of the Italian version of the SCI questionnaire in a large sample of NMSC patients. Methods: This is a cross-sectional, single-center, observational study. Firstly, different factor models proposed in the literature were compared and the model with the best fit was identified. Secondly, the psychometric properties of the SCI, convergent validity and reliability, were evaluated. Results: The sample was composed of 371 NMSC patients. The factor analysis revealed that a revised version of the original model had the best fit [χ2(df = 85) = 354.53, p < 0.001, RMSEA = 0.09, CFI = 0.98, TLI = 0.97, SRMR = 0.03]. The SCI had satisfactory internal consistency for all subscales (Emotional subscale: ordinal alpha = 0.95; Social subscale: ordinal alpha = 0.94; Appearance subscale: ordinal alpha = 0.94). The convergent validity with Skindex-17 psychosocial subscale was adequate for all the SCI subscales (Emotional Subscale: rho = -0.50; Social Subscale: rho = -0.54; Appearance subscale: rho = -0.44; Total Skin Cancer Index: rho = -0.56; and p < 0.001). Conclusion: The tested psychometric properties of the Italian version of the SCI may suggest that it is an appropriate tool to measure the HRQoL in NMSC patients, however, further studies are needed in order to confirm and tested other psychometric features of this tool.

Psychometric Properties of the Italian Mentalization Questionnaire: Assessing Structural Invariance and Construct Validity.

Mentalization is an important interpersonal ability, necessary for adaptive interpersonal relationships and emotion regulation. Deficits in mentalization have been associated with poor psychological outcomes and have been observed in patients with Borderline Personality Disorder. The Mentalization Questionnaire (MZQ) has been developed as self-report measure of mentalization deficit. The aim of the study was to investigate the dimensionality of the MZQ in a nonclinical sample composed of Italian adults from the general population and to analyze its performance in categorizing individuals with higher risk of borderline symptoms. A non-clinical sample of 1,015 adults (709 women and 306 men) was administered the Italian versions of the MZQ, the Reflective Functioning Questionnaire (RFQ), and a measure of borderline psychopathology. A revised single-factor solution fitted the data well and demonstrated metric invariance across gender. The internal consistency (Ordinal α = 0.87) and stability (r = 0.84) were satisfactory. The MZQ was moderately associated with the RFQ dimensions. The ROC curve analysis showed that the MZQ was able to discriminate satisfactorily people with higher risk for borderline symptomatology from those with lower risk. The MZQ may, therefore, be considered a reliable and valid measure of mentalization for categorizing people at higher risk for borderline pathology.

Preclinical testing of oncolytic adenovirus sensitivity in patient-derived tumor organoids.

Patient-derived organoids (PDOs) have shown the potential to reflect patient sensitivity to chemotherapeutic or targeted drugs. Recently, we showed that organoid models can also serve as a platform to screen for selectivity and potency of oncolytic adenoviruses (OAds). In this protocol, we describe the steps for tumor organoid adenoviral infection and functional assessment of patient-specific responses to OAds. We provide methods to determine OAd relative efficacy by evaluation of PDO viability after infection and adenoviral replication within cancer cells. For complete details on the use and execution of this protocol, please refer to Raimondi et al. (2020).

Inhibition of miR-222 by Oncolytic Adenovirus-Encoded miRNA Sponges Promotes Viral Oncolysis and Elicits Antitumor Effects in Pancreatic Cancer Models.

Oncolytic adenoviruses (OA) are envisioned as a therapeutic option for patients with cancer, designed to preferentially replicate in cancer cells. However, the high number of genetic alterations in tumors can generate a context in which adenoviruses have difficulties replicating. Abnormal miRNAs expression is a trademark of pancreatic cancer, with several oncogenic miRNAs playing essential roles in cancer-associated pathways. The perturbed miRNome induces reprogramming of gene expression in host cells that can impact the complex interplay between cellular processes and viral replication. We have studied the effects of overexpressed miRNAs on oncolytic adenoviral activity and identified miRNAs modulators of adenoviral oncolysis in pancreatic cancer cells. Inhibition of the highly upregulated miR-222 sensitized cancer cells to oncolysis. To provide a therapeutic application to this insight, we engineered the oncolytic adenovirus AdNuPARmE1A with miR-222 binding sites, working as sponges to withdraw the miRNA from the cellular environment. AdNuPAR-E-miR222-S mediated-decrease of miR-222 expression in pancreatic cancer cells strongly improved the viral yield and enhanced the adenoviral cytotoxic effects. Antitumoral studies confirmed a high activity for AdNuPARmE1A-miR222-S in vivo, controlling tumor progression more effectively than the scrambled control virus in xenografts. We demonstrated that the increased antitumor potency of the novel oncolytic virus resulted from the combinatory effects of miR-222 oncomiR inhibition and the restoration of miR-222 target genes activity enhancing viral fitness.

The association between adult ADHD and food addiction: A mediation analysis.

OBJECTIVES: The aim of this study was to investigate the association between food addiction severity (FA) and ADHD symptomatology. Furthermore, we investigated whether emotional distress, and the mentalization deficits could mediate this relationship. METHODS: Three hundred eighty-five Italian adults (307 women and 78 men) participated in the study and completed the Italian versions of the Modified Yale Food Addiction Scale version 2.0, the Adult ADHD Self-Report Scale, the Depression Anxiety Stress Scales 21 and the Mentalization Questionnaire. RESULTS: ADHD symptoms severity and general distress were significantly and independently associated with FA. Emotional distress partly mediated the relationship between FA and ADHD symptoms severity. In addition, mentalization deficits partly mediated this relationship only when evaluating the influence of FA on ADHD symptoms severity. LIMITATIONS: This is a cross-sectional study and causal interpretations of the relationships among the variables are speculative. CONCLUSIONS: It is important to assess emotional distress and mentalization deficits in individuals at risk of ADHD and FA because these conditions could increase the risk for the presence of disordered eating patterns.

Neurocognitive and Psychopathological Predictors of Weight Loss After Bariatric Surgery: A 4-Year Follow-Up Study.

Twenty to thirty percent of patients experience weight regain at mid and long-term follow-up. Impaired cognitive functions are prevalent in people suffering from obesity and in those with binge eating disorder, thereby, affecting the weight-loss outcomes. The aim of our study was to investigate neurocognitive and psychopathological predictors of surgical efficacy in terms of percentage of excess weight loss (%EWL) at follow-up intervals of one year and 4-year. Psychosocial evaluation was completed in a sample of 78 bariatric surgery candidates and included psychometric instruments and a cognitive battery of neuropsychological tests. A schedule of 1-year and 4-year follow-ups was implemented. Wisconsin Sorting Card Test total correct responses, scores on the Raven's Progressive Matrices Test, and age predicted %EWL at, both, early and long-term periods after surgery while the severity of pre-operative binge eating (BED) symptoms were associated with lower %EWL only four years after the operation. Due to the role of pre-operative BED in weight loss maintenance, the affected patients are at risk of suboptimal response requiring ongoing clinical monitoring, and psychological and pharmacological interventions when needed. As a result of our findings and in keeping with the latest guidelines we encourage neuropsychological assessment of bariatric surgery candidates. This data substantiated the rationale of providing rehabilitative interventions tailored to cognitive domains and time specific to the goal of supporting patients in their post-surgical course.

Evaluating the Factor Structure of the Emotion Dysregulation Scale-Short (EDS-s): A Preliminary Study.

Emotion dysregulation (ED) can be considered a psychopathological transdiagnostic dimension, the presence of which should be reliably screened in clinical settings. The aim of the current study was to validate the Italian version of the Emotion Dysregulation Scale-short (EDS-s), a brief self-report tool assessing emotion dysregulation, in a non-clinical sample of 1087 adults (768 women and 319 men). We also assessed its convergent validity with scales measuring binge eating and general psychopathology. Structural equation modeling suggested the fit of a one-factor model refined with correlations between the errors of three pairs of items (χ2 = 255.56, df = 51, p < 0.001, RMSEA = 0.08, CFI = 0.94, TLI = 0.93, SRMR = 0.04). The EDS-s demonstrated satisfactory internal consistency (ordinal alpha = 0.94). Moreover, EDS-s scores partly explained the variance of both binge eating (0.35, p < 0.001) and general psychopathology (0.60, p < 0.001). In conclusion, the EDS-s can be considered to be a reliable and valid measure of ED.

Patient-derived pancreatic tumour organoids identify therapeutic responses to oncolytic adenoviruses.

BACKGROUND: Pancreatic patient-derived organoids (PDOs) are a well-established model for studying pancreatic ductal adenocarcinoma (PDAC) carcinogenesis and are potential predictors of clinical responses to chemotherapy. Oncolytic virotherapy is envisioned as a novel treatment modality for pancreatic cancer, and candidate viruses are being tested in clinical trials. Here, we explore the feasibility of using PDOs as a screening platform for the oncolytic adenovirus (OA) response. METHODS: Organoids were established from healthy pancreas and PDAC tissues and assessed for infectivity, oncoselectivity, and patient-dependent sensitivity to OA. Antitumour effects were studied in vivo in organoid xenografts. Further evaluation of oncolytic responses was conducted in organoids derived from orthotopic models or metastastic tissues. FINDINGS: Oncolytic adenoviruses display good selectivity, with replication only in organoids derived from PDAC tumours. Furthermore, responses of PDOs to a set of OAs reveal individual differences in cytotoxicity as well as in synergism with standard chemotherapy. Adenoviral cytotoxicity in PDOs is predictive of antitumour efficacy in a subcutaneous xenograft setting. Organoids from orthotopic tumours and metastases in nude mice mirror the viral preference of PDOs, indicating that PDO sensitivity to OAs could be informative about responses in both primary tumours and metastatic foci. INTERPRETATION: Our data imply that pancreatic PDOs can serve as predictive tools for screening for sensitivity to OA.

MiR-93 is related to poor prognosis in pancreatic cancer and promotes tumor progression by targeting microtubule dynamics.

Biomarkers and effective therapeutic agents to improve the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) are urgently required. We aimed to analyze the prognostic value and mechanistic action of miR-93 in PDAC. Correlation of miR-93 tumor levels from 83 PDAC patients and overall survival (OS) was analyzed by Kaplan-Meier. MiR-93 depletion in PANC-1 and MIA PaCa-2 cells was achieved by CRISPR/Cas9 and miR-93 overexpression in HPDE cells by retroviral transduction. Cell proliferation, migration and invasion, cell cycle analysis, and in vivo tumor xenografts in nude mice were assessed. Proteomic analysis by mass spectrometry and western-blot was also performed. Finally, miR-93 direct binding to candidate mRNA targets was evaluated by luciferase reporter assays. High miR-93 tumor levels are significantly correlated with a worst prognosis in PDAC patients. MiR-93 abolition altered pancreatic cancer cells phenotype inducing a significant increase in cell size and a significant decrease in cell invasion and proliferation accompanied by a G2/M arrest. In vivo, lack of miR-93 significantly impaired xenograft tumor growth. Conversely, miR-93 overexpression induced a pro-tumorigenic behavior by significantly increasing cell proliferation, migration, and invasion. Proteomic analysis unveiled a large group of deregulated proteins, mainly related to G2/M phase, microtubule dynamics, and cytoskeletal remodeling. CRMP2, MAPRE1, and YES1 were confirmed as direct targets of miR-93. MiR-93 exerts oncogenic functions by targeting multiple genes involved in microtubule dynamics at different levels, thus affecting the normal cell division rate. MiR-93 or its direct targets (CRMP2, MAPRE1, or YES1) are new potential therapeutic targets for PDAC.

Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer.

BACKGROUND & AIMS: A significant proportion of colorectal cancer (CRC) cases have familial aggregation but little is known about the genetic factors that contribute to these cases. We performed an exhaustive functional characterization of genetic variants associated with familial CRC. METHODS: We performed whole-exome sequencing analyses of 75 patients from 40 families with a history of CRC (including early-onset cases) of an unknown germline basis (discovery cohort). We also sequenced specific genes in DNA from an external replication cohort of 473 families, including 488 patients with colorectal tumors that had normal expression of mismatch repair proteins (validation cohort). We disrupted the Fas-associated factor 1 gene (FAF1) in DLD-1 CRC cells using CRISPR/Cas9 gene editing; some cells were transfected with plasmids that express FAF1 missense variants. Cells were analyzed by immunoblots, quantitative real-time polymerase chain reaction, and functional assays monitoring apoptosis, proliferation, and assays for Wnt signaling or nuclear factor (NF)-kappa-B activity. RESULTS: We identified predicted pathogenic variant in the FAF1 gene (c.1111G>A; p.Asp371Asn) in the discovery cohort; it was present in 4 patients of the same family. We identified a second variant in FAF1 in the validation cohort (c.254G>C; p.Arg85Pro). Both variants encoded unstable FAF1 proteins. Expression of these variants in CRC cells caused them to become resistant to apoptosis, accumulate beta-catenin in the cytoplasm, and translocate NF-kappa-B to the nucleus. CONCLUSIONS: In whole-exome sequencing analyses of patients from families with a history of CRC, we identified variants in FAF1 that associate with development of CRC. These variants encode unstable forms of FAF1 that increase resistance of CRC cells to apoptosis and increase activity of beta-catenin and NF-kappa-B.