The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Développer les compétences en leadership chez les enfants

This thesis examined how adolescents and young people conceptualize leadership. More specifically, the thesis examined their beliefs and perceptions of what is means to be a leader in Greece and understood the factors that contribute to their ideas and concepts about leadership. The thesis aimed to answer the following research questions: in what ways do leadership programmes influence adolescent and young peoples’ thoughts and behaviors with regard to their ideas about leadership, what factors influence the thoughts and behaviors of adolescents with regard to their ideas about leadership, which incidents do adolescents identify as influencing their thoughts and behaviors with regard to leadership. The thesis presents the results of a systematic review and two qualitative studies. In the discussion section, the thesis reflects on the contributions made by the research to the study of leadership development among adolescents. The thesis makes recommendations concerning how the Greek educational system can integrate the findings within the Greek curriculum. The implications of the thesis are important for policy makers and school administrators. Finally, future directions for research are discussed.Αυτή η διατριβή εξέτασε πώς οι έφηβοι και οι νέοι αντιλαμβάνονται την ηγεσία. Πιο συγκεκριμένα, η διατριβή εξέτασε τις πεποιθήσεις και τις αντιλήψεις τους για το τι σημαίνει να είσαι ηγέτης στην Ελλάδα και κατανοήθηκαν οι παράγοντες που συμβάλλουν στις ιδέες και τις αντιλήψεις τους για την ηγεσία. Η διατριβή στόχευε να απαντήσει στα ακόλουθα ερευνητικά ερωτήματα: με ποιους τρόπους τα προγράμματα ηγεσίας επηρεάζουν τις σκέψεις και τις συμπεριφορές των εφήβων και των νέων σε σχέση με τις ιδέες τους για την ηγεσία, ποιοι παράγοντες επηρεάζουν τις σκέψεις και τις συμπεριφορές των εφήβων σε σχέση με τις ιδέες τους για την ηγεσία, ποια περιστατικά εντοπίζουν οι έφηβοι ότι επηρεάζουν τις σκέψεις και τις συμπεριφορές τους όσον αφορά την ηγεσία. Η διατριβή παρουσιάζει τα αποτελέσματα μιας συστηματικής ανασκόπησης και δύο ποιοτικών μελετών. Στην ενότητα συζήτησης, η διατριβή αντικατοπτρίζει τη συμβολή της έρευνας στη μελέτη της ανάπτυξης ηγεσίας μεταξύ των εφήβων. Περιορισμοί και θέματα αναστοχαστικότητας συζητούνται λεπτομερώς. Η διατριβή κάνει συστάσεις σχετικά με το πώς το ελληνικό εκπαιδευτικό σύστημα μπορεί να ενσωματώσει τα ευρήματα στο ελληνικό αναλυτικό πρόγραμμα σπουδών. Τα θέματα της διατριβής είναι σημαντικά για τους υπεύθυνους χάραξης πολιτικής στα σχολεία. Τέλος, συζητούνται μελλοντικές κατευθύνσεις για έρευνα

Developing leadership skills among adolescents and young adults: a review of leadership programmes

Our understanding of leadership is skewed towards the adult experience of leadership. There is a gap in the literature with regard to the experience of leadership among school children and young adults. Young people experience their first formal organization at school and models of leadership are developed from this critical period. The present review identified studies on leadership development programmes for young adults from 2003 to 2015 via electronic databases: Scopus, PubMed and Science direct. Nine studies met all the inclusion criteria and were analysed with regard to; selection, content, outcomes and theoretical background. Considerable heterogeneity in the methods used was observed. The review presents key research questions that need to be addressed in future studies

Women’s Mental Health as a Factor Associated with Exclusive Breastfeeding and Breastfeeding Duration: Data from a Longitudinal Study in Greece

Background: This study investigated the relationship between exclusive breastfeeding and breastfeeding duration, and maternal psychological well-being in the perinatal period. Methods: A longitudinal study involving a retrospective follow-up of a group of 1080 women from pregnancy to the 1st year postpartum, who gave birth during the 5-year period between January 2014 and January 2019 in Athens, Greece, was designed. Women’s history and two psychometric tools—the Edinburg Postpartum Depression Scale (EPDS) and the Patient Health Questionnaire-9 (PHQ-9) administered at 5-time points—were used for data collection. Logistic regression analysis and a series of multiple analysis of variance (MANOVA) tests were performed. Results: The chance for exclusive breastfeeding (giving only breast milk) appeared to decrease (a) with an increase of the scores for psychometric tools antenatally (PHQ-9, p = 0.030) or at the 6th week postpartum (EPDS, p < 0.001 and PHQ-9, p < 0.001), (b) with an increase in the number of psychotherapeutic sessions needed antenatally (p = 0.030), and (c) when the initiation of psychotherapy was necessary postpartum (p = 0.002). Additionally, a shorter duration of any breastfeeding (with or without formula or other types of food/drink) seems to be associated with (a) the occurrence of pathological mental health symptoms (p = 0.029), (b) increased PHQ-9 scores antenatally (p = 0.018), (c) increased EPDS scores at the 6th week (p = 0.004) and the 12th month postpartum (p = 0.031), (d) the initiation of psychotherapy postpartum (p = 0.040), and e) the need for more than 13 psychotherapeutic sessions (p = 0.020). Conclusions: This study demonstrates a negative relationship between exclusive breastfeeding and breastfeeding duration, and poor maternal mental health in the perinatal period

Body composition and lung cancer-associated cachexia in TRACERx

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial–mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC