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BACKGROUND Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P = 4.4×10-4), which remained significant in multivariate analysis. CONCLUSIONS Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. [ABSTRACT FROM AUTHOR]

Neoantigen immunogenicity prediction is a highly challenging problem in the development of personalised medicines. Low reactivity rates in called neoantigens result in a difficult prediction scenario with limited training datasets. Here we describe ImmugenX, a modular protein language modelling approach to immunogenicity prediction for CD8+ reactive epitopes. ImmugenX comprises of a pMHC encoding module trained on three pMHC prediction tasks, an optional TCR encoding module and a set of context specific immunogenicity prediction head modules. Compared with state-of-the-art models for each task, ImmugenX's encoding module performs comparably or better on pMHC binding affinity, eluted ligand prediction and stability tasks. ImmugenX outperforms all compared models on pMHC immunogenicity prediction (Area under the receiver operating characteristic curve = 0.619, average precision: 0.514), with a 7% increase in average precision compared to the next best model. ImmugenX shows further improved performance on immunogenicity prediction with the integration of TCR context information. ImmugenX performance is further analysed for interpretability, which locates areas of weakness found across existing immunogenicity models and highlight possible biases in public datasets., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: S.A.Q. is co-founder and chief scientific officer and own shares in Achilles Therapeutics. C.S. acknowledges grants from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc., a collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical and Personalis. He is chief investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the steering committee chair. He is also co-chief investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s scientific advisory board (SAB). He receives consultant fees from Achilles Therapeutics (also an SAB member); Bicycle Therapeutics (also an SAB member); Genentech; Medicxi; the China Innovation Centre of Roche (CICoR), formerly Roche Innovation Centre Shanghai; Metabomed (until July 2022); Relay Therapeutics; and the Sarah Cannon Research Institute. C.S has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer and Roche-Ventana; previously held stock options in Apogen Biotechnologies and GRAIL; currently has stock options in Epic Bioscience and Bicycle Therapeutics; and has stock options and is co-founder of Achilles Therapeutics. S.R.H. is the cofounder of PokeAcell and is co-inventor of licensed patents related to T cell detection. H.O’B., M.S., L.M. and F.O’F. are employees of Achilles Therapeutics. H.O’B. and M.S. are both named inventors on patents for ImmugenX., (Copyright: © 2024 O’Brien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The growing awareness of colonialism's role in global health partnerships between HICs and LMICs and the associated calls for decolonization in global health has led to discussion for a paradigm shift that would lead to new ways of engagement and partnerships, as well as an acknowledgement that colonialism, racism, sexism, and capitalism contribute to inequity. While there is general agreement among those involved in global health partnerships that the current system needs to be made more equitable, suggestions for how to address the issue of decolonization vary greatly, and moving from rhetoric to reform is complicated. Based on a comprehensive (but not exhaustive) review of the literature, there are several recurring themes that should be addressed in order for the inequities in the current system to be changed. The degree to which decolonization of global health will be successful depends on how the global health community in both the HICs and LMICs move forward to discuss these issues. Specifically, as part of a paradigm shift, attention needs to be paid to creating a more equal and equitable representation of researchers in LMICs in decision-making, leadership roles, authorship, and funding allocations. There needs to be agreement in defining basic principles of best practices for global partnership, including a universal definition of 'decolonization of global health'; the extent to which current policies allow the perpetuation of power imbalance between HICs and LMICs; a set of principles, best practices, and models for equitable sharing of funds and institutional costs among partners; a mechanism to monitor progress prospectively the equitable sharing of credits (e.g., leadership, authorship), including a set of principles, best practices, and models; and, a mechanism to monitor progress prospectively the extent to which decolonialization will contribute to strengthening institutional capacity in the LMIC institutions., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)