Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma

Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative ‘enhancer rewiring’ events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.

Team eDyNAmiC
Journal Nature Genetics
Authors Owen S. Chapman et al
DATE 09 November 2023
Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer

Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1,2,3. Consequently, spatially resolved omics-level analyses are gaining traction4,5,6,7,8,9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.

Team Rosetta
Journal Nature Metabolism
Authors Peter Kreuzaler et al
DATE 09 November 2023
Association of DCIS size and margin status with risk of developing breast cancer post-treatment: multinational, pooled cohort…

Objective To examine the association between size and margin status of ductal carcinoma in situ (DCIS) and risk of developing ipsilateral invasive breast cancer and ipsilateral DCIS after treatment, and stage and subtype of ipsilateral invasive breast cancer.

Design Multinational, pooled cohort study.

Setting Four large international cohorts.

Participants Patient level data on 47 695 women with a diagnosis of pure, primary DCIS between 1999 and 2017 in the Netherlands, UK, and US who underwent surgery, either breast conserving or mastectomy, often followed by radiotherapy or endocrine treatment, or both.

Main outcome measures The main outcomes were 10 year cumulative incidence of ipsilateral invasive breast cancer and ipsilateral DCIS estimated in relation to DCIS size and margin status, and adjusted hazard ratios and 95% confidence intervals, estimated using multivariable Cox proportional hazards analyses with multiple imputed data

Results The 10 year cumulative incidence of ipsilateral invasive breast cancer was 3.2%. In women who underwent breast conserving surgery with or without radiotherapy, only adjusted risks for ipsilateral DCIS were significantly increased for larger DCIS (20-49 mm) compared with DCIS <20 mm (hazard ratio 1.38, 95% confidence interval 1.11 to 1.72). Risks for both ipsilateral invasive breast cancer and ipsilateral DCIS were significantly higher with involved compared with clear margins (invasive breast cancer 1.40, 1.07 to 1.83; DCIS 1.39, 1.04 to 1.87). Use of adjuvant endocrine treatment was not significantly associated with a lower risk of ipsilateral invasive breast cancer compared to treatment with breast conserving surgery only (0.86, 0.62 to 1.21). In women who received breast conserving treatment with or without radiotherapy, higher DCIS grade was not significantly associated with ipsilateral invasive breast cancer, only with a higher risk of ipsilateral DCIS (grade 1: 1.42, 1.08 to 1.87; grade 3: 2.17, 1.66 to 2.83). Higher age at diagnosis was associated with lower risk (per year) of ipsilateral DCIS (0.98, 0.97 to 0.99) but not ipsilateral invasive breast cancer (1.00, 0.99 to 1.00). Women with large DCIS (≥50 mm) more often developed stage III and IV ipsilateral invasive breast cancer compared to women with DCIS <20 mm. No such association was found between involved margins and higher stage of ipsilateral invasive breast cancer. Associations between larger DCIS and hormone receptor negative and human epidermal growth factor receptor 2 positive ipsilateral invasive breast cancer and involved margins and hormone receptor negative ipsilateral invasive breast cancer were found.

Conclusions The association of DCIS size and margin status with ipsilateral invasive breast cancer and ipsilateral DCIS was small. When these two factors were added to other known risk factors in multivariable models, clinicopathological risk factors alone were found to be limited in discriminating between low and high risk DCIS.

Journal BMJ
Authors Renée S J M Schmitz et al
DATE 30 October 2023
The microbiome and rise of early-onset cancers: knowledge gaps and research opportunities

Accumulating evidence indicates an alarming increase in the incidence of early-onset cancers, which are diagnosed among adults under 50 years of age, in the colorectum, esophagus, extrahepatic bile duct, gallbladder, liver, stomach, pancreas, as well as the bone marrow (multiple myeloma), breast, head and neck, kidney, prostate, thyroid, and uterine corpus (endometrium). While the early-onset cancer studies have encompassed research on the wide variety of organs, this article focuses on research on digestive system cancers. While a minority of early-onset cancers in the digestive system are associated with cancer-predisposing high penetrance germline genetic variants, the majority of those cancers are sporadic and multifactorial. Although potential etiological roles of diets, lifestyle, environment, and the microbiome from early life to adulthood (i.e. in one’s life course) have been hypothesized, exact contribution of each of these factors remains uncertain. Diets, lifestyle patterns, and environmental exposures have been shown to alter the oral and intestinal microbiome. To address the rising trend of early-onset cancers, transdisciplinary research approaches including lifecourse epidemiology and molecular pathological epidemiology frameworks, nutritional and environmental sciences, multi-omics technologies, etc. are needed. We review current evidence and discuss emerging research opportunities, which can improve our understanding of their etiologies and help us design better strategies for prevention and treatment to reduce the cancer burden in populations.

Journal Gut Microbes
Authors Kosuke Mima et al
DATE 30 October 2023
HLA3DB: comprehensive annotation of peptide/HLA complexes enables blind structure prediction of T cell epitopes

The class I proteins of the major histocompatibility complex (MHC-I) display epitopic peptides derived from endogenous proteins on the cell surface for immune surveillance. Accurate modeling of peptides bound to the human MHC, HLA, has been mired by conformational diversity of the central peptide residues, which are critical for recognition by T cell receptors. Here, analysis of X-ray crystal structures within our curated database (HLA3DB) shows that pHLA complexes encompassing multiple HLA allotypes present a discrete set of peptide backbone conformations. Leveraging these backbones, we employ a regression model trained on terms of a physically relevant energy function to develop a comparative modeling approach for nonamer pHLA structures named RepPred. Our method outperforms the top pHLA modeling approach by up to 19% in structural accuracy, and consistently predicts blind targets not included in our training set. Insights from our work may be applied towards predicting antigen immunogenicity, and receptor cross-reactivity.

Team NexTGen
Journal Nature Communications
Authors Sagar Gupta et al
DATE 10 October 2023