bims-tumhet 2023-03-19 papers

Issue of 2023–03–19
seven papers selected by
Sergio Marchini, Humanitas Research

Cancer. 2023 Mar 17.

Clinical implications of tumor-based next-generation sequencing in high-grade epithelial ovarian cancer.

Katherine I Foster, Kenna R M Shaw, Jeff Jin, Shannon N Westin, Timothy A Yap, Deanna M Glassman, Amir A Jazaeri, Jose A Rauh-Hain, Sanghoon Lee, Bryan M Fellman, Zhenlin Ju, Yuexin Liu, Nicole D Fleming, Anil K Sood.

BACKGROUND: Tumor-based next-generation sequencing is used inconsistently as a tool to tailor treatment of ovarian cancer, yet beyond detection of somatic BRCA1 and BRCA2 mutations, the clinical benefit is not well established. This study aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in patients with ovarian cancer.
METHODS: This retrospective study included patients with high-grade epithelial ovarian carcinoma. tbNGS results were identified in the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected. Progression-free survival (PFS) and overall survival were calculated and compared using log-rank tests. Multivariate Cox regression and clustering analyses were used to identify patterns of genetic alterations associated with survival.
RESULTS: Of 1092 patients in the described population, 409 (37.5%) had tbNGS results. Nearly all (96.1% [393/409]) had one or more genetic alterations. In 25.9% (106/409) of patients, an alteration that aligned with a targeted treatment was identified, and in an additional 48.7% (199/409), tbNGS results suggested eligibility for an investigational agent or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations, and CCNE1 amplification. Together, BRCA1 and BRCA2 mutations were associated with longer PFS (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.42-0.92; p = .02), whereas AKT2 amplification was associated with shorter PFS (HR, 3.86; 95% CI, 1.002-14.88; p < .05). Multivariate Cox regression and clustering analyses identified several combinations of genetic alterations that corresponded to outcomes in patients with high-grade serous carcinoma.
CONCLUSIONS: tbNGS often yields clinically relevant information. Detailed analysis of population-level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools.
PLAIN LANGUAGE SUMMARY: Although more and more patients with ovarian cancer are undergoing tumor-based next-generation sequencing to identify genetic mutations in their tumors, the benefits of such testing are not well established. In a group of over 400 patients with ovarian cancer who underwent tumor-based next-generation sequencing in the course of their treatment, nearly all patients had one or more genetic alterations detected, and one out of four patients had a mutation that qualified them for a personalized treatment option.

Keywords: genetic testing; high-throughput nucleotide sequencing; mutation; natural language processing; ovarian epithelial carcinoma; ovarian neoplasms; retrospective studies

DOI: https://doi.org/10.1002/cncr.34724

Cell. 2023 Mar 14. pii: S0092-8674(23)00163-0. [Epub ahead of print]

Macrophages at the interface of the co-evolving cancer ecosystem.

Daan J Kloosterman, Leila Akkari.

Macrophages are versatile and heterogeneous innate immune cells undertaking central functions in balancing immune responses and tissue repair to maintain homeostasis. This plasticity, once co-opted by malignant outgrowth, orchestrates manifold reciprocal interactions within the tumor microenvironment, fueling the evolution of the cancer ecosystem. Here, we review the multilayered sources of influence that jointly underpin and longitudinally shape tumor-associated macrophage (TAM) phenotypic states in solid neoplasms. We discuss how, in response to these signals, TAMs steer tumor evolution in the context of natural selection, biological dispersion, and treatment resistance. A number of research frontiers to be tackled are laid down in this review to therapeutically exploit the complex roles of TAMs in cancer. Building upon knowledge obtained from currently applied TAM-targeting strategies and using next generation technologies, we propose conceptual advances and novel therapeutic avenues to rewire TAM multifaceted regulation of the co-evolving cancer ecosystem.

Keywords: cancer evolution; immunity; macrophages; tumor microenvironment

DOI: https://doi.org/10.1016/j.cell.2023.02.020

Nat Commun. 2023 Mar 11. 14(1): 1353

Short-term molecular consequences of chromosome mis-segregation for genome stability.

Chromosome instability (CIN) is the most common form of genome instability and is a hallmark of cancer. CIN invariably leads to aneuploidy, a state of karyotype imbalance. Here, we show that aneuploidy can also trigger CIN. We found that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN. This generates a repertoire of genetically diverse cells with structural chromosomal abnormalities that can either continue proliferating or stop dividing. Cycling aneuploid cells display lower karyotype complexity compared to the arrested ones and increased expression of DNA repair signatures. Interestingly, the same signatures are upregulated in highly-proliferative cancer cells, which might enable them to proliferate despite the disadvantage conferred by aneuploidy-induced CIN. Altogether, our study reveals the short-term origins of CIN following aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for aneuploidy occurrence in tumors.

DOI: https://doi.org/10.1038/s41467-023-37095-7

Cancer Cell. 2023 Mar 13. pii: S1535-6108(23)00040-5. [Epub ahead of print]41(3): 573-580

Cancer hallmarks intersect with neuroscience in the tumor microenvironment.

Douglas Hanahan, Michelle Monje.

The mechanisms underlying the multistep process of tumorigenesis can be distilled into a logical framework involving the acquisition of functional capabilities, the so-called hallmarks of cancer, which are collectively envisaged to be necessary for malignancy. These capabilities, embodied both in transformed cancer cells as well as in the heterotypic accessory cells that together constitute the tumor microenvironment (TME), are conveyed by certain abnormal characteristics of the cancerous phenotype. This perspective discusses the link between the nervous system and the induction of hallmark capabilities, revealing neurons and neuronal projections (axons) as hallmark-inducing constituents of the TME. We also discuss the autocrine and paracrine neuronal regulatory circuits aberrantly activated in cancer cells that may constitute a distinctive "enabling" characteristic contributing to the manifestation of hallmark functions and consequent cancer pathogenesis.

DOI: https://doi.org/10.1016/j.ccell.2023.02.012

Nat Genet. 2023 Mar 16.

Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity.

Lise Mangiante, Nicolas Alcala, Alexandra Sexton-Oates, Alex Di Genova, Abel Gonzalez-Perez, Azhar Khandekar, Erik N Bergstrom, Jaehee Kim, Xiran Liu, Ricardo Blazquez-Encinas, Colin Giacobi, Nolwenn Le Stang, Sandrine Boyault, Cyrille Cuenin, Severine Tabone-Eglinger, Francesca Damiola, Catherine Voegele, Maude Ardin, Marie-Cecile Michallet, Lorraine Soudade, Tiffany M Delhomme, Arnaud Poret, Marie Brevet, Marie-Christine Copin, Sophie Giusiano-Courcambeck, Diane Damotte, Cecile Girard, Veronique Hofman, Paul Hofman, Jérôme Mouroux, Charlotte Cohen, Stephanie Lacomme, Julien Mazieres, Vincent Thomas de Montpreville, Corinne Perrin, Gaetane Planchard, Nathalie Rousseau, Isabelle Rouquette, Christine Sagan, Arnaud Scherpereel, Francoise Thivolet, Jean-Michel Vignaud, Didier Jean, Anabelle Gilg Soit Ilg, Robert Olaso, Vincent Meyer, Anne Boland-Auge, Jean-Francois Deleuze, Janine Altmuller, Peter Nuernberg, Alejandro Ibáñez-Costa, Justo P Castaño, Sylvie Lantuejoul, Akram Ghantous, Charles Maussion, Pierre Courtiol, Hector Hernandez-Vargas, Christophe Caux, Nicolas Girard, Nuria Lopez-Bigas, Ludmil B Alexandrov, Françoise Galateau-Salle, Matthieu Foll, Lynnette Fernandez-Cuesta.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.

DOI: https://doi.org/10.1038/s41588-023-01321-1

Curr Opin Microbiol. 2023 Mar 15. pii: S1369-5274(23)00029-2. [Epub ahead of print]73 102292

Moving beyond DNA: towards functional analysis of the vaginal microbiome by non-sequencing-based methods.

Gonçalo Ds Correia, Julian R Marchesi, David A MacIntyre.

Over the last two decades, sequencing-based methods have revolutionised our understanding of niche-specific microbial complexity. In the lower female reproductive tract, these approaches have enabled identification of bacterial compositional structures associated with health and disease. Application of metagenomics and metatranscriptomics strategies have provided insight into the putative function of these communities but it is increasingly clear that direct measures of microbial and host cell function are required to understand the contribution of microbe-host interactions to pathophysiology. Here we explore and discuss current methods and approaches, many of which rely upon mass-spectrometry, being used to capture functional insight into the vaginal mucosal interface. In addition to improving mechanistic understanding, these methods offer innovative solutions for the development of diagnostic and therapeutic strategies designed to improve women's health.

DOI: https://doi.org/10.1016/j.mib.2023.102292

Int J Cancer. 2023 Mar 13.

DNA methylation testing for endometrial cancer detection in urine, cervicovaginal self-samples, and cervical scrapes.

Birgit M M Wever, Rianne van den Helder, Annina P van Splunter, Mignon D J M van Gent, Jenneke C Kasius, Johannes W Trum, Harold R Verhoeve, Wilhelmina M van Baal, Alicia Hulbert, Lisanne Verhoef, Daniëlle A M Heideman, Birgit I Lissenberg-Witte, Nienke E van Trommel, Renske D M Steenbergen, Maaike C G Bleeker.

Endometrial cancer incidence is rising and current diagnostics often require invasive biopsy procedures. DNA methylation marker analysis of minimally- and non-invasive sample types could provide an easy-to-apply and patient-friendly alternative to determine cancer risk. Here, we compared the performance of DNA methylation markers to detect endometrial cancer in urine, cervicovaginal self-samples, and clinician-taken cervical scrapes. Paired samples were collected from 103 patients diagnosed with stage I to IV endometrial cancer. Urine and self-samples were collected at home. All samples were tested for nine DNA methylation markers using quantitative methylation-specific PCR. Methylation levels measured in endometrial cancer patients were compared with unpaired samples of 317 healthy controls. Diagnostic performances were evaluated by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Each methylation marker showed significantly higher methylation levels in all sample types of endometrial cancer patients compared to healthy controls (P < 0.01). Optimal three-marker combinations demonstrated excellent diagnostic performances with area under the receiver operating curve values of 0.95 (95%-CI, 0.92 to 0.98), 0.94 (0.90 to 0.97), and 0.97 (0.96 to 0.99), for endometrial cancer detection in urine, self-samples and scrapes, respectively. Sensitivities ranged from 89-93% at specificities of 90-92%. Virtually equal performances were obtained after cross-validation and excellent diagnostic performances were maintained for stage I endometrial cancer detection. Our study shows the value of methylation analysis in patient-friendly sample types for endometrial cancer detection of all stages. This approach has great potential to screen patient populations at risk for endometrial cancer. This article is protected by copyright. All rights reserved.

Keywords: Cervical scrape; DNA methylation; Endometrial cancer; Urine; Vaginal sample

DOI: https://doi.org/10.1002/ijc.34504