bims-ovdlit 2023-09-24 papers

Issue of 2023–09–24
five papers selected by
Lara Paracchini, Humanitas Research

Nat Commun. 2023 09 20. 14(1): 5846

epiAneufinder identifies copy number alterations from single-cell ATAC-seq data.

Akshaya Ramakrishnan, Aikaterini Symeonidi, Patrick Hanel, Katharina T Schmid, Maria L Richter, Michael Schubert, Maria Colomé-Tatché.

Single-cell open chromatin profiling via scATAC-seq has become a mainstream measurement of open chromatin in single-cells. Here we present epiAneufinder, an algorithm that exploits the read count information from scATAC-seq data to extract genome-wide copy number alterations (CNAs) for individual cells, allowing the study of CNA heterogeneity present in a sample at the single-cell level. Using different cancer scATAC-seq datasets, we show that epiAneufinder can identify intratumor clonal heterogeneity in populations of single cells based on their CNA profiles. We demonstrate that these profiles are concordant with the ones inferred from single-cell whole genome sequencing data for the same samples. EpiAneufinder allows the inference of single-cell CNA information from scATAC-seq data, without the need of additional experiments, unlocking a layer of genomic variation which is otherwise unexplored.

DOI: https://doi.org/10.1038/s41467-023-41076-1

Cell Rep. 2023 Sep 19. pii: S2211-1247(23)01156-7. [Epub ahead of print]42(10): 113144

Replication stress and defective checkpoints make fallopian tube epithelial cells putative drivers of high-grade serous ovarian cancer.

Pamoda Galhenage, Yunlan Zhou, Erica Perry, Brenda Loc, Kelly Fietz, Sonia Iyer, Ferenc Reinhardt, Tiego Da Silva, Vladimir Botchkarev, Jie Chen, Christopher P Crum, Robert A Weinberg, Shailja Pathania.

Clinical and molecular evidence indicates that high-grade serous ovarian cancer (HGSOC) primarily originates from the fallopian tube, not the ovarian surface. However, the reasons for this preference remain unclear. Our study highlights significant differences between fallopian tube epithelial (FTE) and ovarian surface epithelial (OSE) cells, providing the molecular basis for FTEs as site of origin of HGSOC. FTEs, unlike OSEs, exhibit heightened replication stress (RS), impaired repair of stalled forks, ineffective G2/M checkpoint, and increased tumorigenicity. BRCA1 heterozygosity exacerbates these defects, resulting in RS suppression haploinsufficiency and an aggressive tumor phenotype. Examination of human and mouse sections reveals buildup of the RS marker 53BP1 primarily in the fallopian tubes, particularly at the fimbrial ends. Furthermore, menopausal status influences RS levels. Our study provides a mechanistic rationale for FTE as the site of origin for HGSOC, investigates the impact of BRCA1 heterozygosity, and lays the groundwork for targeting early HGSOC drivers.

Keywords: BRCA1; CP: Cancer; Cell of origin; DNA damage checkpoints; DNA damage repair; High-grade serous ovarian cancer; fallopian tube; fimbrial ends; ovarian fat pad injection; replication stress; replication stress marker

DOI: https://doi.org/10.1016/j.celrep.2023.113144

Br J Cancer. 2023 Sep 19.

Evaluating multi-cancer early detection tests: an argument for the outcome of recurrence-updated stage.

Matthew E J Callister, Emma J Crosbie, Philip A J Crosbie, Hilary A Robbins.

The advent of multi-cancer early detection (MCED) tests has the potential to revolutionise the diagnosis of cancer, improving patient outcomes through early diagnosis and increased use of curative therapies. The ongoing NHS-Galleri trial is evaluating an MCED test developed by GRAIL, and is using as its primary endpoint the absolute incidence of late-stage cancer. Proponents of this outcome argue that if the test reduces the number of patients with advanced, incurable cancer, it can be reasonably assumed to be benefitting patients by reducing cancer mortality. Here, we argue that this assumption may not always hold due to the phenomenon of micro-metastatic disease, and propose an adjustment to the trial outcome so that it may better reflect the expected effect of the test on cancer mortality.

DOI: https://doi.org/10.1038/s41416-023-02434-4

Annu Rev Med. 2023 Sep 20.

Multi-Cancer Early Detection: The New Frontier in Cancer Early Detection.

Carmen E Guerra, Prateek V Sharma, Brenda S Castillo.

The new generation of cancer early detection tests holds remarkable promise for revolutionizing and changing the paradigm of cancer early detection. Dozens of cancer early detection tests are being developed and evaluated. Some are already commercialized and available for use, most as a complement to and not in place of existing recommended cancer screening tests. This review evaluates existing single- and multi-cancer early detection tests (MCEDs), discussing their performance characteristics including sensitivity, specificity, positive and negative predictive values, and accuracy. It also critically looks at the potential harms that could result from these tests, including false positive and negative results, the risk of overdiagnosis and overtreatment, psychological and economic harms, and the risk of widening cancer inequities. We also review the large-scale, population-based studies that are being launched in the United States and United Kingdom to determine the impact of MCEDs on clinically relevant outcomes and implications for current practice. Expected final online publication date for the Annual Review of Medicine, Volume 75 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-med-050522-033624

Nat Cancer. 2023 Sep 21.

A phase 1 trial of adoptive transfer of vaccine-primed autologous circulating T cells in ovarian cancer.

We have previously shown that vaccination with tumor-pulsed dendritic cells amplifies neoantigen recognition in ovarian cancer. Here, in a phase 1 clinical study ( NCT01312376 /UPCC26810) including 19 patients, we show that such responses are further reinvigorated by subsequent adoptive transfer of vaccine-primed, ex vivo-expanded autologous peripheral blood T cells. The treatment is safe, and epitope spreading with novel neopeptide reactivities was observed after cell infusion in patients who experienced clinical benefit, suggesting reinvigoration of tumor-sculpting immunity.

DOI: https://doi.org/10.1038/s43018-023-00623-x