bims-ovdlit 2022-02-06 papers

Cancer Cell. 2022 Feb 03. pii: S1535-6108(22)00014-9. [Epub ahead of print]

New genomic technologies for multi-cancer early detection: Rethinking the scope of cancer screening.

Allan Hackshaw, Christina A Clarke, Anne-Renee Hartman.

Cancers other than breast, colorectal, cervical, and lung do not have guideline-recommended screening. New multi-cancer early detection (MCED) tests-using a single blood sample-have been developed based on circulating cell-free DNA (cfDNA) or other analytes. In this commentary, we review the current evidence on these tests, provide several major considerations for new MCED tests, and outline how their evaluation will need to differ from that established for traditional single-cancer screening tests.

DOI: https://doi.org/10.1016/j.ccell.2022.01.012

Nat Cancer. 2021 Jan;2(1): 6-8

Advances in ovarian cancer, from biology to treatment.

Michelle McMullen, Katherine Karakasis, Robert Rottapel, Amit M Oza.

DOI: https://doi.org/10.1038/s43018-020-00166-5

Sci Rep. 2022 Feb 04. 12(1): 1928

Refined characterization of circulating tumor DNA through biological feature integration.

Havell Markus, Dineika Chandrananda, Elizabeth Moore, Florent Mouliere, James Morris, James D Brenton, Christopher G Smith, Nitzan Rosenfeld.

Circulating tumor DNA (ctDNA) in blood plasma is present at very low concentrations compared to cell-free DNA (cfDNA) of non-tumor origin. To enhance ctDNA detection, recent studies have been focused on understanding the non-random fragmentation pattern of cfDNA. These studies have investigated fragment sizes, genomic position of fragment end points, and fragment end motifs. Although these features have been described and shown to be aberrant in cancer patients, there is a lack of understanding of how the individual and integrated analysis of these features enrich ctDNA fraction and enhance ctDNA detection. Using whole genome sequencing and copy number analysis of plasma samples from 5 high grade serious ovarian cancer patients, we observed that (1) ctDNA is enriched not only in fragments shorter than mono-nucleosomes (~ 167 bp), but also in those shorter than di-nucleosomes (~ 240-330 bp) (28-159% enrichment). (2) fragments that start and end at the border or within the nucleosome core are enriched in ctDNA (5-46% enrichment). (3) certain DNA motifs conserved in regions 10 bp up- and down- stream of fragment ends (i.e. cleavage sites) could be used to detect tumor-derived fragments (10-44% enrichment). We further show that the integrated analysis of these three features resulted in a higher enrichment of ctDNA when compared to using fragment size alone (additional 7-25% enrichment after fragment size selection). We believe these genome wide features, which are independent of genetic mutational changes, could allow new ways to analyze and interpret cfDNA data, as significant aberrations of these features from a healthy state could improve its utility as a diagnostic biomarker.

DOI: https://doi.org/10.1038/s41598-022-05606-z

Nat Biomed Eng. 2022 Jan 31.

Limitations and opportunities of technologies for the analysis of cell-free DNA in cancer diagnostics.

Ping Song, Lucia Ruojia Wu, Yan Helen Yan, Jinny X Zhang, Tianqing Chu, Lawrence N Kwong, Abhijit A Patel, David Yu Zhang.

Cell-free DNA (cfDNA) in the circulating blood plasma of patients with cancer contains tumour-derived DNA sequences that can serve as biomarkers for guiding therapy, for the monitoring of drug resistance, and for the early detection of cancers. However, the analysis of cfDNA for clinical diagnostic applications remains challenging because of the low concentrations of cfDNA, and because cfDNA is fragmented into short lengths and is susceptible to chemical damage. Barcodes of unique molecular identifiers have been implemented to overcome the intrinsic errors of next-generation sequencing, which is the prevailing method for highly multiplexed cfDNA analysis. However, a number of methodological and pre-analytical factors limit the clinical sensitivity of the cfDNA-based detection of cancers from liquid biopsies. In this Review, we describe the state-of-the-art technologies for cfDNA analysis, with emphasis on multiplexing strategies, and discuss outstanding biological and technical challenges that, if addressed, would substantially improve cancer diagnostics and patient care.

DOI: https://doi.org/10.1038/s41551-021-00837-3

Nat Cancer. 2020 Mar;1(3): 276-290

Circulating tumor DNA and liquid biopsy in oncology.

David W Cescon, Scott V Bratman, Steven M Chan, Lillian L Siu.

Techniques for analyzing circulating tumor DNA (ctDNA) to detect, characterize and monitor cancer have matured rapidly. An increasing body of clinical evidence is demonstrating the capabilities of this technology as a diagnostic test. The full potential of ctDNA liquid biopsy in the diagnosis, characterization and management of solid and hematological malignancies will be uncovered through interventional clinical trials evaluating clinical utility. In this Review, we discuss the current landscape of ctDNA liquid-biopsy applications across the cancer continuum and highlight opportunities for clinical investigation.

DOI: https://doi.org/10.1038/s43018-020-0043-5

Gynecol Oncol. 2022 Jan 31. pii: S0090-8258(22)00050-6. [Epub ahead of print]

Efficacy and safety of olaparib according to age in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer: Analysis of the phase III SOLO2/ENGOT-Ov21 study.

BACKGROUND: Olaparib has significantly improved outcome and patient-centered endpoints in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer (PSOC). Specific information on efficacy and safety of olaparib for older patients appears of special interest.METHODS: 295 patients from the SOLO2 trial randomly assigned to olaparib or placebo were categorized according to age-cutoff at 65 years. Efficacy, tolerability, and quality of life (QoL) of olaparib relative to placebo within in each age group was analyzed.
RESULTS: Baseline characteristics were similar in patients ≥65 years (N = 62;21.0%) compared to patients <65 years (N = 233;78.9%). No significant difference in the magnitude of progression-free survival (PFS) benefit from olaparib for older patients (N = 40, hazard ratio [HR]≥65 0.43, 95%-confidence interval [CI] 0.24-0.81) as compared with younger patients (N = 155, HR<65 0.31 (95%-CI 0.22-0.43) was seen (interaction P = 0.33). The overall survival (OS)benefit seen in younger patients in the olaparib arm was not observed in older patients. Older and younger patients had comparable safety profiles and QoL scores although higher discontinuation rates for toxicity, and higher frequency of AML/MDS were noted in the older subset. TWiST analysis revealed clinically meaningful duration of good QoL on olaparib for both age groups (≥65: 13.5 vs <65: 18.4 months, P = 0.05).
CONCLUSIONS: Results of this large phase III cohort of BRCA1/2-mutated PSOC patients treated with olaparib underline impressive efficacy of olaparib maintenance irrespective of age. Although toxicity and tolerability did not raise significant concerns, some caution, close monitoring, and follow-up needs to be exercised for older patients given higher discontinuation rates, frequency of AML/MDS, and no clear effects on OS.

Keywords: Age dependency; Olaparib; Ovarian cancer; PARP inhibitors; Quality of life

DOI: https://doi.org/10.1016/j.ygyno.2022.01.024

Nature. 2022 Feb 03.

Huge cancer database yields genetic clues to metastasis.

Keywords: Cancer

DOI: https://doi.org/10.1038/d41586-022-00236-x

Nat Commun. 2022 Feb 01. 13(1): 448

The DNA methylome of cervical cells can predict the presence of ovarian cancer.

James E Barrett, Allison Jones, Iona Evans, Daniel Reisel, Chiara Herzog, Kantaraja Chindera, Mark Kristiansen, Olivia C Leavy, Ranjit Manchanda, Line Bjørge, Michal Zikan, David Cibula, Martin Widschwendter.

The vast majority of epithelial ovarian cancer arises from tissues that are embryologically derived from the Müllerian Duct. Here, we demonstrate that a DNA methylation signature in easy-to-access Müllerian Duct-derived cervical cells from women with and without ovarian cancer (i.e. referred to as the Women's risk IDentification for Ovarian Cancer index or WID-OC-index) is capable of identifying women with an ovarian cancer in the absence of tumour DNA with an AUC of 0.76 and women with an endometrial cancer with an AUC of 0.81. This and the observation that the cervical cell WID-OC-index mimics the epigenetic program of those cells at risk of becoming cancerous in BRCA1/2 germline mutation carriers (i.e. mammary epithelium, fallopian tube fimbriae, prostate) further suggest that the epigenetic misprogramming of cervical cells is an indicator for cancer predisposition. This concept has the potential to advance the field of risk-stratified cancer screening and prevention.

DOI: https://doi.org/10.1038/s41467-021-26615-y

Nat Methods. 2022 Feb 01.

How single-cell multi-omics builds relationships.

Vivien Marx.

DOI: https://doi.org/10.1038/s41592-022-01392-8

Clin Chem Lab Med. 2022 Feb 03.

Multicancer early detection.

Eric A Klein, Tomasz M Beer, Michael Seiden.

Keywords: cancer screening; iiquid biopsy; multicancer early detection

DOI: https://doi.org/10.1515/cclm-2022-0058

Nat Rev Genet. 2022 Jan 31.

Temporal modelling using single-cell transcriptomics.

Jun Ding, Nadav Sharon, Ziv Bar-Joseph.

Methods for profiling genes at the single-cell level have revolutionized our ability to study several biological processes and systems including development, differentiation, response programmes and disease progression. In many of these studies, cells are profiled over time in order to infer dynamic changes in cell states and types, sets of expressed genes, active pathways and key regulators. However, time-series single-cell RNA sequencing (scRNA-seq) also raises several new analysis and modelling issues. These issues range from determining when and how deep to profile cells, linking cells within and between time points, learning continuous trajectories, and integrating bulk and single-cell data for reconstructing models of dynamic networks. In this Review, we discuss several approaches for the analysis and modelling of time-series scRNA-seq, highlighting their steps, key assumptions, and the types of data and biological questions they are most appropriate for.

DOI: https://doi.org/10.1038/s41576-021-00444-7