bims-ovdlit 2023-02-19 papers

Issue of 2023–02–19
three papers selected by
Lara Paracchini, Humanitas Research

Am J Med. 2023 Mar;pii: S0002-9343(22)00403-X. [Epub ahead of print]136(3): e46-e47

The Promise of Multicancer Early Detection.

Eric A Klein, Tomasz M Beer, Michael Seiden.

DOI: https://doi.org/10.1016/j.amjmed.2022.05.016

Sci Rep. 2023 Feb 13. 13(1): 2552

Genetic analysis of heterogeneous subsets of circulating tumour cells from high grade serous ovarian carcinoma patients.

Du-Bois Asante, Ganendra R K A Mohan, Emmanuel Acheampong, Melanie Ziman, Leslie Calapre, Tarek M Meniawy, Elin S Gray, Aaron B Beasley.

Circulating tumour cells (CTCs) are heterogenous and contain genetic information from the tumour of origin. They bear specific intra- and extra-cellular protein markers aiding in their detection. However, since these markers may be shared with other rare cells in the blood, only genetic testing can confirm their malignancy. Herein, we analyse different CTC subsets using single cell whole genome DNA sequencing to validate their malignant origin. We randomly selected putative CTCs identified by immunostaining that were isolated from 4 patients with high grade serous ovarian cancer (HGSOC) and one with benign cystadenoma. We specifically targeted CTCs positive for epithelial (CK/EpCAMpos), mesenchymal (vimentinpos), and pseudoendothelial (CK/EpCAMpos plus CD31pos) markers. We isolated these cells and performed whole genome amplification (WGA) and low-pass whole-genome sequencing (LP-WGS) for analysis of copy number alterations (CNA). Of the CK/EpCAMpos cells analysed from the HGSOC patients, 2 of 3 cells showed diverse chromosomal CNAs. However, the 4 pseudoendothelial cells (CK/EpCAMpos plus CD31pos) observed in the HGSOC cases did not carry any CNA. Lastly, two of the clusters of vimentin positive cells sequenced from those found in the benign cystadenoma case had CNA. Despite the low number of cells analysed, our results underscore the importance of genetic analysis of putative CTCs to confirm their neoplastic origin. In particular, it highlights the presence of a population of CK/EpCAMpos cells that are not tumour cells in patients with HGSOC, which otherwise would be counted as CTCs.

DOI: https://doi.org/10.1038/s41598-023-29416-z

Clin Epigenetics. 2023 Feb 14. 15(1): 24

Early diagnosis of ovarian cancer based on methylation profiles in peripheral blood cell-free DNA: a systematic review.

Simone Karlsson Terp, Malene Pontoppidan Stoico, Karen Dybkær, Inge Søkilde Pedersen.

Patients diagnosed with epithelial ovarian cancer (OC) have a 5-year survival rate of 49%. For early-stage disease, the 5-year survival rate is above 90%. However, advanced-stage disease accounts for most cases as patients with early stages often are asymptomatic or present with unspecific symptoms, highlighting the need for diagnostic tools for early diagnosis. Liquid biopsy is a minimal invasive blood-based approach that utilizes circulating tumor DNA (ctDNA) shed from tumor cells for real-time detection of tumor genetics and epigenetics. Increased DNA methylation of promoter regions is an early event during tumorigenesis, and the methylation can be detected in ctDNA, accentuating the promise of methylated ctDNA as a biomarker for OC diagnosis. Many studies have investigated multiple methylation biomarkers in ctDNA from plasma or serum for discriminating OC patients from patients with benign diseases of the ovaries and/or healthy females. This systematic review summarizes and evaluates the performance of the currently investigated DNA methylation biomarkers in blood-derived ctDNA for early diagnosis of OC. PubMed's MEDLINE and Elsevier's Embase were systematically searched, and essential results such as methylation frequency of OC cases and controls, performance measures, as well as preanalytical factors were extracted. Overall, 29 studies met the inclusion criteria for this systematic review. The most common method used for methylation analysis was methylation-specific PCR, with half of the studies using plasma and the other half using serum. RASSF1A, BRCA1, and OPCML were the most investigated gene-specific methylation biomarkers, with OPCML having the best performance measures. Generally, methylation panels performed better than single gene-specific methylation biomarkers, with one methylation panel of 103,456 distinct regions and 1,116,720 CpGs having better performance in both training and validation cohorts. However, the evidence is still limited, and the promising methylation panels, as well as gene-specific methylation biomarkers highlighted in this review, need validation in large, prospective cohorts with early-stage asymptomatic OC patients to assess the true diagnostic value in a clinical setting.

Keywords: Biomarker; Cell-free DNA; Circulating tumor DNA; DNA methylation; Diagnosis; Epigenetics; Liquid biopsy; Ovarian cancer; Systematic review

DOI: https://doi.org/10.1186/s13148-023-01440-w