bims-tumhet 2024-12-08 papers

Issue of 2024–12–08
seven papers selected by
Sergio Marchini, Humanitas Research

Clin Cancer Res. 2024 Dec 02.

Non-invasive multi-cancer detection using DNA hypomethylation of LINE-1 retrotransposons.

PURPOSE: The detection of circulating tumor DNA, which allows non-invasive tumor molecular profiling and disease follow-up, promises optimal and individualized management of patients with cancer. However, detecting small fractions of tumor DNA released when the tumor burden is reduced remains a challenge.
EXPERIMENTAL DESIGN: We implemented a new highly sensitive strategy to detect base-pair resolution methylation patterns from plasma DNA and assessed the potential of hypomethylation of LINE-1 retrotransposons as a non-invasive multi-cancer detection biomarker. The DIAMOND (Detection of Long Interspersed Nuclear Element Altered Methylation ON plasma DNA) method targets 30-40,000 young L1 scattered throughout the genome, covering about 100,000 CpG sites and is based on a reference-free analysis pipeline.
RESULTS: Resulting machine learning-based classifiers showed powerful correct classification rates discriminating healthy and tumor plasmas from 6 types of cancers (colorectal, breast, lung, ovarian, gastric cancers and uveal melanoma including localized stages) in two independent cohorts (AUC = 88% to 100%, N = 747). DIAMOND can also be used to perform copy number alterations (CNA) analysis which improves cancer detection.
CONCLUSIONS: This should lead to the development of more efficient non-invasive diagnostic tests adapted to all cancer patients, based on the universality of these factors.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2669

Cancer Discov. 2024 Dec 02. 14(12): 2315-2316

Targeting RNA and Protein Turnover in Aneuploid Cancers.

Samuel F Bakhoum.

Aneuploidy, an imbalance in chromosome number, is a hallmark of human cancers with chromosomal instability, and it remains a major therapeutic challenge. In this issue, Ippolito and colleagues identify RNA and protein turnover as targetable therapeutic vulnerabilities in aneuploid cancers. See related article by Ippolito et al., p. 2532.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1350

Clin Epigenetics. 2024 Dec 03. 16(1): 176

Genome-wide DNA methylation analysis reveals a unique methylation pattern for pleural mesothelioma compared to healthy pleura and other lung diseases.

Janah Vandenhoeck, Joe Ibrahim, Nele De Meulenaere, Dieter Peeters, Jo Raskin, Jeroen M H Hendriks, Paul Van Schil, Jan van Meerbeeck, Guy Van Camp, Ken Op de Beeck.

BACKGROUND: Pleural mesothelioma (PM) is a rare and aggressive cancer type, typically diagnosed at advanced stages. Distinguishing PM from other lung diseases is often challenging. There is an urgent need for biomarkers that can enable early detection. Interest in the field of epigenetics has increased, particularly in the context of tumour development and biomarker discovery. This study aims to identify specific changes in DNA methylation from healthy pleural tissue to PM and to compare these methylation patterns with those found in other lung diseases.
RESULTS: EPIC methylation array data (850 K) were generated for 11 PM and 29 healthy pleura in-house collected samples. This is the first time such a large dataset of healthy pleura samples has been generated. Additional EPIC methylation array data (850 K) for pleural mesothelioma and other lung-related diseases were downloaded from public databases. We conducted pairwise differential methylation analyses across all tissue types, which facilitated the identification of significantly differentially methylated CpG sites. Extensive differential methylation between PM and healthy pleura was observed, identifying 81,968 differentially methylated CpG sites across all genomic regions. Among these, five CpG sites located within four genes (MIR21, RNF39, SPEN and C1orf101) exhibited the most significant and pronounced methylation differences between PM and healthy pleura. Moreover, our analysis delineated distinct methylation patterns specific to PM subtypes. Finally, the methylation profiles of PM were distinctly different from those of other lung cancers, enabling accurate differentiation.
CONCLUSIONS: DNA methylation analyses provide a robust method for distinguishing PM from healthy pleural tissues, and specific methylation patterns exist within PM subtypes. These methylation differences underscore their importance in understanding disease progression and may serve as viable biomarkers or therapeutic targets. Moreover, differential methylation patterns between PM and other lung cancers highlights its diagnostic potential. These findings necessitate further translational studies to explore their clinical applications.

Keywords: DNA methylation; Epigenetics; Healthy pleura; Lung cancer; Pleural mesothelioma

DOI: https://doi.org/10.1186/s13148-024-01790-z

J Ovarian Res. 2024 Dec 03. 17(1): 240

Subtype-specific analysis of gene co-expression networks and immune cell profiling reveals high grade serous ovarian cancer subtype linkage to variable immune microenvironment.

Kaylin M Carey, Corey D Young, Alexis J Clark, Eric B Dammer, Rajesh Singh, James W Lillard.

High-grade serous ovarian cancer (HGSOC) is marked by significant molecular diversity, presenting a major clinical challenge due to its aggressive nature and poor prognosis. This study aims to deepen the understanding of HGSOC by characterizing mRNA subtypes and examining their immune microenvironment (TIME) and its role in disease progression. Using transcriptomic data and an advanced computational pipeline, we investigated four mRNA subtypes: immunoreactive, differentiated, proliferative, and mesenchymal, each associated with distinct gene expression profiles and clinical behaviors. We performed differential expression analysis among mRNA subtypes using DESeq2 and conducted Weighted Gene Co-Expression Network Analysis (WGCNA) to identify co-expressed gene modules related to clinical traits, e.g., age, survival, and subtype classification. Gene Ontology (GO) analysis highlighted key pathways involved in tumor progression and immune evasion. Additionally, we utilized TIMER 2.0 to assess immune cell infiltration across different HGSOC subtypes, providing insights into the interplay between tumor immune microenvironment (TIME). Our findings show that the immunoreactive subtype, particularly the M3 module-associated network, was marked by high immune cell infiltration, including M1 (p < 0.0001) and M2 macrophages (p < 0.01), and Th1 cells (p < 0.01) along with LAIR-1 expression (p = 1.63e-101). The M18 module exhibited strong B cell signatures (p = 6.24e-28), along with significant FCRL5 (adj. p = 3.09e-30) and IRF4 (adj. p = 3.09e-30) coexpression. In contrast, the M5 module was significantly associated with the mesenchymal subtype, along with fibroblasts (p < 0.0001). The proliferative subtype was characterized by M15 module-driven cellular growth and proliferation gene expression signatures, along with significant ovarian stromal cell involvement (p < 0.0001). Our study reveals the complex interplay between mRNA subtypes and suggests genes contributing to molecular subtypes, underscoring the important clinical implications of mRNA subtyping in HGSOC.

Keywords: Gene expression; High-grade serous ovarian cancer; Immune microenvironment; Patient outcomes; Transcriptomic subtypes

DOI: https://doi.org/10.1186/s13048-024-01556-4

Signal Transduct Target Ther. 2024 Dec 02. 9(1): 336

Liquid biopsy in cancer current: status, challenges and future prospects.

Liwei Ma, Huiling Guo, Yunxiang Zhao, Zhibo Liu, Chenran Wang, Jiahao Bu, Ting Sun, Jianwei Wei.

Cancer has a high mortality rate across the globe, and tissue biopsy remains the gold standard for tumor diagnosis due to its high level of laboratory standardization, good consistency of results, relatively stable samples, and high accuracy of results. However, there are still many limitations and drawbacks in the application of tissue biopsy in tumor. The emergence of liquid biopsy provides new ideas for early diagnosis and prognosis of tumor. Compared with tissue biopsy, liquid biopsy has many advantages in the diagnosis and treatment of various types of cancer, including non-invasive, quickly and so on. Currently, the application of liquid biopsy in tumor detection has received widely attention. It is now undergoing rapid progress, and it holds significant potential for future applications. Around now, liquid biopsies encompass several components such as circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. In addition, advances in the identification of liquid biopsy indicators have significantly enhanced the possibility of utilizing liquid biopsies in clinical settings. In this review, we will discuss the application, advantages and challenges of liquid biopsy in some common tumors from the perspective of diverse systems of tumors, and look forward to its future development prospects in the field of cancer diagnosis and treatment.

DOI: https://doi.org/10.1038/s41392-024-02021-w

Cancer Discov. 2024 Dec 02. 14(12): 2332-2345

Precision Oncology: 2024 in Review.

Matteo Repetto, Nicole Fernandez, Alexander Drilon, Debyani Chakravarty.

This article discusses the specific advances made in precision oncology in 2024. We comment on the evolving nature of predictive molecular events used to select patients who will most benefit clinically from treatment. We also discuss advances in the development of strategic treatment regimens for combination therapies, rational drug design of small-molecule inhibitors, and structurally informed drug repurposing.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1476