bims-tumhet 2024-06-23 papers

Issue of 2024–06–23
three papers selected by
Sergio Marchini, Humanitas Research

Cell Rep Methods. 2024 Jun 17. pii: S2667-2375(24)00149-8. [Epub ahead of print]4(6): 100793

Systematic biases in reference-based plasma cell-free DNA fragmentomic profiling.

Xiaoyi Liu, Mengqi Yang, Dingxue Hu, Yunyun An, Wanqiu Wang, Huizhen Lin, Yuqi Pan, Jia Ju, Kun Sun.

Plasma cell-free DNA (cfDNA) fragmentation patterns are emerging directions in cancer liquid biopsy with high translational significance. Conventionally, the cfDNA sequencing reads are aligned to a reference genome to extract their fragmentomic features. In this study, through cfDNA fragmentomics profiling using different reference genomes on the same datasets in parallel, we report systematic biases in such conventional reference-based approaches. The biases in cfDNA fragmentomic features vary among races in a sample-dependent manner and therefore might adversely affect the performances of cancer diagnosis assays across multiple clinical centers. In addition, to circumvent the analytical biases, we develop Freefly, a reference-free approach for cfDNA fragmentomics profiling. Freefly runs ∼60-fold faster than the conventional reference-based approach while generating highly consistent results. Moreover, cfDNA fragmentomic features reported by Freefly can be directly used for cancer diagnosis. Hence, Freefly possesses translational merit toward the rapid and unbiased measurement of cfDNA fragmentomics.

Keywords: CP: Systems biology; cancer diagnosis; end motif; liquid biopsy; size profile

DOI: https://doi.org/10.1016/j.crmeth.2024.100793

Nat Rev Cancer. 2024 Jun 17.

Exploiting temporal aspects of cancer immunotherapy.

Rachael M Zemek, Valsamo Anagnostou, Inês Pires da Silva, Georgina V Long, Willem Joost Lesterhuis.

Many mechanisms underlying an effective immunotherapy-induced antitumour response are transient and critically time dependent. This is equally true for several immunological events in the tumour microenvironment induced by other cancer treatments. Immune checkpoint therapy (ICT) has proven to be very effective in the treatment of some cancers, but unfortunately, with many cancer types, most patients do not experience a benefit. To improve outcomes, a multitude of clinical trials are testing combinations of ICT with various other treatment modalities. Ideally, those combination treatments should take time-dependent immunological events into account. Recent studies have started to map the dynamic cellular and molecular changes that occur during treatment with ICT, in the tumour and systemically. Here, we overlay the dynamic ICT response with the therapeutic response following surgery, radiotherapy, chemotherapy and targeted therapies. We propose that by combining treatments in a time-conscious manner, we may optimally exploit the interactions between the individual therapies.

DOI: https://doi.org/10.1038/s41568-024-00699-2

Cancers (Basel). 2024 May 27. pii: 2027. [Epub ahead of print]16(11):

Landscape of Endometrial Cancer: Molecular Mechanisms, Biomarkers, and Target Therapy.

Ioana-Stefania Bostan, Mirela Mihaila, Viviana Roman, Nicoleta Radu, Monica Teodora Neagu, Marinela Bostan, Claudia Mehedintu.

Endometrial cancer is one the most prevalent gynecological cancers and, unfortunately, has a poor prognosis due to low response rates to traditional treatments. However, the progress in molecular biology and understanding the genetic mechanisms involved in tumor processes offers valuable information that has led to the current classification that describes four molecular subtypes of endometrial cancer. This review focuses on the molecular mechanisms involved in the pathogenesis of endometrial cancers, such as genetic mutations, defects in the DNA mismatch repair pathway, epigenetic changes, or dysregulation in angiogenic or hormonal signaling pathways. The preclinical genomic and molecular investigations presented allowed for the identification of some molecules that could be used as biomarkers to diagnose, predict, and monitor the progression of endometrial cancer. Besides the therapies known in clinical practice, targeted therapy is described as a new cancer treatment that involves identifying specific molecular targets in tumor cells. By selectively inhibiting these targets, key signaling pathways involved in cancer progression can be disrupted while normal cells are protected. The connection between molecular biomarkers and targeted therapy is vital in the fight against cancer. Ongoing research and clinical trials are exploring the use of standard therapy agents in combination with other treatment strategies like immunotherapy and anti-angiogenesis therapy to improve outcomes and personalize treatment for patients with endometrial cancer. This approach has the potential to transform the management of cancer patients. In conclusion, enhancing molecular tools is essential for stratifying the risk and guiding surgery, adjuvant therapy, and cancer treatment for women with endometrial cancer. In addition, the information from this review may have an essential value in the personalized therapy approach for endometrial cancer to improve the patient's life.

Keywords: biomarkers; endometrial cancer; immunotherapy; molecular mechanisms; targeted therapy

DOI: https://doi.org/10.3390/cancers16112027