bims-tumhet 2022-05-01 papers

Issue of 2022‒05‒01
six papers selected by
Sergio Marchini
Humanitas Research

Clin Cancer Res. 2022 Apr 27. pii: clincanres.0336.2022. [Epub ahead of print]

Double trouble: whole genome doubling distinguishes early from late ovarian cancer.

Shih Yu Cindy Yang, Trevor J Pugh, Amit M Oza.

Dramatic differences in outcome between early- and late-stage HGSC suggest perhaps distinct genetic origins due to differences in exposures to mutational processes. Evidence to support this hypothesis was recently reported by comparative analysis of copy number signatures between early- and late-stage HGSCs.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-0336

Clin Cancer Res. 2022 Apr 29. pii: clincanres.2138.2021. [Epub ahead of print]

Molecular Pathways and Mechanisms of BRAF in Cancer Therapy.

Poulikos I Poulikakos, Ryan J Sullivan, Rona Yaeger.

With the identification of activating mutations in BRAF across a wide variety of malignancies, substantial effort was placed in designing safe and effective therapeutic strategies to target BRAF. These efforts have led to the development and regulatory approval of three BRAF inhibitors as well as five combinations of a BRAF inhibitor plus an additional agent(s) to manage cancer such as melanoma, non-small cell lung cancer, anaplastic thyroid cancer, and colorectal cancer. To date, each regimen is effective only in patients with tumors harboring BRAFV600 mutations and the duration of benefit is often short-lived. Further limitations preventing optimal management of BRAF mutant malignancies are that treatments of non-V600 BRAF mutations have been less profound and combination therapy is likely necessary to overcome resistance mechanisms, but multi-drug regimens are often too toxic. With the emergence of a deeper understanding of how BRAF mutations signal through the RAS/mitogen activated protein kinase (MAPK) pathway, newer RAF inhibitors are being developed that may be more effective and potentially safer and more rational combination therapies are being tested in the clinic. In this review, we identify the mechanics of RAF signaling through the RAS/MAPK pathway, present existing data on single-agent and combination RAF targeting efforts, describe emerging combinations, summarize the toxicity of the various agents in clinical testing, and speculate as to where the field may be headed.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-2138

PLoS One. 2022 ;17(4): e0266889

Direct comparison of circulating tumor DNA sequencing assays with targeted large gene panels.

Lizhi Yu, Gonzalo Lopez, John Rassa, Yixin Wang, Tara Basavanhally, Andrew Browne, Chang-Pin Huang, Lauren Dorsey, Jin Jen, Sarah Hersey.

Next generation sequencing (NGS) assays with large targeted gene panels can comprehensively profile cancer somatic mutations in a tumor sample. Given the rapid adoption of such assays for circulating tumor DNA (ctDNA) analysis in clinical oncology, it is essential for the community to understand their analytical performance in liquid biopsy settings. Here, we directly compared five ctDNA NGS assays, most of which having a panel of 400 or more genes, with simulated samples harboring mutations relevant to solid tumors or myeloid malignancy. Our results indicate that the detection sensitivity and reproducibility of all five assays was 90% or higher when the mutations were at 0.5% or 1.0% allele frequency, and with optimal DNA input of 30 ng or 50 ng per vendor's protocol. The performances decreased and varied dramatically, when mutations were at a 0.1% allele frequency and/or when a lower genomic input of 10 ng DNA was used. Interestingly, one of the assays repeatedly showed higher rate of false positivity than the others across two different sample sets. Multiple intrinsic technical factors pertaining to the NGS assays were further investigated. Notable differences among the assays were seen for depth of coverage and background noise, which profoundly impacted assay performance. The results derived from this study are highly informative and provide a framework to assess and select suitable assays for specific application in cancer monitoring and potential clinical use.

DOI: https://doi.org/10.1371/journal.pone.0266889

Nat Commun. 2022 Apr 29. 13(1): 2339

Reference-free cell type deconvolution of multi-cellular pixel-resolution spatially resolved transcriptomics data.

Brendan F Miller, Feiyang Huang, Lyla Atta, Arpan Sahoo, Jean Fan.

Recent technological advancements have enabled spatially resolved transcriptomic profiling but at multi-cellular pixel resolution, thereby hindering the identification of cell-type-specific spatial patterns and gene expression variation. To address this challenge, we develop STdeconvolve as a reference-free approach to deconvolve underlying cell types comprising such multi-cellular pixel resolution spatial transcriptomics (ST) datasets. Using simulated as well as real ST datasets from diverse spatial transcriptomics technologies comprising a variety of spatial resolutions such as Spatial Transcriptomics, 10X Visium, DBiT-seq, and Slide-seq, we show that STdeconvolve can effectively recover cell-type transcriptional profiles and their proportional representation within pixels without reliance on external single-cell transcriptomics references. STdeconvolve provides comparable performance to existing reference-based methods when suitable single-cell references are available, as well as potentially superior performance when suitable single-cell references are not available. STdeconvolve is available as an open-source R software package with the source code available at https://github.com/JEFworks-Lab/STdeconvolve .

DOI: https://doi.org/10.1038/s41467-022-30033-z

J Obstet Gynaecol Res. 2022 Apr 27.

The clinical features and management of Lynch syndrome-associated ovarian cancer.

Xuting Ran, Huining Jing, Zhengyu Li.

AIM: Lynch syndrome (LS) is one of the most common hereditary cancer syndromes, characterized by mutations in mismatch repair genes and autosomal dominant inheritance. Women with LS have an additional increased risk of gynecologic malignancies, including endometrial cancer (EC) and ovarian cancer (OC). Compared with EC, OC is relatively under investigation. This review thoroughly summarizes the current clinical evidence of surveillance, screening, and prevention strategies, and describes the molecular and clinical characteristics of LS-associated OC.METHODS: An electronic search from databases of PubMed and Google Scholar was carried out using key words pertaining to Lynch syndrome and ovarian cancer. A review of the literatures including review articles, experimental, and observational studies published between 2000 and 2021 was conducted.
RESULTS: The lifetime risk of OC in women with LS of MLH1, MSH2, and MSH6 mutations is approximately 7%, with the median age at onset being 46 years, 10-15 years earlier than that in sporadic cases. Histologically, LS-associated OCs are primarily endometrioid (40%), high-grade (25%), and low-grade (11%) serous, or clear cell (6%) in nature. Eighty-five percent of patients are diagnosed at an early stage, presenting with a good prognosis at 84% 5-year survival. Optimal screening strategies for OC in LS are controversial; combined screening of patients' clinical and family history, immunohistochemical analysis, and microsatellite instability testing for mismatch repair deficiency have been proven efficient.
CONCLUSION: The clinical features were different between ovarian cancer in Lynch syndrome and sporadic cases. More research are needed for a greater understanding of the prevention and medical treatment of LS-associated OC.

Keywords: Lynch syndrome; mismatch repair; ovarian cancer; surveillance

DOI: https://doi.org/10.1111/jog.15273

Cancer Cell Int. 2022 Apr 29. 22(1): 172

Emerging role of circular RNAs in the pathogenesis of ovarian cancer.

Soudeh Ghafouri-Fard, Tayyebeh Khoshbakht, Bashdar Mahmud Hussen, Mohammad Taheri, Majid Samsami.

Ovarian cancer is a female malignancy with high fatality-to-case ratio, which is due to late detection of cancer. Understanding the molecular mechanisms participating in these processes would facilitate design of therapeutic modalities and identification of novel tumor markers. Recent investigations have shown contribution of circular RNAs (circRNAs) in the evolution of ovarian cancer. These transcripts are produced through a back-splicing mechanism. The enclosed configuration of circRNAs protects them from degradation and potentiates them as biomarkers. Several circRNAs such as circMUC16, circRNA_MYLK, circRNA-UBAP2, circWHSC1, hsa_circ_0013958, circFGFR3, hsa_circRNA_102958 and circ_0072995 have been found to be up-regulated in this cancer, acting as oncogenes. On the other hand, circ-ITCH, circPLEKHM3, circ_100395, circ_0078607, circATRNL1, circHIPK3, circRHOBTB3, circEXOC6B, circ9119 and CDR1as are among down-regulated circRNAs in ovarian cancer. Expression levels of circCELSR1, circ_CELSR1, circATL2, circNRIP1, circTNPO3 and hsa_circ_0000714 have been shown to affect resistance of ovarian cancer cells to chemotherapy. Moreover, circ_100395, circFGFR3, circ_0000554, circCELSR1, circ-PTK2, circLNPEP, circ-CSPP1, circ_0000745, circ_100395 and circPLEKHM3 have been shown to regulate epithelial-mesenchymal transition and metastatic ability of ovarian cancer cells. In the current review, we explain the roles of circRNAs in the evolution and progression of ovarian cancer.

Keywords: Biomarker; Expression; Ovarian cancer; circRNA

DOI: https://doi.org/10.1186/s12935-022-02602-1