bims-tumhet 2023-02-12 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2023–02–12
eight papers selected by
Sergio Marchini, Humanitas Research

Homologous recombination deficiency prediction using low-pass whole genome sequencing in breast cancer.
Spatially resolved transcriptomics: advances and applications.
A gene signature driven by abnormally methylated DEGs was developed for TP53 wild-type ovarian cancer samples by integrative omics analysis of DNA methylation and gene expression data.
Can spatially resolved metabolomics uncover weak points in tumors?
Nanomedicines targeting activation of STING to reshape tumor immune microenvironment and enhance immunotherapeutic efficacy.
Implementing HRD Testing in Routine Clinical Practice on Patients with Primary High-Grade Advanced Ovarian Cancer.
Advances in Ovarian Cancer Treatment Beyond PARP Inhibitors.
A Rapid, Shallow Whole Genome Sequencing Workflow Applicable to Limiting Amounts of Cell-Free DNA.

Cancer Genet. 2023 Feb 04. pii: S2210-7762(23)00005-4. [Epub ahead of print]272-273 35-40

Homologous recombination deficiency prediction using low-pass whole genome sequencing in breast cancer.

Yang Liu, Yalun Li, Min-Zhe Zhang, Dan Chen, Yang Leng, Juan Wang, Bo-Wei Han, Ji Wang.

  Homologous recombination repair deficiency (HRD) results in a defect in DNA repair and is a frequent driver of tumorigenesis. Poly(ADP-ribose) polymerase inhibitors (PARPi) or platinum-based therapies have increased theraputic effectiveness when treating HRD positive cancers. For breast cancer and ovairan cancer HRD companion diagnostic tests are commonly used. However, the currently used HRD tests are based on high-depth genome sequencing or hybridization-based capture sequencing, which are technically complex and costly. In this study, we modified an existing method named shallowHRD, which uses low-pass whole genome sequencing (WGS) for HRD detection, and estimated the performance of the modified shallowHRD pipeline. Our shallowHRD pipeline achieved an AUC of 0.997 in simulated low-pass WGS data, with a sensitivity of 0.981 and a specificity of 0.964; and achieved a higher HRD risk score in clinical BRCA-deficient breast cancer samples (p = 5.5 × 10-5, compared with BRCA-intact breast cancer samples). We also estimated the limit of detection the shallowHRD pipeline could accurately predict HRD status with a minimum sequencing depth of 0.1 ×, a tumor purity of > 20%, and an input DNA amount of 1 ng. Our study demostrates using low-pass sequencing, HRD status can be determined with high accuracy using a simple approach with greatly reduced cost.

Keywords:  Breast cancer; Copy number variations; Homologous recombination repair deficiency; Whole genome sequencing

DOI:  https://doi.org/10.1016/j.cancergen.2023.02.001
Blood Sci. 2023 Jan;5(1): 1-14

Spatially resolved transcriptomics: advances and applications.

Honglin Duan, Tao Cheng, Hui Cheng.

  Spatial transcriptomics, which is capable of both measuring all gene activity in a tissue sample and mapping where this activity occurs, is vastly improving our understanding of biological processes and disease. The field has expanded rapidly in recent years, and the development of several new technologies has resulted in spatially resolved transcriptomics (SRT) becoming highly multiplexed, high-resolution, and high-throughput. Here, we summarize and compare the major methods of SRT, including imaging-based methods, sequencing-based methods, and in situ sequencing methods. We also highlight some typical applications of SRT in neuroscience, cancer biology, developmental biology, and hematology. Finally, we discuss future possibilities for improving spatially resolved transcriptomic methods and the expected applications of such methods, especially in the adult bone marrow, anticipating that new developments will unlock the full potential of spatially resolved multi-omics in both biological research and the clinic.

Keywords:  In situ hybridization; In situ sequencing; Spatially resolved multi-omics; Spatially resolved transcriptomics

DOI:  https://doi.org/10.1097/BS9.0000000000000141
Ann Transl Med. 2023 Jan 15. 11(1): 20

A gene signature driven by abnormally methylated DEGs was developed for TP53 wild-type ovarian cancer samples by integrative omics analysis of DNA methylation and gene expression data.

Zhu Zhou, Hang Jin, Jian Xu.

   Background: Integrated omics analysis based on transcriptome and DNA methylation data combined with machine learning methods is very promising for the diagnosis, prognosis, and classification of cancer. In this study, the DNA methylation and gene expression data of ovarian cancer (OC) were analyzed to identify abnormally methylated differentially expressed genes (DEGs), screen potential therapeutic agents for OC, and construct a risk model based on the abnormally methylated DEGs to predict patient prognosis.
Methods: The gene expression and DNA methylation data of primary OC samples with tumor protein 53 (TP53) wild-type and normal samples were obtained from The Cancer Genome Atlas (TCGA) database. DEGs with aberrant methylation were analyzed by screening the intersection between DEGs and differentially methylated genes (DMGs). We attempted to search for potential drugs targeting DEGs with aberrant methylation by employing a network medicine framework. A gene signature based on the DEGs with aberrant methylation was constructed by regularized least absolute shrinkage and selection operator (LASSO) regression analysis.
Results: A total of 440 aberrant methylated DEGs were screened. Based on their gene expression profiles and methylation data from different regions, the results of both discriminative pattern recognition analysis and principal component analysis (PCA) showed a significant separation between tumor tissue and healthy ovarian tissue. In total, 126 potential therapeutic drugs were identified for OC by network-based proximity analysis. Five genes were identified in 440 aberrant methylated DEGs, which formed an aberrant methylated DEGs-driven gene signature. This signature could significantly distinguish the different overall survivals (OS) of OC patients and showed better predictive performance in both the training and validation sets.
Conclusions: In this study, the DNA methylation and gene expression data of OC were analyzed to identify abnormally methylated DEGs and potential therapeutic drugs, and a gene signature based on five aberrant methylation DEGs was constructed, which could better predict the risk of death in patients.

Keywords:  DNA methylation; Ovarian cancer (OC); gene signature; prognosis; therapeutic drugs

DOI:  https://doi.org/10.21037/atm-22-5764
Expert Rev Proteomics. 2023 Feb 06. 1-4

Can spatially resolved metabolomics uncover weak points in tumors?

Zhen Ning, Guowang Xu.



Keywords:  Metabolomics; Tumor; mass spectrometry imaging; spatially resolved metabolomics; tumor heterogeneity

DOI:  https://doi.org/10.1080/14789450.2023.2176754
Front Oncol. 2022 ;12 1093240

Nanomedicines targeting activation of STING to reshape tumor immune microenvironment and enhance immunotherapeutic efficacy.

Shanshan Chen, Anghui Peng, Muhe Chen, Meixiao Zhan.

  Immunotherapy has greatly enhanced the effectiveness of cancer treatments, but the efficacy of many current immunotherapies is still limited by the tumor-suppressive immune microenvironment. Multiple studies have shown that activating the stimulation of IFN genes (STING) pathway and inducing innate immunity can significantly impact the tumor immune microenvironment and improve antitumor therapy. While natural or synthetic STING agonists have been identified or developed for preclinical and clinical use, small molecule agonists have limited utility due to degradation and lack of targeting. As such, the delivery and release of STING agonists into tumor tissue is a major challenge that must be addressed in order to further advance the use of STING agonists. To address this challenge, various nanomedicines have been developed. In this paper, we concisely review the antitumor immunotherapeutic mechanisms of STING agonists, highlighting the latest developments in STING agonists and the current progress of nanomedicines for activating STING. We classify the different nanomedicines according to the STING agonists they utilize in order to facilitate understanding of recent advances in this field. Finally, we also discuss the prospects and challenges of this field.

Keywords:  STING agonists; antitumor therapy; innate immune; nanomedicines; tumor immune microenvironment (TIME)

DOI:  https://doi.org/10.3389/fonc.2022.1093240
Cancers (Basel). 2023 Jan 29. pii: 818. [Epub ahead of print]15(3):

Implementing HRD Testing in Routine Clinical Practice on Patients with Primary High-Grade Advanced Ovarian Cancer.

Florian Heitz, Beyhan Ataseven, Claudia Staniczok, Carsten Denkert, Kerstin Rhiem, Eric Hahnen, Sebastian Heikaus, Malak Moubarak, Julia Welz, Timoleon Dagres, Vasilios Vrentas, Mareike Bommert, Stephanie Schneider, Nicole Concin, Philipp Harter.

  The chemotherapy backbone for patients with high-grade advanced epithelial ovarian cancer (HG-AOC) is carboplatin and paclitaxel followed by a maintenance therapy either with bevacizumab, with a PARP inhibitor, or with a combination of both, which is defined by the presence of a homologous recombination deficiency (HRD) and by the BRCA1/2 status. This study included patients with a primary diagnosis of HG-AOC treated between December 2019 and December 2021. The HRD status was measured using the Myriad myChoice® test on all the patients with an indication for tumor HRD testing. Germline testing was conducted on all the patients using the TruRisk® panel as recommended by the national guidelines. HRD testing was requested for 190 patients, and, for 163 patients (85.8%), an HRD test result was available. An HRD test result could not be reported in 27 patients due to an insufficient tumor yield. The median time that it took to receive the HRD test results was 37 days (range of 8-97). In total, an HRD was present in 44.7% (73/163) of the patients based on a GIS ≥ 42 in 42.9% of the patients and based on a tumor BRCA1/2 mutation in 3 cases (all with a GIS < 42). The germline testing results were available for 148 patients, and, in 18 patients (12.2%), a deleterious germline mutation was detected. Of the 27 patients without sufficient HRD testing, BRCA1/2 germline testing results were available for 19 patients (70.4%), and a deleterious germline mutation was detected in 2 patients (7.4%). The implementation of HRD testing is feasible, and the results become available for treatment decisions in a timely manner for most patients. The prerequisite for HRD testing with the Myriad myChoice® test is a sufficient amount of tumor tissue. The cotesting of HRD and BRCA1/2 germline testing should be aimed for in order to enable optimal and timely treatment decisions on maintenance therapy as well as to test patients on whom the HRD test will not be evaluable.

Keywords:  BRCA1/2; PARP inhibitor; homologue recombination deficiency; primary high-grade advanced ovarian cancer; tumor testing

DOI:  https://doi.org/10.3390/cancers15030818
Curr Cancer Drug Targets. 2023 Feb 09.

Advances in Ovarian Cancer Treatment Beyond PARP Inhibitors.

Fine Aliyuda, Michele Moschetta, Aruni Ghose, Kathrine Sofia Rallis, Matin Sheriff, Elisabet Sanchez, Elie Rassy, Stergios Boussios.

  Ovarian cancer has become the largest cause of gynaecological cancer-related mortality. It is typically diagnosed at a late stage and has no effective screening strategy. Ovarian cancer is a highly heterogeneous disease that can be subdivided into several molecular subsets. As a result of a greater understanding of molecular pathways involved in carcinogenesis and tumor growth, targeted agents have been approved or are in several stages of development. Poly(ADP-ribose) polymerase (PARP) inhibitors and the anti-vascular endothelial growth factor (VEGF)-A antibodies are two types of approved and most effective targeted drugs for ovarian cancer at present. With the success of bevacizumab, tyrosine kinase inhibitors which could target alternate angiogenic pathways are being studied. Furthermore, many treatments targeting the PI3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways, are being developed or are already in clinical studies. MicroRNAs have also become novel biomarkers for the therapy and clinical diagnosis of ovarian cancer. This manuscript reviews the molecular, preclinical and clinical evidence supporting the targeting of growth-dependent pathways in ovarian cancer and assesses current data related to targeted treatments beyond PARP inhibitors.

Keywords:  AKT Inhibitors; Angiogenesis Inhibitors; EGFR Inhibitors; MiRNA-related targets; Ovarian Cancer; PI3K Inhibitors

DOI:  https://doi.org/10.2174/1568009623666230209121732
Clin Chem. 2023 Feb 07. pii: hvac220. [Epub ahead of print]

A Rapid, Shallow Whole Genome Sequencing Workflow Applicable to Limiting Amounts of Cell-Free DNA.

Rebecca C Allsopp, Karen Page, Bana Ambasager, Marc K Wadsley, Emmanuel Acheampong, Tumisang P Ntereke, Qi Guo, Gurdeep Matharu Lall, Kelly L T Gleason, Evie Wren, Georgios Nteliopoulos, Amelia J Rushton, R Charles Coombes, Jacqueline A Shaw.

   BACKGROUND: Somatic copy number alterations (sCNAs) acquired during the evolution of breast cancer provide valuable prognostic and therapeutic information. Here we present a workflow for screening sCNAs using picogram amounts of cell-free DNA (cfDNA) and single circulating tumor cells (CTCs).
METHODS: We repurposed the Ion ReproSeq PGS™ preimplantation genetic testing kit to perform shallow whole genome sequencing on 178 cfDNA samples (300 pg) and individual CTCs from 10 MBC patients with metastatic breast cancer (MBC) recovered by CellSearch®/DEPArray™. Results were analyzed using a tailored ichorCNA workflow.
RESULTS: sCNAs were detected in cfDNA of 41/105 (39%) patients with MBC and 3/23 (13%) primary breast cancers on follow-up (PBC FU), all of whom subsequently relapsed. In 8 of 10 MBCs, individual CTCs had a higher copy number count than matched cfDNA. The median tumor fraction detected by ichorCNA was 0.34 (range 0.17-0.58) for MBC and 0.36 (range 0.31-0.37) for PBC FU. Patients with detectable tumor fraction (≥ 0.1) and TFx and OncomineTM variants had significantly lower overall survival rates (P values P = 0.002 and P < 0.0001 for the log-rank test, respectively).
CONCLUSIONS: The ReproSeq PGS assay is rapid, at approximately $120 per sample, providing both a sCNA profile and estimation of the tumor DNA fraction from limiting cfDNA template (300pg) and individual CTCs. The approach could be used to examine the copy number landscape over time to guide treatment decisions, support future trial designs, and be applied to low volume blood spot samples enabling remote monitoring.

Keywords:  Oncomine™ Breast cfDNA Assay; ReproSeq™; breast cancer; circulating tumor DNA; liquid biopsy; shallow low pass sequencing

DOI:  https://doi.org/10.1093/clinchem/hvac220