bims-tumhet 2022-06-12 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2022–06–12
ten papers selected by
Sergio Marchini, Humanitas Research

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45).
Pan-cancer analysis of genomic scar patterns caused by homologous repair deficiency (HRD).
spatialLIBD: an R/Bioconductor package to visualize spatially-resolved transcriptomics data.
Mutation profiles in circulating cell-free DNA predict acquired resistance to Olaparib in high-grade serous ovarian carcinoma.
Functional RECAP (REpair CAPacity) assay identifies homologous recombination deficiency undetected by DNA-based BRCAness tests.
Application and prospect of single-cell sequencing in cancer metastasis.
Single-cell RNA sequencing reveals the tissue architecture in human high-grade serous ovarian cancer.
Detection of ovarian cancer using plasma cell-free DNA methylomes.
Targeting the Tumor Microenvironment: A Close Up of Tumor-Associated Macrophages and Neutrophils.
The Role of Cancer-Associated Fibroblasts in Ovarian Cancer.

J Clin Oncol. 2022 Jun 06. JCO2201003

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45).

Bradley J Monk, Christine Parkinson, Myong Cheol Lim, David M O'Malley, Ana Oaknin, Michelle K Wilson, Robert L Coleman, Domenica Lorusso, Paul Bessette, Sharad Ghamande, Athina Christopoulou, Diane Provencher, Emily Prendergast, Fuat Demirkiran, Olga Mikheeva, Oladapo Yeku, Anita Chudecka-Glaz, Michael Schenker, Ramey D Littell, Tamar Safra, Hung-Hsueh Chou, Mark A Morgan, Vít Drochýtek, Joyce N Barlin, Toon Van Gorp, Fred Ueland, Gabriel Lindahl, Charles Anderson, Dearbhaile C Collins, Kathleen Moore, Frederik Marme, Shannon N Westin, Iain A McNeish, Danny Shih, Kevin K Lin, Sandra Goble, Stephanie Hume, Keiichi Fujiwara, Rebecca S Kristeleit.

PURPOSE: ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo.
METHODS: Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population.
RESULTS: As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%).
CONCLUSION: Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

DOI: https://doi.org/10.1200/JCO.22.01003
NPJ Precis Oncol. 2022 Jun 09. 6(1): 36

Pan-cancer analysis of genomic scar patterns caused by homologous repair deficiency (HRD).

E Rempel, K Kluck, S Beck, I Ourailidis, D Kazdal, O Neumann, A L Volckmar, M Kirchner, H Goldschmid, N Pfarr, W Weichert, D Hübschmann, S Fröhling, C Sutter, C P Schaaf, P Schirmacher, V Endris, A Stenzinger, J Budczies.

Homologous repair deficiency (HRD) is present in many cancer types at variable prevalence and can indicate response to platinum-based chemotherapy and PARP inhibition. We developed a tumor classification system based on the loss of function of genes in the homologous recombination repair (HRR) pathway. To this end, somatic and germline alterations in BRCA1/2 and 140 other HRR genes were included and assessed for the impact on gene function. Additionally, information on the allelic hit type and on BRCA1 promoter hypermethylation was included. The HRDsum score including LOH, LST, and TAI was calculated for 8847 tumors of the TCGA cohort starting from genotyping data and for the subcohort of ovarian cancer also starting from WES data. Pan-cancer, deleterious BRCA1/2 alterations were detected in 4% of the tumors, while 18% of the tumors were HRD-positive (HRDsum ≥ 42). Across 33 cancer types, both BRCA1/2 alterations and HRD-positivity were most prevalent in ovarian cancer (20% and 69%). Pan-cancer, tumors with biallelic deleterious alterations in BRCA1/2 were separated strongly from tumors without relevant alterations (AUC = 0.89), while separation for tumors with monoallelic deleterious BRCA1/2 alterations was weak (AUC = 0.53). Tumors with biallelic deleterious alterations in other HHR genes were separated moderately from tumors without relevant alterations (AUC = 0.63), while separation for tumors with such monoallelic alterations was weaker (AUC = 0.57). In ovarian cancer, HRDsum scores calculated from WES data correlated strongly with HRDsum scores calculated from genotyping data (R = 0.87) and were slightly (4%) higher. We comprehensively analyzed HRD scores and their association with mutations in HRR genes in common cancer types. Our study identifies important parameters influencing HRD measurement and argues for an integration of HRDsum score with specific mutational profiles.

DOI: https://doi.org/10.1038/s41698-022-00276-6
BMC Genomics. 2022 Jun 10. 23(1): 434

spatialLIBD: an R/Bioconductor package to visualize spatially-resolved transcriptomics data.

Brenda Pardo, Abby Spangler, Lukas M Weber, Stephanie C Page, Stephanie C Hicks, Andrew E Jaffe, Keri Martinowich, Kristen R Maynard, Leonardo Collado-Torres.

   BACKGROUND: Spatially-resolved transcriptomics has now enabled the quantification of high-throughput and transcriptome-wide gene expression in intact tissue while also retaining the spatial coordinates. Incorporating the precise spatial mapping of gene activity advances our understanding of intact tissue-specific biological processes. In order to interpret these novel spatial data types, interactive visualization tools are necessary.
RESULTS: We describe spatialLIBD, an R/Bioconductor package to interactively explore spatially-resolved transcriptomics data generated with the 10x Genomics Visium platform. The package contains functions to interactively access, visualize, and inspect the observed spatial gene expression data and data-driven clusters identified with supervised or unsupervised analyses, either on the user's computer or through a web application.
CONCLUSIONS: spatialLIBD is available at https://bioconductor.org/packages/spatialLIBD . It is fully compatible with SpatialExperiment and the Bioconductor ecosystem. Its functionality facilitates analyzing and interactively exploring spatially-resolved data from the Visium platform.

Keywords:  10x Genomics Visium; Interactive visualization; Spatially-resolved transcriptomics

DOI:  https://doi.org/10.1186/s12864-022-08601-w
Cancer Sci. 2022 Jun 05.

Mutation profiles in circulating cell-free DNA predict acquired resistance to Olaparib in high-grade serous ovarian carcinoma.

Dianxing Hu, Ensong Guo, Bin Yang, Xu Qin, Yu Fu, Junpeng Fan, Xucui Zhuang, Qianqian Yao, Funian Lu, Wenting Li, Rourou Xiao, Xue Wu, Xiaohang Yang, Zizhuo Wang, Chen Liu, Lixin You, Rongyu Zang, Qi Zhou, Weidong Zhao, Gang Chen, Chaoyang Sun.

  Although Poly (ADP-ribose) polymerase (PARP) inhibitors' resistance has gradually become a major challenge in the maintenance therapy for high-grade serous ovarian carcinoma (HGSOC), there are no universal indicators for resistance monitoring in patients. A key resistance mechanism to PARP inhibitors (PARPis) is the restoration of homologous recombination repair (HRR), including BRCA reversion mutations and changes in DNA damage repair proteins. To explore mutation profiles associated with PARPis' resistance, we performed targeted 42-gene deep sequencing of circulating cell-free DNA (cfDNA) extracted from pre-treatment and post-treatment in HGSOC patients with Olaparib maintenance therapy. We found that pathogenic germline mutations in the HRR pathway, including BRCA1/2, were strongly associated with improved clinical outcomes, and newly acquired MRE11A mutations significantly shortened the progression-free survival (PFS) of patients. Furthermore, dynamic fluctuations of somatic mutation sites in CHEK2:p.K373E and CHEK2:p.R406H can be used for evaluating the therapeutic efficacy of patients. MRE11A:p.K464R may be a vital driving factor of Olaparib resistance, which patients who newly acquired MRE11A:p.K464R in post-treatment cfDNA had significantly shorter PFS than those without it. These findings provide potential noninvasive biomarkers for efficacy evaluation and resistance monitoring of Olaparib treatment, and lay the foundation for developing combination treatment after Olaparib resistance.

Keywords:  Biomarkers; HGSOC; Mutation profiles; PARP inhibitor resistance; cfDNA

DOI:  https://doi.org/10.1111/cas.15456
Oncogene. 2022 Jun 03.

Functional RECAP (REpair CAPacity) assay identifies homologous recombination deficiency undetected by DNA-based BRCAness tests.

Titia G Meijer, Luan Nguyen, Arne Van Hoeck, Anieta M Sieuwerts, Nicole S Verkaik, Marjolijn M Ladan, Kirsten Ruigrok-Ritstier, Carolien H M van Deurzen, Harmen J G van de Werken, Esther H Lips, Sabine C Linn, Yasin Memari, Helen Davies, Serena Nik-Zainal, Roland Kanaar, John W M Martens, Edwin Cuppen, Agnes Jager, Dik C van Gent.

Germline BRCA1/2 mutation status is predictive for response to Poly-[ADP-Ribose]-Polymerase (PARP) inhibitors in breast cancer (BC) patients. However, non-germline BRCA1/2 mutated and homologous recombination repair deficient (HRD) tumors are likely also PARP-inhibitor sensitive. Clinical validity and utility of various HRD biomarkers are under investigation. The REpair CAPacity (RECAP) test is a functional method to select HRD tumors based on their inability to form RAD51 foci. We investigated whether this functional test defines a similar group of HRD tumors as DNA-based tests. An HRD enriched cohort (n = 71; 52 primary and 19 metastatic BCs) selected based on the RECAP test (26 RECAP-HRD; 37%), was subjected to DNA-based HRD tests (i.e., Classifier of HOmologous Recombination Deficiency (CHORD) and BRCA1/2-like classifier). Whole genome sequencing (WGS) was carried out for 38 primary and 19 metastatic BCs. The RECAP test identified all bi-allelic BRCA deficient samples (n = 15) in this cohort. RECAP status partially correlated with DNA-based HRD test outcomes (70% concordance for both RECAP-CHORD and RECAP-BRCA1/2-like classifier). RECAP selected additional samples unable to form RAD51 foci, suggesting that this functional assay identified deficiencies in other DNA repair genes, which could also result in PARP-inhibitor sensitivity. Direct comparison of these HRD tests in clinical trials will be required to evaluate the optimal predictive test for clinical decision making.

DOI: https://doi.org/10.1038/s41388-022-02363-1
Future Oncol. 2022 Jun 10.

Application and prospect of single-cell sequencing in cancer metastasis.

Yue Zheng, Xiaofeng Yang.

  Cancer metastasis is a complicated process driven by internal genetic variations and developed through interactions with the external environment. This process usually causes therapeutic resistance and results in a low survival rate. In recent years, single-cell sequencing has become a popular method for revealing the tumor evolutionary genetic lineage, intra-tumoral heterogeneity and tumor microenvironment of the metastasis process. So as to find more therapeutic targets for clinical application, the spatial transcriptomics method has become a new rising field of cancer studies, which promotes the combination between clinical medicine and molecular biology. In future prospects, more accurate and personalized treatment models will come into reality.

Keywords:  cancer metastasis; circulating tumor cell; epithelial-mesenchymal transformation; intra-tumoral heterogeneity; single-cell sequencing; spatial transcriptomics; tumor microenvironment

DOI:  https://doi.org/10.2217/fon-2022-0156
Clin Cancer Res. 2022 Jun 08. pii: clincanres.0296.2022-1-28 03:44:54.997. [Epub ahead of print]

Single-cell RNA sequencing reveals the tissue architecture in human high-grade serous ovarian cancer.

Junfen Xu, Yifeng Fang, Kelie Chen, Sen Li, Sangsang Tang, Yan Ren, Yixuan Cen, Weidong Fei, Bo Zhang, Yuanming Shen, Weiguo Lu.

PURPOSE: The heterogeneity of high-grade serous ovarian cancer (HGSOC) is not well studied, which severely hinders clinical treatment of HGSOC. Thus, it is necessary to characterize the heterogeneity of HGSOC within its tumor microenvironment (TME).
EXPERIMENTAL DESIGN: The tumors of seven treatment-naïve HGSOC patients at early or late stages and five age-matched non-malignant ovarian samples were analyzed by deep single-cell RNA sequencing (scRNA-seq).
RESULTS: A total of 59,324 single cells obtained from HGSOC and non-malignant ovarian tissues were sequenced by scRNA-seq. Among those cells, tumor cells were characterized by a set of EMT-associated gene signature, in which NOTCH1, SNAI2, TGFBR1 and WNT11 was further selected as a genetic panel to predict the poor outcomes of HGSOC patients. Matrix CAFs (mCAFs) expressing α-SMA, vimentin, COL3A, COL10A and MMP11, were the dominant CAFs in HGSOC tumors and could induce epithelial-to-mesenchymal transition (EMT) properties of OC cells in the co-culture system. Specific immune cell subsets such as C7-APOBEC3A M1 macrophages, CD8+ TRM and TEX cells were preferentially enriched in early-stage tumors. Additionally, an immune co-inhibitory receptor TIGIT was highly expressed on CD8+ TEX cells and TIGIT blockade could significantly reduce OC tumor growth in mouse models.
CONCLUSIONS: Our transcriptomic results analyzed by scRNA-seq delineate a ecosystemic landscape of HGSOC at early or late stages with a focus on its heterogeneity with TME. The major applications of our findings are a four EMT-gene model for prediction of HGSOC patient outcomes, mCAFs' capability of enhancing OC cell invasion and potential therapeutic value of anti-TIGIT treatment.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-0296
Clin Epigenetics. 2022 Jun 09. 14(1): 74

Detection of ovarian cancer using plasma cell-free DNA methylomes.

Huaiwu Lu, Yunyun Liu, Jingyu Wang, Shaliu Fu, Lingping Wang, Chunxian Huang, Jing Li, Lingling Xie, Dongyan Wang, Dan Li, Hui Zhou, Qunxian Rao.

   BACKGROUND: Ovarian cancer (OC) is a highly lethal gynecologic cancer, and it is hard to diagnose at an early stage. Clinically, there are no ovarian cancer-specific markers for early detection. Here, we demonstrate the use of cell-free DNA (cfDNA) methylomes to detect ovarian cancer, especially the early-stage OC.
EXPERIMENTAL DESIGN: Plasma from 74 epithelial ovarian cancer patients, 86 healthy volunteers, and 20 patients with benign pelvic masses was collected. The cfDNA methylomes of these samples were generated by cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq). The differentially methylated regions (DMRs) were identified by the contrasts between tumor and non-tumor groups, and the discrimination performance was evaluated with the iterative training and testing method.
RESULTS: The DMRs identified for cfDNA methylomes can well discriminate tumor groups and non-tumor groups (ROC values from 0.86 to 0.98). The late-stage top 300 DMRs are more late-stage-specific and failed to detect early-stage OC. However, the early-stage markers have the potential to discriminate all-stage OCs from non-tumor samples.
CONCLUSIONS: This study demonstrates that cfDNA methylomes generated with cfMeDIP-seq could be used to identify OC-specific biomarkers for OC, especially early OC detection. To detect early-stage OC, the biomarkers should be directly identified from early OC plasma samples rather than mix-stage ones. Further exploration of DMRs from a k larger early-stage OC cohort is warranted.

Keywords:  Biomarkers; Early cancer detection; Ovarian cancer; cfDNA methylation; cfMeDIP-seq

DOI:  https://doi.org/10.1186/s13148-022-01285-9
Front Oncol. 2022 ;12 871513

Targeting the Tumor Microenvironment: A Close Up of Tumor-Associated Macrophages and Neutrophils.

Massimo Russo, Claudia Nastasi.

  The importance of the tumor microenvironment (TME) in dynamically regulating cancer progression and influencing the therapeutic outcome is widely accepted and appreciated. Several therapeutic strategies to modify or modulate the TME, like angiogenesis or immune checkpoint inhibitors, showed clinical efficacy and received approval from regulatory authorities. Within recent decades, new promising strategies targeting myeloid cells have been implemented in preclinical cancer models. The predominance of specific cell phenotypes in the TME has been attributed to pro- or anti-tumoral. Hence, their modulation can, in turn, alter the responses to standard-of-care treatments, making them more or less effective. Here, we summarize and discuss the current knowledge and the correlated challenges about the tumor-associated macrophages and neutrophils targeting strategies, current treatments, and future developments.

Keywords:  TAMs; TANs; anti-cancer therapy; cancer; macrophages; neutrophils; tumor-microenvironment

DOI:  https://doi.org/10.3389/fonc.2022.871513
Cancers (Basel). 2022 May 26. pii: 2637. [Epub ahead of print]14(11):

The Role of Cancer-Associated Fibroblasts in Ovarian Cancer.

Mo Zhang, Zhixian Chen, Yan Wang, Hongbo Zhao, Yan Du.

  Ovarian cancer is a lethal gynecologic tumor and is generally resistant to conventional treatments. Stable cancer-associated fibroblasts (CAFs) are important cellular components in the ovarian cancer tumor microenvironment and may provide novel resources for future treatment strategies. Different subtypes of CAFs display specific functions in tumor pathogenesis and various CAF markers suggest potential treatment targets, such as FAP and GPR77. Both autocrine and paracrine cytokines play important roles in the CAF activation process and regulate tumor progression. Downstream mediators and pathways, including IL-6, TGF-β, NF-κB, mitogen-activated protein kinase (MAPK), and AKT/mTOR/(p70S6K), play important roles in the initiation, proliferation, invasiveness, and metastasis of ovarian cancer cells and also participate in angiogenesis, therapeutic resistance, and other biological processes. Several clinical or preclinical trials have targeted stromal fibroblasts and focused on the properties of CAFs to enhance ovarian cancer treatment outcomes. This review concentrates on the origins, subtypes, and activation of CAFs, as well as specific roles of CAFs in regulating tumor development and drug resistance, and aims to provide potential and prospective targets for improving the therapeutic efficacy of ovarian cancer treatment.

Keywords:  cancer-associated fibroblasts; ovarian cancer; stroma; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14112637