bims-tumhet 2025-02-02 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2025–02–02
nine papers selected by
Sergio Marchini, Humanitas Research

Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer.
Comprehensive evaluation of genomic and functional assays for homologous recombination deficiency with high-grade epithelial ovarian cancer: Platinum sensitivity and prognosis.
LINE-1 Retrotransposons as Cell-free DNA Biomarkers for Multi-Cancer Early Detection.
Liquid biopsy for diagnosing epithelial ovarian cancer: quantification of cell-free DNA and p53 mutational analysis.
Cancer phylogenetic inference using copy number alterations detected from DNA sequencing data.
From Genes to Clinical Practice: Exploring the Genomic Underpinnings of Endometrial Cancer.
The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity.
Immune evasion in ovarian cancer: implications for immunotherapy and emerging treatments.
Tertiary Lymphoid Structures as a Biomarker in Immunotherapy and Beyond: Advancing Towards Clinical Application.

J Ovarian Res. 2025 Jan 30. 18(1): 19

Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer.

Ying-Cheng Chiang, Hsien-Neng Huang, Kuan-Ting Kuo, Wuh-Liang Hwu, Po-Han Lin.

   BACKGROUND: The homologous recombination deficiency (HRD) test is an important tool for identifying patients with epithelial ovarian cancer (EOC) benefit from the treatment with poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi). Using whole exome sequencing (WES)-based platform can provide information of gene mutations and HRD score; however, the clinical value of WES-based HRD test was less validated in EOC.
METHODS: We enrolled 40 patients with EOC in the training cohort and 23 in the validation cohort. The WES-based HRD score was calculated using the scarHRD software. We first evaluated the concordance of the HRD status defined by the Myriad MyChoice CDx and then assessed the value of HRD on clinical prognosis in patients with EOC.
RESULTS: The HRD score defined by the WES-based test was positively correlated with that of the Myriad MyChoice® CDx test (r = 0.82, p < 0.01) in the training cohort. In compared to HRD status of Myriad test, the sensitivity, specificity, positive predictive value, and negative predictive value of the WES-based HRD test were 93.5% (29/31), 77.8% (7/9), 93.5% (29/31), and 77.8% (7/9), respectively. Patients with positive HRD status defined by WES-based scarHRD test and Myriad MyChoice® CDx test were both highly associated with platinum sensitive response (both Fisher's exact test, p = 0.002) as well as the superior progression-free survival (both log-rank p = 0.002). The multi-variate Cox regression model incorporated with optimal debulking surgery showed that the recurrence risk was decreased in the patients with positive HRD status, either defined by Myriad MyChoice® CDx test (Hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.14-0.79, p = 0.013) or WES-based test Myriad MyChoice® CDx test (HR 0.34, 95% CI 0.14-0.80, p = 0.014). Nine patients had mutations in the genes involved in HR DNA repair, and all of them were positive for HRD. In the validation group, 23 patients were defined as positive HRD by WES-based testing. Six positive HRD patients and 5 negative HRD patients received maintenance PARPi. The median responsive interval of PARPi was 17 months in positive HRD patients and 3 months in negative HRD patients.
CONCLUSION: The WES-based test is a potential option for determining the HRD status in EOC patients, and desires for further validation in large-scale cohorts.

Keywords:  Epithelial ovarian cancer; Homologous recombination deficiency test; Whole-exome sequencing; scarHRD

DOI:  https://doi.org/10.1186/s13048-024-01565-3
Int J Gynecol Cancer. 2025 Jan;pii: S1048-891X(24)01979-0. [Epub ahead of print]35(1): 100031

Comprehensive evaluation of genomic and functional assays for homologous recombination deficiency with high-grade epithelial ovarian cancer: Platinum sensitivity and prognosis.

Zheng Feng, Changbin Zhu, Xiaotian Zhang, Zhan Huang, Xingzhu Ju, Qinhao Guo, Xing Li, Xiaohua Wu, Hao Wen.

   OBJECTIVE: Homologous recombination deficiency assays, guiding treatment of poly (adenosine diphosphate ribose) polymerase inhibitors, are increasingly applied in clinics. This study aimed to evaluate the predictive performance of homologous recombination deficiency status at genomic and functional perspective on the efficacy of platinum-based chemotherapy in ovarian cancer.
METHODS: Between 2016 and 2019, 134 patients with high-grade ovarian cancer were retrospectively analyzed. Formalin-fixed paraffin-embedded tissues were subjected to DNA sequencing using the AmoyDx HRD Complete Panel. The genomic scar score and the genomic instability score were calculated based on copy number variation events. Furthermore, the RAD51 and SLFN11 protein levels in tumors were assessed by immunohistochemistry.
RESULTS: Of all patients, 106 of 134 (79.1%) were homologous recombination deficiency (genomic scar score)-positive, with a higher platinum sensitivity rate than those who were homologous recombination deficiency (genomic scar score)-negative (78.3% vs 57.1%, p = .023). Similarly, 104 of 134 (77.6%) were homologous recombination deficiency (genomic instability score)-positive, with increased platinum sensitivity compared with homologous recombination deficiency (genomic instability score)-negative (77.9% vs 60.0%, p = .049). The overall concordance rate of homologous recombination deficiency status defined by the 2 scores was 98.5%. Genomic scar score and genomic instability score determined homologous recombination deficiency-positive statuses correlated with better progression-free survival (p = .0019, p = .0041) and overall survival (p = .018, p = .031). Patients with nuclear RAD51-loss or SLFN11-positive expression were likely to be homologous recombination deficiency-positive by genomic scar score/genomic instability score (94.1% and 97.6%; 94.1% and 95.2%, respectively). Patients with nuclear RAD51-loss and SLFN11-positive expression had better overall survival than those with RAD51-positive and SLFN11-negative expression. Among homologous recombination deficiency statuses, RAD51 and SLFN11 expressions, homologous recombination deficiency (genomic scar score)-positive was most associated with progression-free survival and platinum sensitivity. Multivariate regression analysis showed that homologous recombination deficiency (genomic scar score)-positive status was a good prognostic factor, implying a higher possibility of platinum sensitivity.
CONCLUSION: Genomic scar score, given by AmoyDx HRD Complete Panel, was most associated with the efficacy of platinum treatment in patients with high-grade ovarian cancer. Validation is warranted via prospective studies.

Keywords:  RAD51; genomic scar score; homologous recombination deficiency; ovarian cancer; platinum sensitivity; survival

DOI:  https://doi.org/10.1016/j.ijgc.2024.100031
Clin Cancer Res. 2025 Jan 29.

LINE-1 Retrotransposons as Cell-free DNA Biomarkers for Multi-Cancer Early Detection.

Jeffrey J Szymanski, Pradeep S Chauhan, Aadel A Chaudhuri.

LINE-1 retrotransposons, comprising 17% of the genome, drive cancer instability through hypomethylation. The DIAMOND assay, targeting LINE-1 hypomethylation with bisulfite sequencing of cell free DNA, achieved AUCs of 88% to 100% across six cancer types, surpassing mutation-based diagnostics and suggesting utility in early cancer detection and management.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-4051
Int J Gynecol Cancer. 2025 Jan;pii: S1048-891X(24)01493-2. [Epub ahead of print]35(1): 100022

Liquid biopsy for diagnosing epithelial ovarian cancer: quantification of cell-free DNA and p53 mutational analysis.

Shalini Rajaram, Aanchal Varma, Bindiya Gupta, Rajarshi Kar, Vinod Kumar Arora, Sandhya Jain, Lakhwinder Singh.

   OBJECTIVE: To isolate and quantify cell-free DNA, analysis for p53 mutations, and correlation with tumor burden in women with epithelial ovarian cancer compared with benign and borderline epithelial ovarian tumors.
METHODS: In this case-control study, plasma samples of eligible women collected 1 hour before surgery and based on final histopathology, women with epithelial ovarian cancer recruited as cases and borderline, and benign ovarian tumors as controls. Cell-free DNA extracted from plasma serum and quantified using Nanodrop Spectrophotometer. Amplification refractory mutation system-based polymerase chain reaction was used to detect point mutation in exon 8, codon 239 of p53 using primer pairs. p53 immunostaining was performed on tissue samples.
RESULTS: A total of 40 women (20 cases of epithelial ovarian cancer and 10 each of benign and borderline ovarian tumors [controls]) were included in a 2:1:1 ratio. The mean cell-free DNA amount was 1330 ± 1705.4 ng/mL in women with epithelial ovarian cancer compared with 748.5 ± 444.8 and 448.5 ± 203.9 ng/mL in benign and borderline ovarian tumors, respectively (p = .023). In those with high-grade serous ovarian cancer, it was 2640 ± 2450.6 ng/mL compared with 600 ± 316.7 and 652.5 ± 158.9 ng/mL in low-grade serous and mucinous ovarian cancer, respectively (p = .006). In stage I and II ovarian cancer, these were 502.5 ± 134.4 and 330 ± 296.9 ng/mL, respectively, compared with 1655 ± 1924.8 ng/mL in stage III disease (p = .004). A total of 11 (55%) women with epithelial ovarian cancer harbored mutation in exon 8, codon 239 of p53 compared with 2 (20%) each in benign and borderline ovarian tumors (p = 0.07). Fair agreement was noted between cell-free DNA p53 mutation and abnormal tissue p53 staining on immunohistochemistry (κ = 0.41).
CONCLUSION: Cell-free DNA amount was higher in women with epithelial ovarian cancer than women with benign and borderline ovarian tumors, with higher levels in advanced stage and high-grade serous carcinoma sub-type. Cell-free DNA p53 mutational analysis yielded fair concordance with tumor tissue p53 immunohistochemical results.

Keywords:  Carcinoma; Ovarian Cancer; Ovarian Epithelial; Pathology; Surgery

DOI:  https://doi.org/10.1016/j.ijgc.2024.100022
Cancer Pathog Ther. 2025 Jan;3(1): 16-29

Cancer phylogenetic inference using copy number alterations detected from DNA sequencing data.

Bingxin Lu.

  Cancer is an evolutionary process involving the accumulation of diverse somatic mutations and clonal evolution over time. Phylogenetic inference from samples obtained from an individual patient offers a powerful approach to unraveling the intricate evolutionary history of cancer and provides insights that can inform cancer treatment. Somatic copy number alterations (CNAs) are important in cancer evolution and are often used as markers, alone or with other somatic mutations, for phylogenetic inferences, particularly in low-coverage DNA sequencing data. Many phylogenetic inference methods using CNAs detected from bulk or single-cell DNA sequencing data have been developed over the years. However, there have been no systematic reviews on these methods. To summarize the state-of-the-art of the field and inform future development, this review presents a comprehensive survey on the major challenges in inference, different types of methods, and applications of these methods. The challenges are discussed from the aspects of input data, models of evolution, and inference algorithms. The different methods are grouped according to the markers used for inference and the types of the reconstructed trees. The applications include using phylogenetic inference to understand intra-tumor heterogeneity, metastasis, treatment resistance, and early cancer development. This review also sheds light on future directions of cancer phylogenetic inference using CNAs, including the improvement of scalability, the utilization of new types of data, and the development of more realistic models of evolution.

Keywords:  Chromosomal instability; Clonal evolution; Copy number change; Phylogenetic inference; Somatic mutation

DOI:  https://doi.org/10.1016/j.cpt.2024.04.003
Cancers (Basel). 2025 Jan 20. pii: 320. [Epub ahead of print]17(2):

From Genes to Clinical Practice: Exploring the Genomic Underpinnings of Endometrial Cancer.

Thulo Molefi, Lloyd Mabonga, Rodney Hull, Motshedisi Sebitloane, Zodwa Dlamini.

  Endometrial cancer (EC), a prevalent gynecological malignancy, presents significant challenges due to its genetic complexity and heterogeneity. The genomic landscape of EC is underpinned by genetic alterations, such as mutations in PTEN, PIK3CA, and ARID1A, and chromosomal abnormalities. The identification of molecular subtypes-POLE ultramutated, microsatellite instability (MSI), copy number low, and copy number high-illustrates the diverse genetic profiles within EC and underscores the need for subtype-specific therapeutic strategies. The integration of multi-omics technologies such as single-cell genomics and spatial transcriptomics has revolutionized our understanding and approach to studying EC and offers a holistic perspective that enhances the ability to identify novel biomarkers and therapeutic targets. The translation of these multi-omics findings into personalized medicine and precision oncology is increasingly feasible in clinical practice. Targeted therapies such as PI3K/AKT/mTOR inhibitors have demonstrated the potential for improved treatment efficacy tailored to specific genetic alterations. Despite these advancements, challenges persist in terms of variability in patient responses, the integration of genomic data into clinical workflows, and ethical considerations. This review explores the genomic underpinnings of EC, from genes to clinical practice. It highlights the ongoing need for multidisciplinary research and collaboration to address the complexities of EC and improve diagnosis, treatment, and patient outcomes.

Keywords:  CRISPR; endometrial cancer; genetic alterations; molecular subtypes; multi-omics; personalized medicine; precision oncology; targeted therapies

DOI:  https://doi.org/10.3390/cancers17020320
Cell Rep. 2025 Jan 24. pii: S2211-1247(24)01580-8. [Epub ahead of print]44(2): 115229

The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity.

DUTRENEO Study Investigators

  Tumors are complex ecosystems of interacting cell types. The concept of cancer hallmarks distills this complexity into underlying principles that govern tumor growth. Here, we explore the spatial distribution of cancer hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that hallmark activity is spatially organized, with the cancer compartment contributing to the activity of seven out of 13 hallmarks, while the tumor microenvironment (TME) contributes to the activity of the rest. Additionally, we discover that genomic distance between tumor subclones correlates with differences in hallmark activity, even leading to clone-hallmark specialization. Finally, we demonstrate interdependent relationships between hallmarks at the junctions of TME and cancer compartments and how they relate to sensitivity to different neoadjuvant treatments in 33 bladder cancer patients from the DUTRENEO trial. In conclusion, our findings may improve our understanding of tumor ecology and help identify new drug biomarkers.

Keywords:  CP: cancer; cancer hallmarks; drug sensitivity; ecosystem; intratumoral heterogeneity; spatial transcriptomics; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2024.115229
Trends Immunol. 2025 Jan 23. pii: S1471-4906(24)00308-9. [Epub ahead of print]

Immune evasion in ovarian cancer: implications for immunotherapy and emerging treatments.

Romi Gupta, Raj Kumar, Courtney A Penn, Narendra Wajapeyee.

  Ovarian cancer (OC) is the most lethal gynecologic malignancy, characterized by multiple histological subtypes, each with distinct pathological and clinical features. Current treatment approaches include cytotoxic chemotherapies, poly(ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, hormonal therapy, immunotherapy, and antibody-drug conjugates (ADCs). In this review we discuss immune evasion mechanisms in OC and the role of genetics, the tumor microenvironment, and tumor heterogeneity in influencing these processes. We also discuss the use of immunotherapies for OC treatment, either alone or in combination with other anticancer agents, with a focus on their clinical outcomes. Finally, we highlight emerging immunotherapies that have either succeeded or are on the verge of significantly impacting cancer treatment, and we discuss their potential utility in the effective treatment of OC.

Keywords:  adaptive immunity; immunotherapy; innate immunity; ovarian cancer; tumor heterogeneity

DOI:  https://doi.org/10.1016/j.it.2024.12.006
Cancer Lett. 2025 Jan 23. pii: S0304-3835(25)00055-2. [Epub ahead of print] 217491

Tertiary Lymphoid Structures as a Biomarker in Immunotherapy and Beyond: Advancing Towards Clinical Application.

Xinyu Cui, Xuanyu Gu, Dongyu Li, Peng Wu, Nan Sun, Chaoqi Zhang, Jie He.

  Tertiary lymphoid structures (TLSs) are ectopic immune cell clusters formed in nonlymphoid tissues affected by persistent inflammation, such as in cancer and prolonged infections. They have features of the structure and function of secondary lymphoid organs, featuring central CD20+ B cells, surrounded by CD3+ T cells, CD21+ follicular dendritic cells, and CD68+ macrophages, with a complex vascular system. TLS formation is governed by lymphotoxin-α1β2, TNF, and chemokines like CCL19, CCL21, and CXCL13, differing from secondary lymphoid organ development in developing later in life at sites of chronic inflammation. Their role in enhancing immune responses, particularly in the context of cancer, makes them a focal point in immunotherapy. This review discusses recent advances in TLS assessment that involves complex gene expression signatures, histological analysis, artificial intelligence, and spatial omics. The presence and maturity of TLS are associated with better outcomes in various cancers, acting as a biomarker for immunotherapy effectiveness. This review explores the structure, formation, and role of TLS in disease prognosis, including their roles in immunotherapy and non-immunotherapy treatments, highlighting a need to develop novel techniques for precise characterization of TLS as well as their significance as predictive biomarkers beyond traditional biomarkers.

Keywords:  Artificial intelligence; Predictive biomarker; Spatial omics; Tertiary lymphoid structure; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.217491