bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2025–03–02
eight papers selected by
Sergio Marchini, Humanitas Research
  1. Controversies in the management of serous tubal intra-epithelial carcinoma lesions of the fallopian tube.
  2. Jellyfish: integrative visualization of spatio-temporal tumor evolution and clonal dynamics.
  3. Homologous recombination deficiency (HRD) testing landscape: clinical applications and technical validation for routine diagnostics.
  4. Early Diagnosis of Ovarian Cancer: A Comprehensive Review of the Advances, Challenges, and Future Directions.
  5. Gynecologic Cancer Screening and Prevention: State of the Science and Practice.
  6. Evaluation of Pan-Cancer Immune Heterogeneity Based on DNA Methylation.
  7. Genomic alterations and transcriptional phenotypes in circulating free DNA and matched metastatic tumor.
  8. Comprehensive Review of Endometrial Cancer: New Molecular and FIGO Classification and Recent Treatment Changes.
  1. Int J Gynecol Cancer. 2025 Feb 05. pii: S1048-891X(25)00192-6. [Epub ahead of print]35(3): 101667
    Controversies in the management of serous tubal intra-epithelial carcinoma lesions of the fallopian tube.
    Olivia Le Saux, Iain McNeish, Maurizio D'Incalci, Fabrice Narducci, Isabelle Ray-Coquard.
      High-grade serous carcinoma is the most lethal gynecological malignancy. Although serous tubal intra-epithelial carcinoma is increasingly recognized as a precursor to high-grade serous carcinoma, its optimal management remains controversial. This review examines the controversies in serous tubal intra-epithelial carcinoma pathogenesis, diagnosis, management, and follow-up, highlighting the need for collaboration, standardized guidelines, and further research to improve patient outcomes.
    Keywords:  Carcinogenesis; Ovarian Cancer; Preneoplastic Lesion
    DOI:  https://doi.org/10.1016/j.ijgc.2025.101667
  2. Bioinformatics. 2025 Feb 25. pii: btaf091. [Epub ahead of print]
    Jellyfish: integrative visualization of spatio-temporal tumor evolution and clonal dynamics.
    Kari Lavikka, Altti Ilari Maarala, Jaana Oikkonen, Sampsa Hautaniemi.
       SUMMARY: Spatial and temporal intra-tumor heterogeneity drives tumor evolution and therapy resistance. Existing visualization tools often fail to capture both dimensions simultaneously. To address this, we developed Jellyfish, a tool that integrates phylogenetic and sample trees into a single plot, providing a holistic view of tumor evolution and capturing both spatial and temporal evolution. Available as a JavaScript library and R package, Jellyfish generates interactive visualizations from tumor phylogeny and clonal composition data. We demonstrate its ability to visualize complex subclonal dynamics using data from ovarian high-grade serous carcinoma.
    AVAILABILITY AND IMPLEMENTATION: Jellyfish is freely available with MIT license at https://github.com/HautaniemiLab/jellyfish (JavaScript library) and https://github.com/HautaniemiLab/jellyfisher (R package).
    DOI:  https://doi.org/10.1093/bioinformatics/btaf091
  3. Biomark Res. 2025 Feb 21. 13(1): 31
    Homologous recombination deficiency (HRD) testing landscape: clinical applications and technical validation for routine diagnostics.
    Andréa Witz, Julie Dardare, Margaux Betz, Cassandra Michel, Marie Husson, Pauline Gilson, Jean-Louis Merlin, Alexandre Harlé.
      The use of poly(ADP-ribose) polymerase inhibitors (PARPi) revolutionized the treatment of BRCA-mutated cancers. Identifying patients exhibiting homologous recombination deficiency (HRD) has been proved useful to predict PARPi efficacy. However, obtaining HRD status remains an arduous task due to its evolution over the time. This causes HRD status to become obsolete when obtained from genomic scars, rendering PARPi ineffective for these patients. Only two HRD tests are currently FDA-approved, both based on genomic scars detection and BRCA mutations testing. Nevertheless, new technologies for obtaining an increasingly reliable HRD status continue to evolve. Application of these tests in clinical practice is an additional challenge due to the need for lower costs and shorter time to results delay.In this review, we describe the currently available methods for HRD testing, including the methodologies and corresponding tests for assessing HRD status, and discuss the clinical routine application of these tests and their technical validation.
    Keywords:   BRCA mutations testing; Genomic scars analysis; HRD status; Homologous recombination deficiency; PARP inhibitors
    DOI:  https://doi.org/10.1186/s40364-025-00740-y
  4. Diagnostics (Basel). 2025 Feb 07. pii: 406. [Epub ahead of print]15(4):
    Early Diagnosis of Ovarian Cancer: A Comprehensive Review of the Advances, Challenges, and Future Directions.
    Mun-Kun Hong, Dah-Ching Ding.
      Ovarian cancer (OC), the seventh most common cancer in women and the most lethal gynecological malignancy, is a significant global health challenge, with >324,000 new cases and >200,000 deaths being reported annually. OC is characterized by late-stage diagnosis, a poor prognosis, and 5-year survival rates ranging from 93% (early stage) to 20% (advanced stage). Despite advances in genomics and proteomics, effective early-stage diagnostic tools and population-wide screening strategies remain elusive, contributing to high mortality rates. The complex pathogenesis of OC involves diverse histological subtypes and genetic predispositions, including BRCA1/2 mutations; notably, a considerable proportion of OC cases have a hereditary component. Current diagnostic modalities, including imaging techniques (transvaginal ultrasound, computed/positron emission tomography, and magnetic resonance imaging) and biomarkers (CA-125 and human epididymis protein 4), with varying degrees of sensitivity and specificity, have limited efficacy in detecting early-stage OC. Emerging technologies, such as liquid biopsy, multiomics, and artificial intelligence (AI)-assisted diagnostics, may enhance early detection. Liquid biopsies using circulating tumor DNA and microRNAs are popular minimally invasive diagnostic tools. Integrated multiomics has advanced biomarker discovery. AI algorithms have improved imaging interpretation and risk prediction. Novel screening methods including organoids and multiplex panels are being explored to overcome current diagnostic limitations. This review highlights the critical need for continued research and innovation to enhance early diagnosis, reduce mortality, and improve patient outcomes in OC and posits personalized medicine, integrated emerging technologies, and targeted global initiatives and collaborative efforts, which address care access disparities and promote cost-effective, scalable screening strategies, as potential tools to combat OC.
    Keywords:  early diagnosis; multiomics; ovarian cancer; pathogenesis; tumor markers
    DOI:  https://doi.org/10.3390/diagnostics15040406
  5. Curr Treat Options Oncol. 2025 Feb 27.
    Gynecologic Cancer Screening and Prevention: State of the Science and Practice.
    C Tran, H Diaz-Ayllon, D Abulez, S Chinta, M Y Williams-Brown, N Desravines.
       OPINION STATEMENT: Gynecological cancers, including cervical, endometrial, ovarian, and vulvovaginal cancer, have increasing incidence and mortality globally over the last three decades. In that time, there have been advances in medical therapies and paradigm shifts in surgical treatment which have resulted in a greater quality of life for patients. Clinicians have also refocused efforts to preventing gynecologic cancer. The state of screening and prevention is varied in each of the cancer types. The most comprehensive screening program and only preventable gynecological cancer is cervical cancer, which has been heavily studied since the 1900s. Cervical cytology, primary high-risk human papillomavirus (HPV) testing only, and co-testing are all effective in detecting cervical dysplasia and touted by the major medical. An additional arsenal is prevention through vaccination which has been shown to decrease cervical cancer. Unfortunately, the other gynecological cancers do not have effective screening strategies. The high rates of symptoms in endometrial cancer facilitate detection at an early stage but thus far, asymptomatic screening is only advocated in very high-risk population due to the invasive nature. Novel non-invasive mechanisms are currently under study though none have translated into clinical practice as of yet. Ovarian cancer remains the most innocuous with vague symptoms at onset resulting in late-stage diagnosis. Recommendations for prophylactic oophorectomy only apply to subsets of the population with predisposing genetic mutations. This has led to an ardent push for creative strategies such as opportunistic salpingectomy and a national genetic screening program. These efforts are in addition to the investigations underway researching radiologic, liquid biopsy, and genetic marker screening modalities for all gynecologic cancer. This review article discusses the state of screening, prevention, and recent advancements and pilot studies for each gynecological cancer.
    Keywords:  Cervical cancer; Endometrial cancer; Gynecological cancer; Ovarian cancer; Prevention; Screening
    DOI:  https://doi.org/10.1007/s11864-025-01301-z
  6. Genes (Basel). 2025 Jan 26. pii: 160. [Epub ahead of print]16(2):
    Evaluation of Pan-Cancer Immune Heterogeneity Based on DNA Methylation.
    Yang Zhou, Jiebiao Liu, Bowen Shi, Te Ma, Peishen Yu, Ji Li, Yue Gu, Yan Zhang.
       BACKGROUND/OBJECTIVES: The heterogeneity of the tumor immune microenvironment is a key determinant of tumor oncogenesis. This study aims to evaluate the composition of seven immune cells across 5323 samples from 14 cancers using DNA methylation data.
    METHODS: A deconvolution algorithm was proposed to estimate the composition of seven immune cells using 1256 immune cell population-specific methylation genes. Based on the immune infiltration features of seven immune cell fractions, 42 subtypes of 14 tumors (2-5 subtypes per tumor) were identified.
    RESULTS: Significant differences in immune cells between subtypes were revealed for each cancer. The study found that the methylation values of the selected specific sites correlated with gene expression in most tumor subtypes. Immune infiltration results were integrated with phenotypic data, including survival data and tumor stages, revealing significant correlations between immune infiltration and phenotypes in some tumors. Subtypes with high proportions of CD4+ T cells, CD8+ T cells, CD56+ NK cells, CD19+ B cells, CD14+ monocytes, neutrophils, and eosinophils were identified, with subtype counts of 9, 24, 22, 13, 19, 9, and 11, respectively. Additionally, 2412 differentially expressed genes between these subtypes and normal tissues were identified. Pathway enrichment analysis revealed that these genes were mainly enriched in pathways related to drug response and chemical carcinogens. Differences in ESTIMATE scores for subtypes of seven tumors and TIDE scores for eight tumors were also observed.
    CONCLUSIONS: This study demonstrates the intra-tumor and inter-tumor immune heterogeneity of pan-cancer through DNA methylation analysis, providing assistance for tumor diagnosis.
    Keywords:  DNA methylation; clustering; deconvolution algorithm; pan-cancer; tumor immune microenvironment
    DOI:  https://doi.org/10.3390/genes16020160
  7. Genome Med. 2025 Feb 25. 17(1): 15
    Genomic alterations and transcriptional phenotypes in circulating free DNA and matched metastatic tumor.
    Nobuyuki Takahashi, Lorinc Pongor, Shivam P Agrawal, Mariya Shtumpf, Ankita Gurjar, Vinodh N Rajapakse, Ahmad Shafiei, Christopher W Schultz, Sehyun Kim, Diana Roame, Paula Carter, Rasa Vilimas, Samantha Nichols, Parth Desai, William Douglas Figg, Mohammad Bagheri, Vladimir B Teif, Anish Thomas.
       BACKGROUND: Profiling circulating cell-free DNA (cfDNA) has become a fundamental practice in cancer medicine, but the effectiveness of cfDNA at elucidating tumor-derived molecular features has not been systematically compared to standard single-lesion tumor biopsies in prospective cohorts of patients. The use of plasma instead of tissue to guide therapy is particularly attractive for patients with small cell lung cancer (SCLC), due to the aggressive clinical course of this cancer, which makes obtaining tumor biopsies exceedingly challenging.
    METHODS: In this study, we analyzed a prospective cohort of 49 plasma samples obtained before, during, and after treatment from 20 patients with recurrent SCLC. We conducted cfDNA low-pass whole genome sequencing (0.1X coverage), comparing it with time-point matched tumor characterized using whole-exome (130X) and transcriptome sequencing.
    RESULTS: A direct comparison of cfDNA and tumor biopsy revealed that cfDNA not only mirrors the mutation and copy number landscape of the corresponding tumor but also identifies clinically relevant resistance mechanisms and cancer driver alterations not detected in matched tumor biopsies. Longitudinal cfDNA analysis reliably tracks tumor response, progression, and clonal evolution. Sequencing coverage of plasma DNA fragments around transcription start sites showed distinct treatment-related changes and captured the expression of key transcription factors such as NEUROD1 and REST in the corresponding SCLC tumors. This allowed for the prediction of SCLC neuroendocrine phenotypes and treatment responses.
    CONCLUSIONS: cfDNA captures a comprehensive view of tumor heterogeneity and evolution. These findings have significant implications for the non-invasive stratification of SCLC, a disease currently treated as a single entity.
    Keywords:  Circulating cell-free DNA; Circulating tumor DNA; Transcription factor binding site; Whole genome sequencing
    DOI:  https://doi.org/10.1186/s13073-025-01438-4
  8. J Clin Med. 2025 Feb 19. pii: 1385. [Epub ahead of print]14(4):
    Comprehensive Review of Endometrial Cancer: New Molecular and FIGO Classification and Recent Treatment Changes.
    Maria-Bianca Anca-Stanciu, Andrei Manu, Maria Victoria Olinca, Cătălin Coroleucă, Diana-Elena Comandașu, Ciprian Andrei Coroleuca, Calina Maier, Elvira Bratila.
      Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with rising incidence due to aging populations and obesity-related factors. This review explores the evolving molecular and FIGO classifications of EC, highlighting their significance in diagnosis, prognosis, and personalized treatment strategies. Molecular subtyping based on The Cancer Genome Atlas (TCGA) classification offers a more precise understanding of EC, dividing it into POLE ultramutated, microsatellite instability-high (MSI-H), copy-number low (CNL), and copy-number high (CNH) subtypes. Each subgroup has distinct genetic, histological, and prognostic characteristics. Recent updates to the FIGO staging system incorporate molecular features, allowing for more tailored treatment approaches. Advances in immunotherapy, targeted therapies, and novel therapeutic combinations have reshaped clinical management. This review emphasizes the integration of molecular diagnostics into routine practice, outlining challenges and future perspectives in managing EC for improved patient outcomes.
    Keywords:  FIGO classification; POLE ultramutated; The Cancer Genome Atlas (TCGA); copy-number high (CNH); copy-number low (CNL); endometrial cancer; immunotherapy; microsatellite instability-high (MSI-H); molecular classification; personalized medicine; targeted therapies
    DOI:  https://doi.org/10.3390/jcm14041385
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