bims-tumhet 2026-03-29 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2026–03–29
ten papers selected by
Sergio Marchini, Humanitas Research

Serous tubal intraepithelial carcinoma-looking into the earliest events of ovarian cancer development.
Liquid biopsy biomarkers for early detection of gastrointestinal cancers: Current landscape and emerging technologies.
Prognostic Value of Circulating Tumor DNA for Minimal Residual Disease Detection in Ovarian Cancer: A Systematic Review and Meta-analysis.
fRagmentomics: an R package for integrating cell-free DNA fragment features with mutational status to support liquid biopsy interpretation.
TiSMeD: A tissue-specific methylation and expression database for biomarker and translational applications.
Assessment of references for the quantitative analysis of LINE-1 and Alu methylation in cellular DNA and circulating cell-free DNA of cancer patients.
Cancer genomic profiling predicts pathogenicity of BRCA1 and BRCA2 variants.
Circulating Tumor DNA in Cholangiocarcinoma: A Precision Oncology Roadmap.
Atezolizumab plus FOLFOX for Stage III Mismatch Repair-Deficient Colon Cancer.
An unbiased approach to measure aberrant DNA methylation alterations.

Acad Oncol. 2025 ;2(1):

Serous tubal intraepithelial carcinoma-looking into the earliest events of ovarian cancer development.

Ie-Ming Shih, Yeh Wang, Russell Vang.

  Among human malignancies, ovarian epithelial neoplasms are unique because they are unlikely to develop from their cognate organs, the ovaries (specifically, the surface mesothelium). The updated paradigm about the origin of high-grade serous carcinoma (HGSC) suggests that many HGSCs derive from the fallopian tubes following a sequential tumor progression, from pathologically defined p53 signature, serous tubal intraepithelial lesion, and serous tubal intraepithelial carcinoma (STIC) to HGSC that later spreads to ovarian tissues and disseminates. Despite the fact that the biological and clinical significance of each of those precursor lesions is yet to be elucidated, molecular and morphological correlative studies demonstrate unique features associated with various precancerous lesions. Chromosomal instability, aneuploidy patterns, and the activation of specific cancer signaling pathways attribute tumor progression to HGSC. The knowledge gained thus far is transforming various aspects of ovarian cancer research and gynecological practice. Opportunistic salpingectomy prevents HGSC in average-risk women, and molecular analyses in routine liquid-based cervical Pap tests hold promise to detect STIC- and HGSC-related tissue biomarkers. This review article will summarize those key findings in the earliest development of HGSC precursors and discuss the future challenges and promises of translating this paradigm shift to leverage standardization in diagnostic, early detection, and prevention of this devastating ovarian cancer.

Keywords:  BRCA mutation; CCNE1 and MYC amplification; aneuploidy; ovarian high-grade serous carcinoma; p53 mutation; serous tubal intraepithelial carcinoma

DOI:  https://doi.org/10.20935/acadonco7620
Clin Transl Med. 2026 Mar;16(3): e70594

Liquid biopsy biomarkers for early detection of gastrointestinal cancers: Current landscape and emerging technologies.

Muhammad Anees, Christopher Sherry, Hyun Y Park, Erin E Grayhack, Arul Goel, Alisha F Khan, Ashten Omstead, David L Bartlett, Ajay Goel, Neda Dadgar, Patrick L Wagner, Ali H Zaidi.

  Early detection of gastrointestinal (GI) cancers remains a critical unmet clinical need, as most patients are diagnosed at advanced stages when prognosis is poor. Liquid biopsy has emerged as a transformative approach for minimally invasive cancer detection by analysing tumour-derived analytes in blood and other body fluids. Recent advances in circulating tumour DNA (ctDNA) sequencing, cell-free DNA methylation profiling, fragmentomics, extracellular vesicle and exosome characterisation, circulating tumour cell isolation and tumour-educated platelets have markedly improved sensitivity and specificity for detecting incipient malignancies. Despite these advances, sensitivity in stage I disease remains limited due to low tumour burden and minimal analyte scaling, resulting in false-negative results for small or indolent lesions. In addition, clonal haematopoiesis derived alterations can confound mutation-based assays, highlighting the need for epigenetic and multi-analyte approaches to improve specificity. Ultimately, widespread clinical adoption will require standardised, prospective trials demonstrating diagnostic accuracy and a reduction in cancer-specific mortality. Multi-analyte and machine learning-driven approaches, integrating DNA, RNA, protein and epigenomic signals, are now in late-stage clinical trials and poised for clinical translation. United States Food and Drug Administration approvals of blood-based colorectal cancer screening tests and laboratory-developed assays for hepatocellular carcinoma exemplify the translational momentum in this field. Here, we review the current landscape of liquid biopsy biomarkers for GI cancers, emphasising technological innovations, clinical performance and ongoing trials. We also discuss key challenges, including sensitivity in stage I disease, specificity amidst clonal haematopoiesis and integration with established screening paradigms. The continued evolution of assay technologies and translational research heralds a paradigm shift towards precision early detection of GI cancers, with the potential to substantially reduce mortality through earlier intervention. KEY POINTS: Liquid biopsy technologies are advancing rapidly for early detecion of GI cancers, using ctDNA, methylation profiling, fragmentomics, EVs, CTCs, and TEPs. Limited sensitivity in stage I disease remains a key barrier, largely due to low tumor burden and analyte scarcity. Clonal hematopoieses confounds mutation-based assays, emphasizing the need for epigenetic and multi-analyte strategies to improve specificity. Multi-analyte, machine-learning-driven platforms are nearing clinical translation, supported by late-stage trials and recent FDA approvals.

Keywords:  cell‐free DNA methylation; circulating tumour DNA (ctDNA); circulating tumour cells (CTCs); early cancer detection; extracellular vesicles/exosomes; fragmentomics; gastrointestinal cancers; liquid biopsy; multi‐cancer early detection (MCED); tumour‐educated platelets (TEPs)

DOI:  https://doi.org/10.1002/ctm2.70594
Crit Rev Oncol Hematol. 2026 Mar 25. pii: S1040-8428(26)00187-3. [Epub ahead of print] 105300

Prognostic Value of Circulating Tumor DNA for Minimal Residual Disease Detection in Ovarian Cancer: A Systematic Review and Meta-analysis.

Mariana Macambira Noronha, Mariana Carvalho Gouveia, Luiz Felipe Costa Almeida, Luís Felipe Leite da Silva, Rafael Lara Nohmi, Pedro Robson Costa Passos, Valbert Oliveira Costa Filho, Otávio Al-Alam, Erick F Saldanha, Ana Carolina Veneziani.

   INTRODUCTION: Epithelial Ovarian Cancer (EOC) is the most lethal gynecological malignancy, with a high rate of recurrence due to minimal residual disease (MRD). Traditional surveillance methods have limited sensitivity for detecting MRD. ctDNA has emerged as a promising biomarker for real-time tumor monitoring and early detection of MRD.
METHODS: We performed a systematic search of Medline, Embase, and CENTRAL through July 2025. Eligible studies included cohort studies involving adults with EOC that reported ctDNA data, collected post-surgery or after adjuvant chemotherapy. Survival outcomes, including progression-free survival (PFS) and overall survival (OS), were extracted and stratified by ctDNA status (detectable vs. undetectable). All statistical analyses were performed at Review Manager version 5.4. This study is prospectively registered in PROSPERO (CRD420251124631).
RESULTS: A total of 1,291 records were identified, of which 11 studies met eligibility criteria, encompassing 627 patients with EOC. The pooled analysis showed that ctDNA positivity after surgery was significantly associated with worse PFS (HR 3.83; 95% CI 2.55- 5.77; I2= 5% p < 0.01) and OS (HR 2.84; 95% CI 1.22-6.57; I2=0; p < 0.01) compared with ctDNA-negative patients. Similarly, post-adjuvant chemotherapy detection of ctDNA yields worse PFS (HR 4.95) and OS (HR 5.95).
CONCLUSION: Our findings suggest that ctDNA is a novel instrument for MRD detection, and its presence serves as a potent prognostic indicator for recurrence and mortality in ovarian cancer. These results support integrating ctDNA into clinical trial designs and highlight its potential for risk-adapted surveillance and treatment strategies.

Keywords:  Ovarian cancer; ctDNA; liquid biopsy; prognosis

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105300
Bioinformatics. 2026 Mar 26. pii: btag152. [Epub ahead of print]

fRagmentomics: an R package for integrating cell-free DNA fragment features with mutational status to support liquid biopsy interpretation.

Killian Maudet, Juliette Samaniego, Yoann Pradat, Elsa Bernard.

SUMMARY: Liquid biopsy offers a non-invasive approach to study tumor-derived genetic material circulating in plasma. Beyond genetic alterations, the fragmentomic features of cell-free DNA-such as fragment size, genomic position, and end-motifs-provide valuable insights into the biological and clinical context of DNA release. fRagmentomics is a user-friendly R package designed to characterize cfDNA fragments overlapping one or multiple small mutations of any type, starting from an aligned sequencing file (BAM). It supports multiple mutation input formats, accommodates one-based and zero-based genomic conventions, resolves mutation representation ambiguities, and accepts any reference file in FASTA format. For each fragment overlapping a mutation of interest, fRagmentomics outputs fragment-level features including its fragment size, end-motifs, and mutational status, along with additional fragment-level or read-level information. The package implements an indel-aware and optionally soft-clip-preserving fragment size computation that improves accuracy over conventional size estimates based solely on aligned positions.
AVAILABILITY AND IMPLEMENTATION: fRagmentomics is licensed under GNU General Public License v3.0 and available at https://github.com/ElsaB-Lab/fRagmentomics and https://anaconda.org/elsab-lab/r-fragmentomics, with documentation and a tutorial.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DOI: https://doi.org/10.1093/bioinformatics/btag152
Mol Ther Nucleic Acids. 2026 Jun 16. 37(2): 102884

TiSMeD: A tissue-specific methylation and expression database for biomarker and translational applications.

Jiao Cheng, Zhe Lin, Lvying Wu, Qianying Li, Huajun Yin, Hao Wang, Hao Chen, Xiaoyan Chen, Zhi-Liang Ji.

  Tissue-specific methylation sites (TSMs) are important epigenetic features associated with gene regulation, tissue development, and disease pathogenesis. However, the lack of comprehensive and reliable resources for TSMs restricts advancements in epigenetic and translational research. We present TiSMeD (http://www.bio-add.org/TiSMeD/), a multi-omics database integrating 6,782 DNA methylation, 16,894 transcriptome, and 241 proteome profiles across 48 normal human tissues. Using a scoring framework based on SPMadjust and Tscore, we identified 67,427 high-confidence TSMs, 4,607 tissue-specific genes, and 2,833 tissue-specific proteins, along with over 11 million housekeeping methylation sites. TiSMeD enables interactive exploration and data retrieval, supporting biomarker discovery and disease research. We demonstrate its utility in tracing the tissue-of-origin of cell-free DNA (cfDNA), prioritizing 1,849 cancer biomarkers from The Cancer Genome Atlas (TCGA), and constructing a multi-cancer tracing and diagnostic model achieving 95.7% accuracy. TiSMeD serves as a robust, user-friendly platform integrating multi-omics data to advance epigenetic research and biomarker translation.

Keywords:  DNA methylation; MT: Bioinformatics; biomarker discovery; cancer; cell-free DNA; epigenomics; multi-omics integration; tissue of origin; tissue specificity

DOI:  https://doi.org/10.1016/j.omtn.2026.102884
PLoS One. 2026 ;21(3): e0345087

Assessment of references for the quantitative analysis of LINE-1 and Alu methylation in cellular DNA and circulating cell-free DNA of cancer patients.

Tung The Pham, Linh Dieu Vuong, Tuan Van Mai, Son Van Ho, Giang Son Vu, Trang Thi Quynh Tran, Trang Hien Do, Oanh Minh Pham, Linh Thi Tu Nguyen, Loan Thi Phuong Pham, Lan Thi Thuong Vo, Uyen Quynh Nguyen.

The LINE-1 and Alu retrotransposon elements, with more than 90% of their sequences being methylated, contribute to 30% of the human genome. Their hypomethylation profile, representing global methylation in cellular and cell-free DNA (cfDNA) from cancer, has been considered an attractive noninvasive biomarker of cancer. LINE-1 and Alu methylation profiling has preferentially been performed by real-time methylation-specific PCR (qMSP), pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM), which are bisulfite-based PCR approaches that require reference sequences amplified by the Methylation Independent PCR (MIP) primers to normalize the quantification data. A technical weakness of MIP primers is unequal amplification, termed PCR amplification bias, leading to an under- or overestimation of expected methylation levels, and thus, hindering the effectiveness of DNA methylation-based biomarkers. To date, the PCR amplification bias of MIP primers that may affect the methylation analysis of repeat sequences such as LINE-1 and Alu has not yet been described. Our study demonstrated for the first time the detrimental impact of biased MIP primers on LINE-1 and Alu methylation profiles, causing a significant shift from the hypomethylated status to hypermethylated in cancer tissues and in cfDNA from cancer patients. Unexpectedly, this shift was also observed in cfDNA, even when quantified by the unbiased MIP primers, depending on the reference sequences. Our results suggest that an impartial reference for the methylation quantitation of repetitive elements, most importantly in cfDNA, should be further established to ensure cross-platform consistencies in DNA methylation profiling through bisulfite-based PCR techniques.

DOI: https://doi.org/10.1371/journal.pone.0345087
medRxiv. 2026 Mar 06. pii: 2026.03.05.26347746. [Epub ahead of print]

Cancer genomic profiling predicts pathogenicity of BRCA1 and BRCA2 variants.

Olga Kondrashova, Rebecca L Johnston, Michael T Parsons, Aimee L Davidson, Daffodil M Canson, Khoa A Tran, Melissa S Cline, Nicola Waddell, Smruthy Sivakumar, Ethan S Sokol, Dexter X Jin, Dean C Pavlick, Brennan Decker, Garrett M Frampton, Amanda B Spurdle, Michael T Parsons, Amanda B Spurdle.

Accurate classification of BRCA1 and BRCA2 variants is essential for cancer risk assessment and therapy selection, yet over one-third remain variants of uncertain significance (VUS). Here, using 120,660 real-world cancer genomic profiles with BRCA1 or BRCA2 variants from a >800,000-sample cohort, we develop machine learning models that predict pathogenicity using clinical and tumor-derived features, including a pan-cancer homologous recombination deficiency signature, co-mutated genes, zygosity, and cancer type. Trained on classified variants from ClinVar, our models achieved near-perfect performance, with validation ROC-AUC of 1.000 for BRCA1 and 0.989 for BRCA2 variants with ≥5 observations, translating to strong benign or pathogenic evidence for VCEP classification. Applying these models to 1,073 BRCA1 and 1,639 BRCA2 VUS, we strengthened or enabled classification of 39.48% BRCA1 and 50.52% BRCA2 assessable variants. This approach transforms underutilized tumor profiling data into evidence that can be directly integrated into variant classification, providing a scalable framework for other tumor profiling datasets and cancer genes associated with defined tumor genomic features.

DOI: https://doi.org/10.64898/2026.03.05.26347746
Cancer Manag Res. 2026 ;18 574678

Circulating Tumor DNA in Cholangiocarcinoma: A Precision Oncology Roadmap.

Haixing Wei, Jie Wang, Qing Wu, Mengbin Qin.

  Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with a rising global incidence and few therapeutic options for advanced disease. In recent decades, precision oncology for CCA has advanced rapidly, particularly through the development of targeted therapies for patients with actionable genetic alterations. These therapies have markedly prolonged survival and improved other clinical outcomes among patients with unresectable, advanced CCA. The implementation of precision oncology largely depends on detecting genetic mutations to guide patient selection and treatment, using tumor tissue biopsies or liquid biopsies, including circulating tumor DNA (ctDNA) from blood or bile. As a minimally invasive biomarker, ctDNA shows great promise for transforming the clinical management of CCA. This review provides a comprehensive overview of the roles of ctDNA in CCA, including early detection, prognostic stratification, minimal residual disease assessment, recurrence monitoring, therapeutic target identification, and treatment response evaluation. A synthesis of existing studies indicates that bile-derived ctDNA shows superior sensitivity compared with blood-based ctDNA in capturing the genetic profiles and heterogeneity of CCA. We also propose an integrative framework that illustrates how ctDNA profiling can inform diagnosis, treatment, and surveillance across the disease continuum. Because research on ctDNA in CCA remains in its infancy, we discuss current challenges and outline future directions for translating these findings into clinical practice. Collectively, the evidence positions ctDNA-particularly bile-derived ctDNA-as a dynamic tool for real-time genomic profiling, sensitive residual disease detection, and therapy monitoring. This integrative framework provides a roadmap for translating these capabilities into clinical practice, with the potential to enable earlier, more personalized interventions and improve outcomes for patients with CCA.

Keywords:  Bile ctDNA; cholangiocarcinoma; circulating tumor DNA; liquid biopsy; targeted therapy

DOI:  https://doi.org/10.2147/CMAR.S574678
N Engl J Med. 2026 Mar 26. 394(12): 1155-1166

Atezolizumab plus FOLFOX for Stage III Mismatch Repair-Deficient Colon Cancer.

Frank A Sinicrope, Fang-Shu Ou, Dirk Arnold, Walter R Peters, Robert J Behrens, Christopher H Lieu, Khalid Matin, Deirdre J Cohen, Samara L Potter, Andrew B Nixon, Lisa A Kottschade, Emily Kathol, Wendy L Frankel, Ardaman Shergill, Dennis Hsu, Anke Reinacher-Schick, Paul Mehan, Philip J Gold, Maged F Khalil, Tyler Zemla, Clare Gatten, Eileen M O'Reilly, Jeffrey A Meyerhardt.

BACKGROUND: Standard adjuvant chemotherapy for stage III colon cancer consists of a fluoropyrimidine-plus-oxaliplatin regimen. Whether the addition of atezolizumab (an anti-programmed death ligand 1 agent) to a modified FOLFOX6 regimen (fluorouracil, oxaliplatin, and leucovorin; called mFOLFOX6) would improve outcomes in patients with stage III colon cancer with mismatch repair-deficient (dMMR) status is unclear.
METHODS: In a phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with resected stage III dMMR tumors to receive either adjuvant atezolizumab plus mFOLFOX6 for 6 months, with atezolizumab continued as monotherapy (for a total of 12 months of therapy), or mFOLFOX6 alone for 6 months. The primary end point was disease-free survival. Secondary end points were overall survival and the adverse-event profile.
RESULTS: A total of 355 patients were assigned to receive atezolizumab plus mFOLFOX6 and 357 to receive mFOLFOX6 alone. The median age of the patients was 64 years, 55.1% were women, and 53.9% had tumors that were T4, N2, or both (indicating high risk). At a median follow-up of 40.9 months, the 3-year disease-free survival was 86.3% (95% confidence interval [CI], 81.8 to 89.8) in the atezolizumab-mFOLFOX6 group, as compared with 76.2% (95% CI, 70.9 to 80.6) in the mFOLFOX6 group (hazard ratio for disease recurrence or death, 0.50; 95% CI, 0.35 to 0.73; P<0.001). Adverse events of grade 3 or 4 occurred in 84.1% of the patients who received atezolizumab plus mFOLFOX6 and in 71.9% of those who received mFOLFOX6 alone.
CONCLUSIONS: The addition of atezolizumab to mFOLFOX6 significantly improved disease-free survival among patients with stage III dMMR colon cancer. (Funded by the National Cancer Institute of the National Institutes of Health and Genentech; ATOMIC ClinicalTrials.gov number, NCT02912559.).

DOI: https://doi.org/10.1056/NEJMoa2507874
Nat Commun. 2026 Mar 27.

An unbiased approach to measure aberrant DNA methylation alterations.

Bradley M Downs, Jiumei Hu, Joon Soo Park, Hanran Lei, Tza-Huei Wang, Thomas R Pisanic, Kuangwen Hsieh, Tra My Hoang.

The ability to accurately measure aberrant DNA methylation levels is integral to the understanding of DNA methylation biology. It is well-established that in cancer, the largest, and thus, most biologically important absolute gains of DNA methylation levels occur at CpG sites with low native levels while the largest losses occur at CpG sites with high native levels. Conventional wisdom assumes that the observed association between the degree of the alterations and the native levels are largely due to the limitations of change within the DNA methylation scale. Here, we present evidence that this association is largely caused by alterations occurring as a global rate of change relative to the native level. We show that DNA methylation alterations can be accurately compared by calculating the rate of change relative to the native level. Most importantly, this approach enables the identification of more biologically significant DNA methylation alterations.

DOI: https://doi.org/10.1038/s41467-026-71089-5