bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2025–01–12
eightteen papers selected by
Sergio Marchini, Humanitas Research
  1. Advances and challenges in precision imaging.
  2. Liquid biopsy entering clinical practice: Past discoveries, current insights, and future innovations.
  3. Chronic viral mimicry induction following p53 loss promotes immune evasion.
  4. Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals.
  5. Molecular Subgroups of HRD Positive Ovarian Cancer and Their Prognostic Significance.
  6. Research Progress of Liquid Biopsy Based on DNA Methylation in Tumor Diagnosis and Treatment.
  7. Incorporating immune checkpoint inhibitors in epithelial ovarian cancer.
  8. Research Progress of DNA Methylation Markers for Endometrial Carcinoma Diagnosis.
  9. Comparison of imaging-based single-cell resolution spatial transcriptomics profiling platforms using formalin-fixed, paraffin-embedded tumor samples.
  10. RAD51 testing in patients with early HER2-negative breast cancer and homologous recombination deficiency: post-hoc analysis of the GeparOla trial.
  11. Promising new drugs and therapeutic approaches for treatment of ovarian cancer-targeting the hallmarks of cancer.
  12. Profiling the epigenome using long-read sequencing.
  13. Treatment of Pleural Mesothelioma: ASCO Guideline Update.
  14. Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.
  15. Evaluating ovarian cancer risk-reducing salpingectomy acceptance: a survey.
  16. Dr. George Papanicolaou: Inventor of the Pap Smear and Father of Modern Cytology.
  17. HapCNV: A Comprehensive Framework for CNV Detection in Low-input DNA Sequencing Data.
  18. Prognostic Indicator for Pleural Mesothelioma.
  1. Lancet Oncol. 2025 Jan;pii: S1470-2045(24)00395-4. [Epub ahead of print]26(1): e34-e45
    Advances and challenges in precision imaging.
    Hedvig Hricak, Marius E Mayerhoefer, Ken Herrmann, Jason S Lewis, Martin G Pomper, Christopher P Hess, Katrine Riklund, Andrew M Scott, Ralph Weissleder.
      Technological innovations in genomics and related fields have facilitated large sequencing efforts, supported new biological discoveries in cancer, and spawned an era of liquid biopsy biomarkers. Despite these advances, precision oncology has practical constraints, partly related to cancer's biological diversity and spatial and temporal complexity. Advanced imaging technologies are being developed to address some of the current limitations in early detection, treatment selection and planning, drug delivery, and therapeutic response, as well as difficulties posed by drug resistance, drug toxicity, disease monitoring, and metastatic evolution. We discuss key areas of advanced imaging for improving cancer outcomes and survival. Finally, we discuss practical challenges to the broader adoption of precision imaging in the clinic and the need for a robust translational infrastructure.
    DOI:  https://doi.org/10.1016/S1470-2045(24)00395-4
  2. Crit Rev Oncol Hematol. 2025 Jan 03. pii: S1040-8428(25)00001-0. [Epub ahead of print]207 104613
    Liquid biopsy entering clinical practice: Past discoveries, current insights, and future innovations.
    Jinghan Song, Xiong Ye, Hui Xiao.
      In recent years, liquid biopsy has gained prominence as an emerging biomarker in cancer research, providing critical insights into tumor biology and metastasis. Technological advancements have enabled its integration into clinical practice, with ongoing trials demonstrating encouraging outcomes. Key applications of liquid biopsy include early cancer detection, cancer staging, prognosis evaluation, and real-time monitoring of tumor progression to optimize treatment decisions. In this review, we present a comprehensive conceptual framework for liquid biopsy, discuss the challenges in its research and clinical application, and highlight its significant potential in identifying therapeutic targets and resistance mechanisms across various cancer types. Furthermore, we explore the emerging role of liquid biopsy-based multicancer screening, which has shown promising advancements. Looking ahead, standardization, multi-omics coanalysis, and the advancement of precision medicine and personalized treatments are expected to drive the future development and integration of liquid biopsy into routine clinical workflows, enhancing cancer diagnosis and treatment management.
    Keywords:  Antineoplastic treatment; Cancer screening; Clinical application; Liquid biopsy; Metastasis; Recurrence
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104613
  3. Cancer Discov. 2025 Jan 07.
    Chronic viral mimicry induction following p53 loss promotes immune evasion.
    Charles A Ishak, Sajid A Marhon, Nairi Tchrakian, Anjelica Hodgson, Helen Loo Yau, Isabela M Gonzaga, Melanie Peralta, Ilinca M Lungu, Stephanie Gomez, Sheng-Ben Liang, Shu Yi Shen, Raymond Chen, Jocelyn Chen, Biji Chatterjee, Kevin N Wanniarachchi, Junwoo Lee, Nicholas Zehrbach, Amir Hosseini, Parinaz Mehdipour, Siyu Sun, Alexander Solovyov, Ilias Ettayebi, Kyle E Francis, Aobo He, Taiyi Wu, Shengrui Feng, Tiago da Silva Medina, Felipe Campos de Almeida, Jane Bayani, Jason Li, Spencer MacDonald, Yadong Wang, Sarah S Garcia, Elisa Arthofer, Noor Diab, Aneil Srivastava, Paul Tran Austin, Peter J B Sabatini, Benjamin D Greenbaum, Catherine A O'Brien, Trevor G Shepherd, Ming Sound Tsao, Katherine B Chiappinelli, Amit M Oza, Blaise A Clarke, Robert Rottapel, Stephanie Lheureux, Daniel D De Carvalho.
      Epigenetic therapies facilitate transcription of immunogenic repetitive elements that cull cancer cells through 'viral mimicry' responses. Paradoxically, cancer-initiating events also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize premalignant lesions of the fallopian tube along with syngeneic epithelial ovarian cancer models to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss permits transcription of immunogenic repetitive elements and chronic viral mimicry activation that increases cellular tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity. This selection process can be partially attenuated pharmacologically. Altogether, these results reveal that viral mimicry conditioning following p53 loss promotes immune evasion and may represent a pharmacological target for early cancer interception.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0094
  4. Nat Commun. 2025 Jan 08. 16(1): 430
    Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals.
    Dimitrios V Vavoulis, Anthony Cutts, Nishita Thota, Jordan Brown, Robert Sugar, Antonio Rueda, Arman Ardalan, Kieran Howard, Flavia Matos Santo, Thippesh Sannasiddappa, Bronwen Miller, Stephen Ash, Yibin Liu, Chun-Xiao Song, Brian D Nicholson, Helene Dreau, Carolyn Tregidgo, Anna Schuh.
      The analysis of circulating tumour DNA (ctDNA) through minimally invasive liquid biopsies is promising for early multi-cancer detection and monitoring minimal residual disease. Most existing methods focus on targeted deep sequencing, but few integrate multiple data modalities. Here, we develop a methodology for ctDNA detection using deep (80x) whole-genome TET-Assisted Pyridine Borane Sequencing (TAPS), a less destructive approach than bisulphite sequencing, which permits the simultaneous analysis of genomic and methylomic data. We conduct a diagnostic accuracy study across multiple cancer types in symptomatic patients, achieving 94.9% sensitivity and 88.8% specificity. Matched tumour biopsies are used for validation, not for guiding the analysis, imitating an early detection scenario. Furthermore, in silico validation demonstrates strong discrimination (86% AUC) at ctDNA fractions as low as 0.7%. Additionally, we successfully track tumour burden and ctDNA shedding from precancerous lesions post-treatment without requiring matched tumour biopsies. This pipeline is ready for further clinical evaluation to extend cancer screening and improve patient triage and monitoring.
    DOI:  https://doi.org/10.1038/s41467-024-55428-y
  5. Int J Mol Sci. 2024 Dec 18. pii: 13549. [Epub ahead of print]25(24):
    Molecular Subgroups of HRD Positive Ovarian Cancer and Their Prognostic Significance.
    Tatiana Kekeeva, Irina Dudina, Yulia Andreeva, Alexander Tanas, Alexey Kalinkin, Victoria Musatova, Natalia Chernorubashkina, Svetlana Khokhlova, Tatiana Tikhomirova, Mikhail Volkonsky, Sergey Kutsev, Dmitry Zaletaev, Vladimir Strelnikov.
      Homologous recombination repair deficiency (HRD) is involved in the development of high-grade serous ovarian carcinoma (HGSOC) and its elevated sensitivity to platinum-based chemotherapy. To investigate the heterogeneity of the HRD-positive HGSOC we evaluated the HRD status, including BRCA mutations, genomic scar score, and methylation status of BRCA1/2 genes in 352 HGSOC specimens. We then divided the HRD-positive cohort into three molecular subgroups, the BRCA mutation cohort (BRCA+), BRCA1 methylation cohort (Meth+), and the rest of the HRD+ cohort (HRD+BRCA-Meth-), and evaluated their first-line chemotherapy response, benefit from olaparib, and progression-free survival (PFS). HRD-positive status was detected in 65% (228/352) of samples. The first group, BRCA+, accounted for 45% (102/228) of HRD positive cases and showed the best outcome in platinum therapy (ORR 96%), the highest olaparib benefit (p = 0.006) and the highest median PFS (46 months). The frequency of the second cohort, Meth+, among HRD-positive patients was 23% (52/228). Patients with Meth+ HGSOC showed a significantly poorer outcome, with a median PFS of 19 months, a significantly lower ORR to platinum therapy (84%) and a modest, but not significant, benefit from olaparib maintenance. The third HRD+BRCA-Meth- group accounted for 32% (74/228) of HRD-positive patients and showed an ORR to platinum therapy similar to that of the BRCA+ group (90%), a higher, but not statistically significant, benefit from olaparib and a median PFS of 23 months. In conclusion, Meth+ subgroup had poor outcomes in terms of chemotherapy response, olaparib benefit, and PFS compared to the other HRD+ subgroups, requiring a more thorough follow-up.
    Keywords:  BRCA1 methylation; homologous recombination deficiency; olaparib maintenance; progression-free survival
    DOI:  https://doi.org/10.3390/ijms252413549
  6. Biomolecules. 2024 Dec 19. pii: 1634. [Epub ahead of print]14(12):
    Research Progress of Liquid Biopsy Based on DNA Methylation in Tumor Diagnosis and Treatment.
    Yunxia Bao, Xianzhao Wang, Bingjie Zeng, Yichun Shi, Yiman Huang, Yiwen Huang, Shuang Shang, Liang Shan, Lifang Ma.
      Liquid biopsy has been gradually applied to the clinical diagnosis and treatment of tumors because of its non-invasive and real-time reflection of the tumor status, as well as the convenience of sample collection, which allows the detection of primary or metastatic malignant tumors and reflects the heterogeneity of the tumors. DNA methylation, which is a type of epigenetic modification, is essential in the progression of tumors. This review introduces the common DNA methylation analysis methods and discusses their advantages and disadvantages, focusing on the new progress of DNA methylation-based liquid biopsy in tumor diagnosis and treatment.
    Keywords:  DNA methylation; epigenetic; liquid biopsy; tumor
    DOI:  https://doi.org/10.3390/biom14121634
  7. Gynecol Oncol. 2025 Jan 06. pii: S0090-8258(24)01229-0. [Epub ahead of print]193 30-40
    Incorporating immune checkpoint inhibitors in epithelial ovarian cancer.
    Giorgio Bogani, Kathleen N Moore, Isabelle Ray-Coquard, Domenica Lorusso, Ursula A Matulonis, Jonathan A Ledermann, Antonio González-Martín, Jean-Emmanuel Kurtz, Eric Pujade-Lauraine, Giovanni Scambia, Giuseppe Caruso, Francesco Raspagliesi, Nicoletta Colombo, Bradley J Monk.
       OBJECTIVE: Therapeutic interventions for epithelial ovarian cancer (EOC) have increased greatly over the last decade but improvements outside of biomarker selected therapies have been limited. There remains a pressing need for more effective treatment options that can prolong survival and enhance the quality of life of patients with EOC. In contrast to the significant benefits of immunotherapy with immune checkpoint inhibitors (CPI) seen in many solid tumors, initial experience in EOC suggests limited efficacy of CPIs monotherapy.
    METHODS: A systematic review of phase III studies testing the role of CPIs in ovarian cancer was performed.
    RESULTS: Seven randomized trials testing CPIs in newly diagnosed (n = 3) and recurrent (n = 4) EOC are evaluated. Overall, those trials included data of 5671 patients. Single-agent PD-L1 inhibitor trials have not shown significant efficacy in newly diagnosed ovarian cancer. Triplet maintenance with bevacizumab plus olaparib and durvalumab is associated with longer progression-free survival than maintenance with bevacizumab alone in patients without tumor BRCA mutations. CPIs were not effective in platinum-sensitive (n = 1031) and platinum-resistant (n = 1420) EOC.
    CONCLUSIONS: The value of adding CPI to standard treatment including poly (ADP-ribose) polymerase (PARP) inhibitors with or without bevacizumab remains unclear and is being addressed in ongoing clinical trials. The combination of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors may enhance the efficacy of immunotherapy in EOC and studies are underway to investigate the combination of CPI with other emerging treatment modalities. PROSPERO registration ID: CRD42024536017.
    Keywords:  Immunity; Immunotherapy; Ovarian cancer; PARP inhibitors
    DOI:  https://doi.org/10.1016/j.ygyno.2024.12.011
  8. J Cancer. 2025 ;16(3): 812-820
    Research Progress of DNA Methylation Markers for Endometrial Carcinoma Diagnosis.
    Haoning Zheng, Cuisong Yu, Lu Yang, Fenghua Zhou, Aijun Liu.
      Endometrial carcinoma (EC) is the most common malignancies of the female reproductive system in developed countries and areas. Ultrasound-guided and hysteroscopic samplings are commonly used to diagnose EC. However, clinicians question their diagnostic efficacy and the associated patient discomfort. DNA methylation is the widely studied epigenetic alteration in human tumors, and tumor screening and diagnosis. This review summarized common methods for collecting clinical samples for methylation testing. Furthermore, we analyzed the diagnostic evaluation indices of different methylation marker assays in clinical diagnosis and discussed the challenges of methylation testing in the future application of EC diagnosis.
    Keywords:  DNA methylation; diagnostic biomarkers; endometrial carcinoma; epigenetics
    DOI:  https://doi.org/10.7150/jca.104214
  9. bioRxiv. 2024 Dec 17. pii: 2024.12.13.628390. [Epub ahead of print]
    Comparison of imaging-based single-cell resolution spatial transcriptomics profiling platforms using formalin-fixed, paraffin-embedded tumor samples.
    Nejla Ozirmak Lermi, Max Molina Ayala, Sharia Hernandez, Wei Lu, Khaja Khan, Alejandra Serrano, Idania Lubo, Leticia Hamana, Katarzyna Tomczak, Sean Barnes, Jinzhuang Dou, Qingnan Liang, Rti Team, Maria Gabriela Raso, Ximing Tang, Mei Jiang, Beatriz Sanchez-Espiridion, Annikka Weissferdt, John Heymach, Jianjun Zhang, Boris Sepesi, Tina Cascone, Anne Tsao, Mehmet Altan, Reza Mehran, Don Gibbons, Ignacio Wistuba, Cara Haymaker, Ken Chen, Luisa M Solis Soto.
      Imaging-based spatial transcriptomics (ST) is evolving rapidly as a pivotal technology in studying the biology of tumors and their associated microenvironments. However, the strengths of the commercially available ST platforms in studying spatial biology have not been systematically evaluated using rigorously controlled experiments. In this study, we used serial 5-m sections of formalin-fixed, paraffin-embedded surgically resected lung adenocarcinoma and pleural mesothelioma tumor samples in tissue microarrays to compare the performance of the single cell ST platforms CosMx, MERFISH, and Xenium (uni/multi-modal) platforms in reference to bulk RNA sequencing, multiplex immunofluorescence, GeoMx Digital Spatial Profiler, and hematoxylin and eosin staining data for the same samples. In addition to objective assessment of automatic cell segmentation and phenotyping, we performed pixel-resolution manual evaluation of phenotyping to carry out pathologically meaningful comparison between ST platforms. Our study detailed the intricate differences between the ST platforms, revealed the importance of parameters such as tissue age and probe design in determining the data quality, and suggested reliable workflows for accurate spatial profiling and molecular discovery.
    DOI:  https://doi.org/10.1101/2024.12.13.628390
  10. Clin Cancer Res. 2024 Dec 30.
    RAD51 testing in patients with early HER2-negative breast cancer and homologous recombination deficiency: post-hoc analysis of the GeparOla trial.
    Guillermo Villacampa, Alba Llop-Guevara, Natalie Filmann, Andrea Herencia, Peter A Fasching, Thomas Karn, Frederik Marmé, Peter Klare, Volkmar Müller, Andrea Stefek, Christian Schem, Christoph Uleer, Tanja Fehm, Gabriele Doering, Elmar Stickeler, Marion van Mackelenbergh, Bärbel Felder, Valentina Nekljudova, Judith Balmaña, Carsten Denkert, Sibylle Loibl, Violeta Serra.
       PURPOSE: The randomized GeparOla trial reported comparable pathological complete response (pCR) rates with neoadjuvant containing olaparib vs. carboplatin treatment. Here, we evaluate the association between functional homologous repair deficiency (HRD) by RAD51 foci and pCR, and the potential of improving patient selection by combining RAD51 and stromal tumor infiltrating lymphocytes (sTILs).
    PATIENTS AND METHODS: This is a post-hoc blinded, biomarker analysis from the randomized GeparOla trial. Patients with early-stage HER2-negative breast cancer and HRD assessed by Myriad myChoice or BRCA1/BRCA2 mutation were randomized 1:1 to receive i) paclitaxel plus olaparib or ii) paclitaxel plus carboplatin, both followed by epirubicin/cyclophosphamide. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low).
    RESULTS: Overall, 90/97 (92.8%) samples were evaluable for RAD51 testing and 72/90 (80.0%) were RAD51-low. The pCR rate in patients with RAD51-low tumors was 66.7% (48/72), while it decreased to 22.2% (4/18) in those with RAD51-high. In the multivariable model including clinicopathological factors and treatment, the RAD51 score remained significantly associated with pCR (OR=12.03, 95%CI 2.60-55.73, p=0.002). Patients with RAD51-low and high sTILs in their tumors achieved a pCR rate of 75.0% (27/36). Similar results were observed for olaparib or carboplatin. In the exploratory DFS analysis, no differences were observed between RAD51 groups (high vs. low: HR=0.85, 95% CI 0.25-2.97).
    CONCLUSIONS: In a pre-selected population with HRD according to a genetic test, RAD51 testing identifies patients with different pCR rates under PARPi or platinum-based therapies. Future biomarker-driven studies should consider this information to refine stratification factors and to improve patient selection.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-3148
  11. BMC Med. 2025 Jan 06. 23(1): 10
    Promising new drugs and therapeutic approaches for treatment of ovarian cancer-targeting the hallmarks of cancer.
    Julia Hillmann, Nicolai Maass, Dirk O Bauerschlag, Inken Flörkemeier.
      Ovarian cancer remains the most lethal gynecological malignancy. Despite the approval of promising targeted therapy such as bevacizumab and PARP inhibitors, 5-year survival has not improved significantly. Thus, there is an urgent need for new therapeutics. New advancements in therapeutic strategies target the pivotal hallmarks of cancer. This review is giving an updated overview of innovative and upcoming therapies for the treatment of ovarian cancer that focuses specific on the hallmarks of cancer. The hallmarks of cancer constitute a broad concept to reenact complexity of malignancies and furthermore identify possible targets for new treatment strategies. For this purpose, we analyzed approvals and current clinical phase III studies (registered at ClinicalTrials.gov (National Library of Medicine, National Institutes of Health; U.S. Department of Health and Human Services, 2024)) for new drugs on the basis of their mechanisms of action and identified new target approaches. A broad spectrum of new promising drugs is currently under investigation in clinical phase III studies targeting mainly the hallmarks "self-sufficiency in growth signals," "genomic instability," and "angiogenesis." The benefit of immune checkpoint inhibitors in ovarian cancer has been demonstrated for the first time. Besides, targeting the tumor microenvironment is of growing interest. Replicative immortality, energy metabolism, tumor promoting inflammation, and the microbiome of ovarian cancer are still barely targeted by drugs. Nevertheless, precision medicine, which focuses on specific disease characteristics, is becoming increasingly important in cancer treatment.
    Keywords:  Hallmarks of cancer; Ovarian cancer; Therapy
    DOI:  https://doi.org/10.1186/s12916-024-03826-w
  12. Nat Genet. 2025 Jan 08.
    Profiling the epigenome using long-read sequencing.
    Tianyuan Liu, Ana Conesa.
      The advent of single-molecule, long-read sequencing (LRS) technologies by Oxford Nanopore Technologies and Pacific Biosciences has revolutionized genomics, transcriptomics and, more recently, epigenomics research. These technologies offer distinct advantages, including the direct detection of methylated DNA and simultaneous assessment of DNA sequences spanning multiple kilobases along with their modifications at the single-molecule level. This has enabled the development of new assays for analyzing chromatin states and made it possible to integrate data for DNA methylation, chromatin accessibility, transcription factor binding and histone modifications, thereby facilitating comprehensive epigenomic profiling. Owing to recent advancements, alternative, nascent and translating transcripts can be detected using LRS approaches. This Review discusses LRS-based experimental and computational strategies for characterizing chromatin states and highlights their advantages over short-read sequencing methods. Furthermore, we demonstrate how various long-read methods can be integrated to design multi-omics studies to investigate the relationship between chromatin states and transcriptional dynamics.
    DOI:  https://doi.org/10.1038/s41588-024-02038-5
  13. J Clin Oncol. 2025 Jan 08. JCO2402425
    Treatment of Pleural Mesothelioma: ASCO Guideline Update.
    Hedy L Kindler, Nofisat Ismaila, Lyudmila Bazhenova, Quincy Chu, Jane E Churpek, Ibiayi Dagogo-Jack, Darren S Bryan, Michael W Drazer, Patrick Forde, Aliya N Husain, Jennifer L Sauter, Valerie Rusch, Penelope A Bradbury, B C John Cho, Marc de Perrot, Azam Ghafoor, David L Graham, Ola Khorshid, Alexandra Lebensohn, Julie White, Raffit Hassan.
       PURPOSE: To provide evidence-based recommendations to practicing physicians and others on the management of pleural mesothelioma (PM).
    METHODS: ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pathology, cancer genetics, and advocacy experts to conduct an updated literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2016 through 2024. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.
    RESULTS: The literature search identified 110 additional relevant studies to inform the evidence base for this guideline.
    RECOMMENDATIONS: Evidence-based recommendations were developed for surgical cytoreduction, immunotherapy, chemotherapy, pathology, and germline testing in patients with PM.Additional information is available at www.asco.org/thoracic-cancer-guidelines.
    DOI:  https://doi.org/10.1200/JCO-24-02425
  14. Nat Cancer. 2025 Jan 09.
    Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.
    TRACERx Consortium
      Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study. We prospectively validate the survival association of a clonal expression biomarker, Outcome Risk Associated Clonal Lung Expression (ORACLE), in combination with clinicopathological risk factors, and in stage I disease. We expand our mechanistic understanding, discovering that clonal transcriptional signals are detectable before tissue invasion, act as a molecular fingerprint for lethal metastatic clones and predict chemotherapy sensitivity. Lastly, we find that ORACLE summarizes the prognostic information encoded by genetic evolutionary measures, including chromosomal instability, as a concise 23-transcript assay.
    DOI:  https://doi.org/10.1038/s43018-024-00883-1
  15. Cancer Res Commun. 2025 Jan 09.
    Evaluating ovarian cancer risk-reducing salpingectomy acceptance: a survey.
    Alexandra Lukey, Ramlogan Sowamber, David Huntsman, Celeste Leigh Pearce, A Fuchsia Howard, Rafael Meza, Michael R Law, Minh Tung Phung, Gillian E Hanley.
      With evidence that salpingectomy is effective in preventing high grade serous carcinoma, it is time to consider offering this procedure to people at higher-than-average lifetime risk for ovarian cancer, despite not having a pathogenic genetic variant that increases risk for ovarian cancer. This targeted approach has potential to be effective at reducing ovarian cancer incidence, and unlike opportunistic salpingectomy is focused on people with an increased lifetime risk of ovarian cancer. However, the acceptability of this approach within the population of potential patients remains unknown. We conducted an online survey of adults in British Columbia, Canada, who were defined as "at risk" for ovarian cancer (i.e., people born with ovaries). Participants completed a questionnaire on demographics, ovarian cancer risk and protective factors, concerns about risk-reducing salpingectomy and the risk they considered high enough to warrant risk-reducing salpingectomy. We included 211 participants. Among these participants, 42% (n = 88) indicated they would consider risk-reducing salpingectomy at any lifetime risk or any risk above the population average. Another 20 participants chose risks between 1.5%- 4% for a cumulative 51% of the sample choosing risks below thresholds for oophorectomy. In contrast, 6% (n=12) indicated they would not consider the procedure at any risk level. None of the factors collected were associated with the likelihood that a person would find risk-reducing salpingectomy acceptable. Overall our participants showed broad interest in risk-reducing salpingectomy as an ovarian cancer prevention strategy. These results suggest there would likely be uptake if RRS was offered.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-24-0566
  16. Cureus. 2024 Dec;16(12): e75106
    Dr. George Papanicolaou: Inventor of the Pap Smear and Father of Modern Cytology.
    Abigail Dugas, Nadiya A Persaud, Latha Ganti.
      The Pap smear is widely recognized in medicine as the single most successful contributor to cancer screening and preventative care. Women have Dr. George Papanicolaou (1870-1962) to thank for this groundbreaking contribution to their healthcare-a discovery that, fascinatingly, was made incidentally during his study of ovulation cycles in guinea pigs. He found that vaginal smears from his subjects with cervical cancer, or those who later developed the disease, yielded abnormal cells that were notably discernible under a microscope when compared to healthy cells. Dr. Papanicolaou, both a physician and scientist, was a devoted researcher who conducted revolutionary studies alongside his wife at Cornell University for nearly 50 years. This paper will highlight the course of Dr. Papanicolau's life, how he found himself searching for his niche in the world of medicine and then scientific research, leading to his incidental discovery of the efficacy of the Pap smear in cancer screening and preventative measures. Dr. Papanicolau's legacy lives on through the contributions he made to the intersection of women's health with cancer prevention, and his devotion to his research continues to serve the field of medicine, now 50 years after his death.
    Keywords:  biographies; cytology; historical vignette; medical innovation; medical stories; pap test
    DOI:  https://doi.org/10.7759/cureus.75106
  17. bioRxiv. 2024 Dec 22. pii: 2024.12.19.629494. [Epub ahead of print]
    HapCNV: A Comprehensive Framework for CNV Detection in Low-input DNA Sequencing Data.
    Xuanxuan Yu, Fei Qin, Shiwei Liu, Noah J Brown, Qing Lu, Guoshuai Cai, Jennifer L Guler, Feifei Xiao.
      Copy number variants (CNVs) are prevalent in both diploid and haploid genomes, with the latter containing a single copy of each gene. Studying CNVs in genomes from single or few cells is significantly advancing our knowledge in human disorders and disease susceptibility. Low-input including low-cell and single-cell sequencing data for haploid and diploid organisms generally displays shallow and highly non-uniform read counts resulting from the whole genome amplification steps that introduce amplification biases. In addition, haploid organisms typically possess relatively short genomes and require a higher degree of DNA amplification compared to diploid organisms. However, most CNV detection methods are specifically developed for diploid genomes without specific consideration of effects on haploid genomes. Challenges also reside in reference samples or normal controls which are used to provide baseline signals for defining copy number losses or gains. In traditional methods, references are usually pre-specified from cells that are assumed to be normal or disease-free. However, the use of pre-defined reference cells can bias results if common CNVs are present. Here, we present the development of a comprehensive statistical framework for data normalization and CNV detection in haploid single- or low-cell DNA sequencing data called HapCNV. The prominent advancement is the construction of a novel genomic location specific pseudo-reference that selects unbiased references using a preliminary cell clustering method. This approach effectively preserves common CNVs. Using simulations, we demonstrated that HapCNV outperformed existing methods by generating more accurate CNV detection, especially for short CNVs. Superior performance of HapCNV was also validated in detecting known CNVs in a real P. falciparum parasite dataset. In conclusion, HapCNV provides a novel and useful approach for CNV detection in haploid low-input sequencing datasets, with easy applicability to diploids.
    DOI:  https://doi.org/10.1101/2024.12.19.629494
  18. Ann Thorac Surg Short Rep. 2024 Dec;2(4): 597-602
    Prognostic Indicator for Pleural Mesothelioma.
    Masaya Yotsukura, Yukihiro Yoshida, Kazuo Nakagawa, Shun-Ichi Watanabe.
       Background: In malignant pleural mesothelioma), it is difficult to evaluate the degree of tumor progression using imaging findings. It is essential to develop an objective index that is independent of imaging findings and useful for assessing the degree of tumor progression and indications for surgery.
    Methods: We retrospectively evaluated the data of 79 patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy or pleurectomy/decortication at our institution between 1999 and 2022. The postoperative prognosis was evaluated based on clinical factors.
    Results: Of the 79 patients, extrapleural pneumonectomy was performed in 41 (51.9%), and pleurectomy/decortication was performed in 38 (48.1%). Univariate analyses identified that percent predicted forced vital capacity (FVC) < 80% (P < .01), rind-like growth pattern on computed tomography (P < .01), Glasgow Prognostic Score ≥ 1 (P < .01), and pathologic stage ≥ II (P < .01) were poor prognostic factors for overall survival. In the multivariate analysis, percent predicted FVC <80% (hazard ratio, 2.76; 95% CI, 1.23-6.18, P = .01) was found to be the only poor prognostic factor for overall survival after surgery. Pathologic stage was a less significant prognostic factor (hazard ratio, 1.83; 95% CI, 0.95-3.53, P = .07). Two-year overall survival in patients with percent predicted FVC ≥80% and <80% was 76.6% ± 6.6% and 16.6% ± 7.5%, respectively.
    Conclusions: FVC is a strong predictor of postoperative survival in patients with malignant pleural mesothelioma independent of imaging findings. FVC is useful for assessing tumor invasion and would help determining surgical indication.
    DOI:  https://doi.org/10.1016/j.atssr.2024.05.011
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