bims-ovdlit 2025-07-27 papers

bims-ovdlit

Biomed News

on Ovarian cancer: early diagnosis, liquid biopsy and therapy

Issue of 2025–07–27
fifteen papers selected by
Lara Paracchini, Humanitas Research

Pathogenesis of peritoneal high-grade serous carcinoma after risk-reducing surgery: a systematic review.
Canadian Management of Serous Tubal Intraepithelial Carcinoma.
Comprehensive fragmentation of cell-free repetitive DNA for enhanced cancer detection in plasma.
Clinical and biological characteristics associated with of loss-of-heterozygosity in endometrial cancer.
Clonal hematopoiesis in myeloid malignancies and solid tumors.
Key highlights from American Society of Clinical Oncology 2025: top 10 studies in gynecologic oncology.
Ovarian Cancer: A Review.
Implementing a chatbot to promote hereditary breast & ovarian cancer genetic screening in women's health: identifying barriers and facilitators to screening adoption.
Inherited Susceptibility to Cancer: Past, Present and Future.
Oxford Classic-defined EMT risk stratification of High Grade Serous Ovarian cancer for guiding treatment decisions.
Multiplexed assays of variant effect for clinical variant interpretation.
Complex genetic variation in nearly complete human genomes.
Genomic and epigenomic ctDNA profiling in liquid biopsies from heavily pre-treated patients with DNA damage response-deficient tumors.
Fragmentomic-based algorithm to computationally predict tumor-somatic, germline, and clonal hematopoiesis variant origin in liquid biopsy.
Longitudinal circulating tumor DNA analysis during treatment of locally advanced resectable gastric or gastroesophageal junction adenocarcinoma: the PLAGAST prospective biomarker study.

J Pathol Clin Res. 2025 Jul;11(4): e70037

Pathogenesis of peritoneal high-grade serous carcinoma after risk-reducing surgery: a systematic review.

Tamar A Gootzen, Anouk B Bouwmeester, Joanne A de Hullu, Jurgen Mj Piek, Jeroen Awm van der Laak, Michiel Simons, Miranda P Steenbeek.

  Germline BRCA1/2 pathogenic variant carriers have an increased risk for high-grade serous carcinoma (HGSC) and are therefore advised to have risk-reducing salpingo-oophorectomy around the age of 40. However, a risk of 0.9% to develop peritoneal HGSC remains in these women, which increases to 27.5% when serous tubal intraepithelial carcinoma (STIC) is detected. The pathophysiological mechanism that leads to the development of peritoneal HGSC after salpingectomy or salpingo-oophorectomy is still largely unknown. In this systematic review, we aim to provide insights into the pathogenic pathways of peritoneal HGSC after salpingectomy or salpingo-oophorectomy. Therefore, we performed a systematic search for studies investigating pathophysiological mechanisms related to peritoneal HGSC in PubMed and EMBASE. A total of 49 articles were included in this study. Most evidence was found on mechanisms following a tubal origin, such as clonality between STIC and peritoneal HGSC as well as molecular similarities between fallopian tube (FT) epithelium and peritoneal HGSC. Additionally, FT epithelium was shown to adhere to the ovary and could therefore stay present after isolated salpingectomy. There might be a role for the endometrium, as it was observed that serous endometrial intraepithelial carcinoma (SEIC) has a clonal relationship with extra-uterine HGSC. The role of the ovary seems limited, although some mouse models show a role for follicular fluid in the dissemination of malignant cells on the peritoneum. In conclusion, different mechanisms might be responsible for peritoneal HGSC development after bilateral salpingectomy or salpingo-oophorectomy. Most available evidence supports the dissemination of precursor cells originating in the FT. Also, a possible role for the endometrium was found. An ovarian origin seems less likely; however, execution of oophorectomy does not seem obsolete in clinical practice as follicular fluid might promote dissemination and residual tubal tissue can be present on the ovary after salpingectomy.

Keywords:  ovarian cancer; pathophysiology; peritoneal carcinomatosis; salpingectomy

DOI:  https://doi.org/10.1002/2056-4538.70037
Obstet Gynecol. 2025 Jul 24.

Canadian Management of Serous Tubal Intraepithelial Carcinoma.

Elisabeth Spénard, Michelle Jacobson, Marjan Rouzbahman, Lien Hoang, Katherine Grondin, Martin Koebel, Janice Kwon, Kimberly Stewart, Marie Plante, Ly-Ann Teo-Fortin, Danielle Vicus, Anna Cameron, Patti Power, Ada Hsieh, Tomer Feigenberg, Lua Eiriksson, Diane Provencher, Walter Gotlieb, Katharina Kieser, Sophia Pin, Alon Altman, Marcus Q Bernardini.

OBJECTIVE: To assess the management and outcomes of patients diagnosed with an isolated serous tubal intraepithelial carcinoma lesion across Canada.
METHODS: This retrospective study included consecutive patients with an isolated serous tubal intraepithelial carcinoma lesion diagnosed between 2006 and 2020 at 15 Canadian centers. Cases underwent multicenter panel pathology review.
RESULTS: Of 107 patients, 41 serous tubal intraepithelial carcinoma cases (38.3%) were identified at prophylactic surgery for germline pathogenic variants, 36 (33.6%) at surgery for suspicion of malignancy, and 30 (28.0%) at surgery for benign conditions. Treatment groups included observation (n=62, 57.9%), staging surgery (n=35, 32.7%), and adjuvant chemotherapy (n=10, 9.3%). Median follow-up was 55.5 months (interquartile range 30.26-82.07 months). Overall, nine patients developed high-grade serous carcinoma. The cumulative incidence of high-grade serous carcinoma was not significantly different between treatment groups (P=.181); however, no patient treated with chemotherapy developed high-grade serous carcinoma. The cumulative incidence of high-grade serous carcinoma was 1.1% (95% CI, 0.1-5.3%) at 2 years and 5.7% (95% CI, 1.8-13.1%) at 5 years. No significant predictive factors were found on univariate analysis. After multicenter pathology review of 59 cases (55.1%), consensus diagnosis was reached: 45 (76.3%) with serous tubal intraepithelial carcinoma, three (5.1%) with serous tubal intraepithelial lesion, seven (11.9%) with high-grade serous carcinoma, and two (3.4%) with normal tissue. Of the cases reviewed, only 1 of 45 patients (2.2%) with confirmed serous tubal intraepithelial carcinoma developed high-grade serous carcinoma at 73 months, indicating a 5-year cumulative incidence of cancer of 2.6% (95% CI, 0.2-11.7).
CONCLUSION: Management of serous tubal intraepithelial carcinoma varied across centers. The 5-year cumulative incidence of high-grade serous carcinoma after isolated serous tubal intraepithelial carcinoma was 5.7%, consistent with recent literature. However, multicenter pathology review revealed initial underdiagnosed high-grade serous carcinoma, and 5-year cumulative incidence of high-grade serous carcinoma after confirmed serous tubal intraepithelial carcinoma decreased to 2.6%, underscoring the importance of diagnostic confirmation by expert pathologists to guide accurate management.

DOI: https://doi.org/10.1097/AOG.0000000000006016
Front Cell Dev Biol. 2025 ;13 1630231

Comprehensive fragmentation of cell-free repetitive DNA for enhanced cancer detection in plasma.

Mingguang Zhang, Shuohui Dong, Wei Rao, Shiwen Mei, Gang Hu, Ling Liu, Zhen Wang, Jianqiang Tang.

   Background: Repetitive elements account for a large proportion of the human genome and undergo alterations during early tumorigenesis. However, the exclusive fragmentation pattern of DNA-derived cell-free repetitive elements (cfREs) remains unclear.
Methods: This study enrolled 32 healthy volunteers and 112 patients with five types of cancer. A novel repetitive fragmentomics approach was proposed to profile cfREs using low-pass whole genome sequencing (WGS). Five innovative repetitive fragmentomic features were designed: fragment ratio, fragment length, fragment distribution, fragment complexity, and fragment expansion. A machine learning-based multimodal model was developed using these features.
Results: The multimodal model achieved high prediction performance for early tumor detection, even at ultra-low sequencing depths (0.1×, AUC = 0.9824). Alu and short tandem repeat (STR) were identified as the primary cfREs after filtering out low-efficiency subfamilies. Characterization of cfREs within tumor-specific regulatory regions enabled accurate tissue-of-origin (TOO) prediction (0.1×, accuracy = 0.8286) and identified aberrantly transcribed tumor driver genes.
Conclusion: This study highlights the abundance of repetitive DNA in plasma. The innovative fragmentomics approach provides a sensitive, robust, and cost-effective method for early tumor detection and localization.

Keywords:  cell-free DNA; early tumor detection; low-pass whole genome sequencing; repetitive element; tissue of origin

DOI:  https://doi.org/10.3389/fcell.2025.1630231
J Gynecol Oncol. 2025 Jul 08.

Clinical and biological characteristics associated with of loss-of-heterozygosity in endometrial cancer.

Felix Blanc-Durand, Etienne Rouleau, Patricia Pautier, Natalie Ngoi, Yi Wan Lim, Siew Eng Lim, Alexandra Leary, David Sp Tan.

   OBJECTIVE: Genomic instability has been identified in a subgroup of endometrial cancers (ECs) that are predominantly TP53 mutated (TP53mut). We report the features associated with loss-of-heterozygosity (LOH) in EC.
METHODS: We conducted a retrospective analysis of EC patients from France and Singapore. All patients underwent comprehensive molecular profiling using the tumor based FoundationOne CDX panel. The degree of LOH was correlated with molecular and clinicopathologic findings. LOH-high, intermediate and low were defined as ≥14%, 4%-14%, and <4%, respectively.
RESULTS: One hundred twelve patients were identified, including 66% Asian and 34% Caucasian. Fifty nine percent had International Federation of Gynecology and Obstetrics III/IV diseases, 34% low-grade endometrioid, 19% high-grade endometrioid, and 15% serous. The 63% and 50% of tumors expressed estrogen receptor (ER) and progesterone receptor (PR). One percent had a POLE mutation, 18% were microsatellite instability (MSI)-, 40% TP53mut and 41% non-specific molecular profiles. The 17% of patients were classified LOH-high, 37% LOH-intermediate and 46% LOH-low. LOH-high was significantly associated with serous and carcinosarcomas, ER/PR negative tumors, TP53 mutations, BRCA1 mutations and TERC amplification whereas LOH-low with low-grade endometrioid, MSI, ARID1A, PIK3CA, CTNNB1, and PTEN mutations. The median overall survival was 42.2, 55.2, and 100.8 months in the LOH-high, intermediate, and low respectively (p=0.034). Among TP53mut EC, LOH-low patients had significantly poorer outcomes (p<0.001).
CONCLUSION: In this large multiethnic cohort, 17% of EC exhibited high LOH and correlated with hormone-receptor-negative tumors and poorer survival rates. LOH may serve as a tool for identifying EC cases with high genomic instability that could potentially benefit from PARP inhibitors.

Keywords:  Endometrial Cancer; Genomic Instability; Homologous Recombination Deficiency; Personalized Treatment; Predictive Biomarkers

DOI:  https://doi.org/10.3802/jgo.2026.37.e10
Nat Cancer. 2025 Jul 18.

Clonal hematopoiesis in myeloid malignancies and solid tumors.

Xiurong Cai, Robert L Bowman, Jennifer J Trowbridge.

Clonal hematopoiesis (CH) results from clonal expansion of hematopoietic stem cells. In specific contexts, CH is linked with an increased risk of blood cancers and mortality in individuals with solid tumors. To understand the mechanisms and clinical relevance of this association, it is crucial to explore the reciprocal relationship between CH and cancer. Here, we provide an updated summary of the mechanisms known to drive CH in blood cancers and solid tumors. In addition, we review proposed strategies to intercept CH and examine their impact on solid tumor-directed therapies, including immunostimulatory therapies.

DOI: https://doi.org/10.1038/s43018-025-01014-0
Int J Gynecol Cancer. 2025 Jun 28. pii: S1048-891X(25)01114-4. [Epub ahead of print]35(9): 101994

Key highlights from American Society of Clinical Oncology 2025: top 10 studies in gynecologic oncology.

Jéssica Monteiro Vasconcellos, Letícia Vecchi Leis, Mariana Carvalho Gouveia, Mariana Scaranti.



Keywords:  Cervical Cancer; Endometrial Cancer; Gynecologic Cancer; Ovarian Cancer

DOI:  https://doi.org/10.1016/j.ijgc.2025.101994
JAMA. 2025 Jul 21.

Ovarian Cancer: A Review.

Giuseppe Caruso, S John Weroha, William Cliby.

Importance: Ovarian cancer is the eighth most common cause of cancer and cancer death in women worldwide. In 2022, ovarian cancer was diagnosed in approximately 324 398 individuals, and 206 839 died of ovarian cancer worldwide. In 2025, it is estimated that 20 890 US women will be diagnosed with ovarian cancer and 12 730 patients will die of ovarian cancer.
Observations: Approximately 90% of ovarian cancers are epithelial malignancies, of which 70% to 80% are high-grade serous ovarian cancers. Less common epithelial subtypes include endometrioid, clear cell, low-grade serous, mucinous, and carcinosarcoma. The median age at diagnosis of ovarian cancer is 63 years. Risk factors include older age, family history of breast or ovarian cancer, endometriosis, and nulliparity. Hereditary factors are associated with 25% of cases, predominantly linked to BRCA1/2 gene variants. At diagnosis, approximately 95% of patients experience nonspecific symptoms, such as abdominal pain, bloating, and urinary urgency and frequency, and about 80% have advanced-stage disease (stage III-IV), including extrapelvic disease, ascites, and abdominal masses. Diagnostic and staging evaluation includes pelvic ultrasound; computed tomography of the chest, abdomen, and pelvis; and serum tumor markers such as carbohydrate antigen 125, carbohydrate antigen 19-9, and carcinoembryonic antigen. First-line treatment for early-stage ovarian cancer, defined as limited to the ovary or fallopian tube (stage I) or confined to the pelvis (stage II), is surgery (hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymphadenectomy), followed by adjuvant chemotherapy (carboplatin and paclitaxel). With treatment, early-stage ovarian cancer has a 5-year overall survival of 70% to 95%. Advanced-stage ovarian cancer may be treated with primary cytoreductive surgery (removal of all visible cancer in the abdominal cavity) and adjuvant chemotherapy (carboplatin and paclitaxel) or with neoadjuvant chemotherapy followed by cytoreductive surgery and adjuvant chemotherapy. Most patients with advanced-stage ovarian cancer receive maintenance therapy with bevacizumab (a monoclonal antibody that blocks angiogenesis) and/or poly-adenosine diphosphate ribose polymerase (PARP) inhibitors. With treatment, the 5-year overall survival rate for advanced-stage ovarian cancer is 10% to 40%. However, individuals with BRCA-related gene variants have a 5-year overall survival rate of approximately 70% with PARP inhibitor treatment. Despite an initial remission rate of 80%, approximately 75% of patients with advanced-stage disease have ovarian cancer relapse within 2 years.
Conclusions and Relevance: Approximately 21 000 women are diagnosed with ovarian cancer annually in the US, and approximately 80% have advanced-stage ovarian cancer at diagnosis. First-line treatment of early-stage ovarian cancer is surgery and adjuvant platinum-based chemotherapy. Treatment of advanced-stage ovarian cancer includes cytoreductive surgery, platinum-based chemotherapy, and targeted maintenance therapies such as bevacizumab and/or PARP inhibitors.

DOI: https://doi.org/10.1001/jama.2025.9495
BMC Public Health. 2025 Jul 19. 25(1): 2516

Implementing a chatbot to promote hereditary breast & ovarian cancer genetic screening in women's health: identifying barriers and facilitators to screening adoption.

Easton N Wollney, Shireen Madani Sims, Luisel J Ricks-Santi, Elizabeth Eddy, Daniel Wiesman, Carla L Fisher.

   BACKGROUND: To promote genetic screening among women at risk for hereditary breast and ovarian cancer (HBOC), the American College of Obstetricians and Gynecologists recommends that risk assessment be integrated into practice. Chatbots like the Genetic Information Assistant (Gia®) are increasingly implemented to expand access to hereditary genetic screening. Factors that impact chatbot implementation for HBOC risk screening and women's uptake are not fully realized. To refine implementation strategies prior to full scale implementation, we sought to identify women's perceived facilitators/barriers to adopting Gia screening in a rural population within a large healthcare system in the southern United States.
METHODS: We recruited both women who agreed to screen using Gia (and then recommended for genetic testing based on National Comprehensive Cancer Network guidelines) as well as women who opted not to do the screen from three Women's Health clinics (OB/GYN) in a northern rural region of Florida. We conducted in-depth, semi-structured interviews with 17 women (nine adopted the screen, eight did not). We conducted a thematic analysis to identify and further define barriers/facilitators to women's uptake of Gia for HBOC cancer risk screening in obstetrics/gynecology care.
RESULTS: Women identified six factors that inhibited and/or facilitated their willingness to use Gia for screening: 1) cancer risk perception, 2) communication with their clinician, 3) feasibility of screening, 4) fiscal and insurance concerns, 5) technology trust/distrust, and 6) previous genetic testing experience. Findings illustrate how each factor functioned as a facilitator and/or barrier in women's uptake (e.g., technology being trusted for accuracy versus concerns for data privacy and security).
CONCLUSIONS: While chatbots can extend women's cancer risk screening access, particularly in rural regions and with college-educated women, systems-level (cost) and individual-level factors (perceived risk, misconceptions about repeating genetic testing) should be addressed to promote adoption. Women's interaction with a clinician may be a key implementation strategy for addressing these factors to personalize the screening opportunity and promote their chatbot screening adoption.

Keywords:  Cancer risk; Chatbot; Genetic screening; Healthcare communication; Hereditary breast and ovarian cancer (HBOC); Implementation; Obstetrics/gynecology (OB/GYN)

DOI:  https://doi.org/10.1186/s12889-025-23488-4
Ann Hum Genet. 2025 Jul 21.

Inherited Susceptibility to Cancer: Past, Present and Future.

Shirley V Hodgson, William D Foulkes, Eamonn R Maher, Clare Turnbull.

Germline pathogenic variants (GPVs, 'mutations') causing inherited susceptibility to certain cancers (cancer susceptibility genes, CSGs) broadly belong to one of two main classes-loss of function variants in tumour suppressor genes (TSGs) or gain of function variants in proto-oncogenes (an over-simplification). Genomic analyses of tumours identify 'driver mutations' promoting tumour growth and somatic variants which contribute to 'mutation signatures' which, with histopathology, can be used to subclassify cancers with implications for causality and treatment. The identification of susceptible individuals is important, as they and their relatives may be at elevated risk of tumours, and this can influence optimal cancer treatment. Classically, cancer risk assessment utilises family history, lifestyle/environment factors, and any non-neoplastic clinical findings, followed by genetic testing of high/moderate penetrance CSGs. In cancer cases not caused by highly penetrant CSGs, multiple variants conferring relatively small risks play a major role. These were discovered by genome-wide association (GWAS) studies. The utility of polygenic risk scores (PRS) derived from multiple such variants for clinical risk profiling is being assessed. Access to genetic tests is improved by widening eligibility criteria for testing and empowering non-genetic clinicians to identify CSG GPVs and manage carriers. This will contribute to expanding programmes of screening, prevention and early detection (SPED), with personalised surveillance and prophylactic interventions, and exploit knowledge of the molecular mechanisms of cancer susceptibility to develop novel cancer therapies. In some jurisdictions, population testing is being considered, but GPV penetrance in this setting can be unclear, and the public health implications are complex.

DOI: https://doi.org/10.1111/ahg.70013
Clin Cancer Res. 2025 Jul 24.

Oxford Classic-defined EMT risk stratification of High Grade Serous Ovarian cancer for guiding treatment decisions.

Lena Rai, Antonella Ravaggi, Eliana Bignotti, Robert L Hollis, Dale W Garsed, Ahwan Pandey, Kyriaki Barbara Papalois, Faheemah Patel, Yasmin Kamel, Leticia Campo, Alistair Easton, Joel Nulsen, Breeshey Roskams-Hieter, Mara Artibani, Lili Wang, Nosheen Hussain, Luyao Wang, Nancy Zaarour, Aneesh Aggarwal, Amro Ahmed-Ebbiary, Aws Al-Deka, Michael Churchman, C Simon Herrington, Laura Ardighieri, Federico Ferrari, Christopher Yau, Charlie Gourley, Franco Odicino, Ahmed Ashour Ahmed.

PURPOSE: The association between epithelial to mesenchymal transition in High Grade Serous Ovarian Cancer (HGSOC) and poor prognosis is known. However, molecularly defining a subset of tumours that reproducibly associates with poor prognosis has been an elusive goal in this disease. A molecular signature that can robustly identify patients with poor prognosis and guide treatment decisions, including surgical strategy and targeted therapies, can improve survival rates.
EXPERIMENTAL DESIGN: We carried out RNA sequencing of 139 tumour samples (Brescia cohort), an external validation on 362 and 126 patients from the Scottish and Garsed cohort, respectively; and meta-analysis of 1023 tumours to develop clinically useful risk groups. Identification of therapeutic targets was carried out by transcriptomic analyses of FLOW-sorted tumour epithelial cells from fresh tumours and multiplex IF assessment of tissue sections.
RESULTS: In this study we have validated the prognostic strength of the OxC-EMT in three independent patient cohorts- Brescia [HR=3.6 (95% CI=1.59-7.97), p=1.99e-03], Scottish [HR=1.71 (95% CI=1.08-2.70), p=2.23e-02] and Garsed [Kruskal-Wallis p=0.00071]. OxC-based risk-stratification of HGSOC can robustly identify poor risk patients with a 5-year median survival for OxC-EMT-high and OxC-EMT-low risk groups of 13% and 50%, respectively (95%CI: 7.1%-23.5% vs. 36.1%-69.3%) in the Brescia cohort. Further analysis of the risk groups suggests that an alternate surgical strategy and a combination therapy involving EMT targeting drugs and immunomodulators could elicit improved clinical response in poor risk patients.
CONCLUSIONS: This study provides a clinically useful risk stratification strategy for HGSOC as well as targeted treatment options for high-risk patients.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-4250
Nat Rev Genet. 2025 Jul 21.

Multiplexed assays of variant effect for clinical variant interpretation.

Abbye E McEwen, Malvika Tejura, Shawn Fayer, Lea M Starita, Douglas M Fowler.

The rapid expansion of clinical genetic testing has markedly improved the detection of genetic variants. However, most variants lack the evidence needed to classify them as pathogenic or benign, resulting in the accumulation of variants of uncertain significance that cannot be used to diagnose or guide treatment of disease. Moreover, targeted therapy for cancer treatment increasingly depends on correctly identifying oncogenic driver mutations, but the oncogenicity of many variants identified in tumours remains unclear. To address these challenges, efforts to classify variants are increasingly using multiplexed assays of variant effect (MAVEs), which are massively scaled experiments that can generate functional data for thousands of variants simultaneously. The rise of MAVEs is accompanied by better guidance on the use of MAVE data for classifying germline variants to aid their clinical implementation. Here, we overview MAVE technologies from their inception to their increased use in the clinic, including their roles in uncovering mechanisms for variant pathogenicity and guiding targeted therapy and drug development.

DOI: https://doi.org/10.1038/s41576-025-00870-x
Nature. 2025 Jul 23.

Complex genetic variation in nearly complete human genomes.

Glennis A Logsdon, Peter Ebert, Peter A Audano, Mark Loftus, David Porubsky, Jana Ebler, Feyza Yilmaz, Pille Hallast, Timofey Prodanov, DongAhn Yoo, Carolyn A Paisie, William T Harvey, Xuefang Zhao, Gianni V Martino, Mir Henglin, Katherine M Munson, Keon Rabbani, Chen-Shan Chin, Bida Gu, Hufsah Ashraf, Stephan Scholz, Olanrewaju Austine-Orimoloye, Parithi Balachandran, Marc Jan Bonder, Haoyu Cheng, Zechen Chong, Jonathan Crabtree, Mark Gerstein, Lisbeth A Guethlein, Patrick Hasenfeld, Glenn Hickey, Kendra Hoekzema, Sarah E Hunt, Matthew Jensen, Yunzhe Jiang, Sergey Koren, Youngjun Kwon, Chong Li, Heng Li, Jiaqi Li, Paul J Norman, Keisuke K Oshima, Benedict Paten, Adam M Phillippy, Nicholas R Pollock, Tobias Rausch, Mikko Rautiainen, Yuwei Song, Arda Söylev, Arvis Sulovari, Likhitha Surapaneni, Vasiliki Tsapalou, Weichen Zhou, Ying Zhou, Qihui Zhu, Michael C Zody, Ryan E Mills, Scott E Devine, Xinghua Shi, Michael E Talkowski, Mark J P Chaisson, Alexander T Dilthey, Miriam K Konkel, Jan O Korbel, Charles Lee, Christine R Beck, Evan E Eichler, Tobias Marschall.

Diverse sets of complete human genomes are required to construct a pangenome reference and to understand the extent of complex structural variation. Here we sequence 65 diverse human genomes and build 130 haplotype-resolved assemblies (median continuity of 130 Mb), closing 92% of all previous assembly gaps1,2 and reaching telomere-to-telomere status for 39% of the chromosomes. We highlight complete sequence continuity of complex loci, including the major histocompatibility complex (MHC), SMN1/SMN2, NBPF8 and AMY1/AMY2, and fully resolve 1,852 complex structural variants. In addition, we completely assemble and validate 1,246 human centromeres. We find up to 30-fold variation in α-satellite higher-order repeat array length and characterize the pattern of mobile element insertions into α-satellite higher-order repeat arrays. Although most centromeres predict a single site of kinetochore attachment, epigenetic analysis suggests the presence of two hypomethylated regions for 7% of centromeres. Combining our data with the draft pangenome reference1 significantly enhances genotyping accuracy from short-read data, enabling whole-genome inference3 to a median quality value of 45. Using this approach, 26,115 structural variants per individual are detected, substantially increasing the number of structural variants now amenable to downstream disease association studies.

DOI: https://doi.org/10.1038/s41586-025-09140-6
Clin Cancer Res. 2025 Jul 24.

Genomic and epigenomic ctDNA profiling in liquid biopsies from heavily pre-treated patients with DNA damage response-deficient tumors.

Ian M Silverman, Joseph D Schonoft, Benjamin Herzberg, Arielle Yablonovitch, Errin Lagow, Patrick C Fiaux, Pegah Safabakhsh, Sunantha Sethuraman, Danielle Ulanet, Julia Yang, Insil Kim, Paul Basciano, Michael Cecchini, Elizabeth Lee, Stephanie Lheureux, Elisa Fontana, Benedito A Carneiro, Jorge S Reis-Filho, Timothy A Yap, Michael Zinda, Ezra Y Rosen, Victoria Rimkunas.

PURPOSE: The development of DNA damage response (DDR)-directed therapies is a major area of clinical investigation, yet to date Poly (ADP-ribose) polymerase inhibitors (PARPi) remain the only approved therapy in this space. Major challenges to DDR-targeted therapies in the post-PARPi era are the context dependency of DDR alterations and the presence of pre-existing resistance in this heavily pre-treated population. Blood samples from patients with tumors harboring defects in DDR genes were evaluated the feasibility of liquid biopsy platform for detecting complex genomic events such as BRCA1/2 reversions, HRD signatures, PV allele status, and differentially methylated regions for accurate quantitation of TF.
PATIENTS AND METHODS: Overall, 173 patients enrolled in two Phase 1/2 clinical trials (TRESR; NCT04497116, ATTACC; NCT04972110) were selected. The pre-treatment circulating tumor DNA (ctDNA) samples were analyzed from these patients, harboring pathogenic variants (PVs) in DDR genes.
RESULTS: In a phase I heavily pretreated patient population with DDR defects, ctDNA can detect complex genomic alterations (HRD, biallelic loss, complex reversions) that historically require tumor tissue biopsies. Within the cohort of BRCA-associated tumor types previously treated with PARPi or platinum, HRD reversions were detected in 44% of evaluable patients and included large genomic rearrangements leading to deletion of whole or partial exons which have been underrepresented in the literature due to technological limitations.
CONCLUSIONS: This study showcases the genomic complexity of DDR-altered tumors as revealed through baseline ctDNA profiling, an understanding of which is crucial for the future clinical development of novel DDR-directed therapies and combinations.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-1248
J Liq Biopsy. 2025 Sep;9 100311

Fragmentomic-based algorithm to computationally predict tumor-somatic, germline, and clonal hematopoiesis variant origin in liquid biopsy.

Derek W Brown, Daokun Sun, Alexander D Fine, Shai He, Michael McDevitt, Kerriann Pontbriand, Eliana Polisecki, Angela Kou, Mingyue Li, Shumeng Zhang, Zheng Kuang, David Fabrizio, Russell W Madison, Jie He, Zoe June Assaf, Thomas Powles, Christopher Sweeney, David Gandara, Emmanuel S Antonarakis, Lee A Albacker, Aparna Aiyer, Bahar Yilmazel, Brennan J Decker, Jason D Hughes, Hanna Tukachinsky, Chang Xu.

   Purpose: Genomic profiling of tumors by liquid biopsy (LBx) is a pragmatic alternative to profiling tissue. Despite recent methodologic advances, clonal hematopoiesis (CH) variants arising from hematopoietic stem cells may confound LBx results. Distinguishing the origin of variants detected by LBx will greatly enhance treatment decision-making for patients with cancer.
Experimental design: We sequenced DNA isolated from paired plasma and white blood cells (WBC) at equal depth to train (n = 1977) and validate (n = 658) Variant Origin Prediction (VOP), a machine learning algorithm that leverages fragmentomics to generate probabilities that a short variant (SV) detected by LBx is tumor-somatic, germline, or CH in origin. The algorithm's classifications were validated for accuracy using paired WBC DNA and for reproducibility using LBx replicates.
Results: We show that 68% of LBx detected at least one reportable variant of CH origin. Our fragmentomic-based algorithm differentiated reportable tumor and CH variants with high sensitivity, high positive predictive value (PPA >93%, PPV >91%), and high reproducibility (>94%). Critically, VOP performs well for SVs with VAFs ≤1% (PPV >90%), as well as in genes known to harbor both CH and tumor-somatic SVs, such as TP53 (PPV >88%). In a longitudinal cohort of 422 metastatic castration-resistant prostate cancer (mCRPC) cases, VOP accurately predicted baseline variant origins, and allowed separate tracking of tumor-somatic and CH variants, including newly detected variants, at subsequent timepoints.
Conclusions: VOP is a highly accurate and reproducible method to predict the origin of SVs detected in LBx without reliance on WBC sequencing. VOP can reduce inappropriate use of targeted therapies and their toxicities for patients with variants of CH origin and enables accurate tumor profiling and monitoring.

Keywords:  Clonal hematopoiesis; Comprehensive genomic profiling; Fragmentomics; Germline; Monitoring; ctDNA; liquid biopsy

DOI:  https://doi.org/10.1016/j.jlb.2025.100311
Nat Commun. 2025 Jul 24. 16(1): 6815

Longitudinal circulating tumor DNA analysis during treatment of locally advanced resectable gastric or gastroesophageal junction adenocarcinoma: the PLAGAST prospective biomarker study.

Aziz Zaanan, Audrey Didelot, Chloé Broudin, George Laliotis, Erik Spickard, Punashi Dutta, Aurélien Saltel-Fulero, Francesco Giulio Sullo, Margot Pizzamiglio, Antoine Mariani, Widad Lahlou, Meenakshi Malhotra, Shruti Sharma, Himanshu Sethi, Adham Jurdi, Minetta C Liu, Pierre Laurent-Puig.

Patients with locally advanced resectable (LAR) gastric/gastroesophageal junction (G/GEJ) adenocarcinomas have a high recurrence risk despite pre- and post-operative treatment. In the PLAGAST prospective study (NCT02674373), we investigated the ability of circulating tumor DNA (ctDNA) to predict treatment response and improve risk stratification. Plasma samples were prospectively collected before neoadjuvant therapy (NAT), during-NAT, post-NAT, and post-surgery. The primary endpoint was recurrence-free survival (RFS), and the secondary endpoints were overall survival (OS), tumor regression grade (TRG), and pathological tumor stage. ctDNA positivity decreased over these four therapeutic timelines (69.6%, 51.2%, 26.8%, and 20%, respectively). ctDNA-positivity was associated with significantly worse outcomes during-NAT (RFS: HR = 6.17, P = 0.002; OS: HR = 4.71, P = 0.022), post-NAT (RFS: HR = 5.26, P = 0.001; OS: HR = 7.35, P = 0.001) and after surgery (RFS: HR = 12.94, P < 0.0001; OS: HR = 14.54, P < 0.0001). Patients with early ctDNA clearance during NAT had better outcomes compared to those who cleared ctDNA post-NAT, while patients who remained ctDNA-positive pre-, during-, and post-NAT had worse outcomes (RFS: HR = 18.57, P = 0.01; OS: HR = 16.06, P = 0.007). Our data suggests that longitudinal ctDNA monitoring is prognostic of patient outcomes and may guide therapeutic decision-making in patients with LAR G/GEJ adenocarcinoma.

DOI: https://doi.org/10.1038/s41467-025-62056-7