bims-ovdlit 2024-06-09 papers

bims-ovdlit

Biomed News

on Ovarian cancer: early diagnosis, liquid biopsy and therapy

Issue of 2024–06–09
eight papers selected by
Lara Paracchini, Humanitas Research

Concurrent RB1 Loss and BRCA-Deficiency Predicts Enhanced Immunological Response and Long-Term Survival in Tubo-Ovarian High-Grade Serous Carcinoma.
Clinical utility of comprehensive liquid molecular profiling in patients with advanced endometrial cancer.
Longitudinal cell-free DNA characterization by low-coverage whole-genome sequencing in patients undergoing high-dose radiotherapy.
Comprehensive next-generation sequencing identifies novel putative pathogenic or likely pathogenic germline variants in patients with concurrent tubo-ovarian and endometrial serous and endometrioid carcinomas or precursors.
The utility of liquid biopsy in clinical genetic diagnosis of cancer and monogenic mosaic disorders.
Cervical cancer screening using DNA methylation triage in a real-world population.
Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection.
Systematic assessment of long-read RNA-seq methods for transcript identification and quantification.

Clin Cancer Res. 2024 Jun 05.

Concurrent RB1 Loss and BRCA-Deficiency Predicts Enhanced Immunological Response and Long-Term Survival in Tubo-Ovarian High-Grade Serous Carcinoma.

Flurina A M Saner, Kazuaki Takahashi, Timothy Budden, Ahwan Pandey, Dinuka Ariyaratne, Tibor A Zwimpfer, Nicola S Meagher, Sian Fereday, Laura Twomey, Kathleen I Pishas, Therese Hoang, Adelyn Bolithon, Nadia Traficante, Kathryn Alsop, Elizabeth L Christie, Eun-Young Kang, Gregg S Nelson, Prafull Ghatage, Cheng-Han Lee, Marjorie J Riggan, Jennifer Alsop, Matthias W Beckmann, Jessica Boros, Alison H Brand, Angela Brooks-Wilson, Michael E Carney, Penny Coulson, Madeleine Courtney-Brooks, Kara L Cushing-Haugen, Cezary Cybulski, Mona El-Bahrawy, Esther Elishaev, Ramona Erber, Simon A Gayther, Aleksandra Gentry-Maharaj, C Blake Gilks, Paul R Harnett, Holly R Harris, Arndt Hartmann, Alexander Hein, Joy Hendley, Brenda Y Hernandez, Anna Jakubowska, Mercedes Jimenez-Linan, Michael E Jones, Scott H Kaufmann, Catherine J Kennedy, Tomasz Kluz, Jennifer M Koziak, Björg Kristjansdottir, Nhu D Le, Marcin Lener, Jenny Lester, Jan Lubiński, Constantina Mateoiu, Sandra Orsulic, Matthias Ruebner, Minouk J Schoemaker, Mitul Shah, Raghwa Sharma, Mark E Sherman, Yurii B Shvetsov, T Rinda Soong, Helen Steed, Paniti Sukumvanich, Aline Talhouk, Sarah E Taylor, Robert A Vierkant, Chen Wang, Martin Widschwendter, Lynne R Wilkens, Stacey J Winham, Michael S Anglesio, Andrew Berchuck, James D Brenton, Ian Campbell, Linda S Cook, Jennifer A Doherty, Peter A Fasching, Renée Turzanski Fortner, Marc T Goodman, Jacek Gronwald, David G Huntsman, Beth Y Karlan, Linda E Kelemen, Usha Menon, Francesmary Modugno, Paul D P Pharoah, Joellen M Schildkraut, Karin Sundfeldt, Anthony J Swerdlow, Ellen L Goode, Anna DeFazio, Martin Köbel, Susan J Ramus, David D L Bowtell, Dale W Garsed.

PURPOSE: To evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).
EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss.
RESULTS: RB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.
CONCLUSIONS: Co-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-3552
Cancer. 2024 Jun 02.

Clinical utility of comprehensive liquid molecular profiling in patients with advanced endometrial cancer.

Félix Blanc-Durand, Geraldine M Camilleri, Arnaud Bayle, Mihaela Aldea, Damien Vasseur, Kaissa Ouali, Judith Michels, Patricia Pautier, Claudio Nicotra, Maud Ngo-Camus, Ludovic Lacroix, Etienne Rouleau, Santiago Ponce-Aix, Antoine Italiano, Alexandra Leary.

   BACKGROUND: Molecular characterization has significantly improved the management of advanced endometrial cancer (EC). It distinguishes four molecular subclasses associated with prognosis and personalized therapeutic strategies. This study assesses the clinical utility of cell-free DNA (cfDNA) profiling in EC to identify targetable alterations.
METHODS: Women with metastatic or recurrent EC were prospectively recruited within the framework of the STING trial (NCT04932525), during which cfDNA was analyzed. Genomic alterations were identified with the FoundationOne CDx assay. Each molecular report underwent review by a molecular tumor board. Alterations were categorized via the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT).
RESULTS: A total of 61 patients were enrolled. The median age was 66.9 years, with 43% presenting frontline metastatic disease. All histologic subgroups were represented. Notably, 89% of patients yielded informative cfDNA analysis. Six tumors were classified with deficient mismatch repair/microsatellite instability (11%) and 37 as TP53 gene mutant (67%), and 12 had nonspecific molecular profiles (22%). Molecular classification based on liquid biopsy showed 87.5% accuracy in correlating with tissue results. Moreover, 65% of cases exhibited ≥1 actionable alteration, including 25% ESCAT I alterations and 13% ESCAT II alterations. Consequently, 16% of patients received a molecularly matched therapy, and presented with a 56% response rate and median progression-free survival of 7.7 months.
CONCLUSIONS: cfDNA sequencing in EC is a feasible approach that produces informative results in 89% of cases and accurately categorizes patients into the main molecular subclasses. It also reveals multiple actionable alterations, which offers the potential for personalized therapeutic strategies.

Keywords:  cell‐free DNA (cfDNA); clonal hematopoiesis; endometrial cancer; molecular profile; personalized treatment

DOI:  https://doi.org/10.1002/cncr.35381
Radiother Oncol. 2024 Jun 02. pii: S0167-8140(24)00634-0. [Epub ahead of print] 110364

Longitudinal cell-free DNA characterization by low-coverage whole-genome sequencing in patients undergoing high-dose radiotherapy.

Zsolt Balázs, Panagiotis Balermpas, Ivna Ivanković, Jonas Willmann, Todor Gitchev, Asher Bryant, Matthias Guckenberger, Michael Krauthammer, Nicolaus Andratschke.

   BACKGROUND AND PURPOSE: Current radiotherapy guidelines rely heavily on imaging-based monitoring. Liquid biopsy monitoring promises to complement imaging by providing frequent systemic information about the tumor. In particular, cell-free DNA (cfDNA) sequencing offers a tumor-agnostic approach, which lends itself to monitoring heterogeneous cohorts of cancer patients.
METHODS: We collected plasma cfDNA from oligometastatic patients (OMD) and head-and-neck cancer patients (SCCHN) at six time points before, during, and after radiotherapy, and compared them to the plasma samples of healthy and polymetastatic volunteers. We performed low-pass (on average 7x) whole-genome sequencing on 93 plasma cfDNA samples and correlated copy number alterations and fragment length distributions to clinical and imaging findings.
RESULTS: We observed copy number alterations in 4/7 polymetastatic cancer patients, 1/7 OMD and 1/7 SCCHN patients, these patients' imaging showed progression following radiotherapy. Using unsupervised learning, we identified cancer-specific fragment length features that showed a strong correlation with copy number-based tumor fraction estimates. In 4/4 HPV-positive SCCHN patient samples, we detected viral DNA that enabled the monitoring of very low tumor fraction samples.
CONCLUSIONS: Our results indicate that an elevated tumor fraction is associated with tumor aggressiveness and systemic tumor spread. This information may be used to adapt treatment strategies. Further, we show that by detecting specific sequences such as viral DNA, the sensitivity of detecting cancer from cell-free DNA sequencing data can be greatly increased.

Keywords:  Cell-free DNA; Copy number alteration; Fragmentomics; Headand-neck cancer; Human papillomavirus; Liquid biopsy; Oligometastasis; Polymetastasis; Radiotherapy

DOI:  https://doi.org/10.1016/j.radonc.2024.110364
Gynecol Oncol. 2024 Jun 03. pii: S0090-8258(24)00250-6. [Epub ahead of print]187 241-248

Comprehensive next-generation sequencing identifies novel putative pathogenic or likely pathogenic germline variants in patients with concurrent tubo-ovarian and endometrial serous and endometrioid carcinomas or precursors.

Omonigho Aisagbonhi, Ida Ghlichloo, Duncan S Hong, Andres Roma, Oluwole Fadare, Ramez Eskander, Cheryl Saenz, Kathleen M Fisch, Wei Song.

   BACKGROUND: Endometrial serous carcinoma (ESC) and tubo-ovarian high-grade serous carcinoma (HGSC) are characterized by late-stage presentation and high mortality. Current guidelines for prevention recommend risk-reducing salpingo-oophorectomy (RRSO) in patients with hereditary mutations in cancer susceptibility genes. However, HGSC displays extensive genetic heterogeneity with alterations in 168 genes identified in TCGA study, but current germline testing panels are often limited to the handful of recurrently mutated genes, leaving families with rare hereditary gene mutations potentially at-risk.
OBJECTIVE: To determine if there are rare germline mutations that may aid in early identification of more patients at-risk for ESC and/or HGSC by evaluating patients with concurrent ESC, HGSC or precursor lesions, and endometrial atypical hyperplasia (CAH) or low-grade endometrial endometrioid adenocarcinoma (LGEEA).
METHODS: We performed targeted next-generation sequencing using TSO 500, a 523 gene panel, on formalin-fixed paraffin-embedded tumor and matched benign non-tumor tissue blocks from 5 patients with concurrent ESC, HGSC or precursor lesions, and CAH or LGEEA.
RESULTS: We identified germline pathogenic, likely pathogenic or uncertain significance variants in cancer susceptibility genes in 4 of 5 patients - affected genes included GLI1, PIK3R1, FOXP1, FANCD2, INPP4B and H3F3C. Notably, none of these genes were included in the commercially available germline testing panels initially used to evaluate the patients at the time of their diagnoses.
CONCLUSION: Comprehensive germline testing of patients with concurrent LGEEA or CAH and ESC, HGSC or precursor lesions may aid in early identification of relatives at-risk for cancer who may be candidates for RRSO with hysterectomy.

Keywords:  Endometrial; Fallopian tube; Genetic; Germline; Molecular; Ovarian; Serous; cancer

DOI:  https://doi.org/10.1016/j.ygyno.2024.05.027
Med Genet. 2023 Dec;35(4): 275-284

The utility of liquid biopsy in clinical genetic diagnosis of cancer and monogenic mosaic disorders.

Ariane Hallermayr, Thomas Keßler, Verena Steinke-Lange, Ellen Heitzer, Elke Holinski-Feder, Michael Speicher.

  Liquid biopsy for minimally invasive diagnosis and monitoring of cancer patients is progressing toward routine clinical practice. With the implementation of highly sensitive next-generation sequencing (NGS) based assays for the analysis of cfDNA, however, consideration of the utility of liquid biopsy for clinical genetic testing is critical. While the focus of liquid biopsy for cancer diagnosis is the detection of circulating tumor DNA (ctDNA) as a fraction of total cell-free DNA (cfDNA), cfDNA analysis reveals both somatic mosaic tumor and germline variants and clonal hematopoiesis. Here we outline advantages and limitations of mosaic and germline variant detection as well as the impact of clonal hematopoiesis on liquid biopsy in cancer diagnosis. We also evaluate the potential of cfDNA analysis for the molecular diagnosis of monogenic mosaic disorders.

Keywords:  cancer diagnostics; clonal hematopoiesis; human genetics; liquid biopsy; mosaic disorders

DOI:  https://doi.org/10.1515/medgen-2023-2066
Nat Med. 2024 Jun 04.

Cervical cancer screening using DNA methylation triage in a real-world population.

Lena Schreiberhuber, James E Barrett, Jiangrong Wang, Elisa Redl, Chiara Herzog, Charlotte D Vavourakis, Karin Sundström, Joakim Dillner, Martin Widschwendter.

Cervical cancer (CC) screening in women comprises human papillomavirus (HPV) testing followed by cytology triage of positive cases. Drawbacks, including cytology's low reproducibility and requirement for short screening intervals, raise the need for alternative triage methods. Here we used an innovative triage technique, the WID-qCIN test, to assess the DNA methylation of human genes DPP6, RALYL and GSX1 in a real-life cohort of 28,017 women aged ≥30 years who attended CC screening in Stockholm between January and March 2017. In the analysis of all 2,377 HPV-positive samples, a combination of WID-qCIN (with a predefined threshold) and HPV16 and/or HPV18 (HPV16/18) detected 93.4% of cervical intraepithelial neoplasia grade 3 and 100% of invasive CCs. The WID-qCIN/HPV16/18 combination predicted 69.4% of incident cervical intraepithelial neoplasia grade 2 or worse compared with 18.2% predicted by cytology. Cytology or WID-qCIN/HPV16/18 triage would require 4.1 and 2.4 colposcopy referrals to detect one cervical intraepithelial neoplasia grade 2 or worse, respectively, during the 6 year period. These findings support the use of WID-qCIN/HPV16/18 as an improved triage strategy for HPV-positive women.

DOI: https://doi.org/10.1038/s41591-024-03014-6
Cancer Discov. 2024 Jun 03.

Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection.

Peter J Mazzone, Peter B Bach, Jacob Carey, Caitlin A Schonewolf, Katalin Bognar, Manmeet S Ahluwalia, Marcia Cruz-Correa, David Gierada, Sonali Kotagiri, Kathryn Lloyd, Fabien Maldonado, Jesse D Ortendahl, Lecia V Sequist, Gerard A Silvestri, Nichole Tanner, Jeffrey C Thompson, Anil Vachani, Kwok-Kin Wong, Ali H Zaidi, Joseph Catallini, Ariel Gershman, Keith Lumbard, Laurel K Millberg, Jeff Nawrocki, Carter Portwood, Aakanksha Rangnekar, Carolina Campos Sheridan, Niti Trivedi, Tony Wu, Yuhua Zong, Lindsey Cotton, Allison Ryan, Christopher Cisar, Alessandro Leal, Nicholas C Dracopoli, Robert B Scharpf, Victor E Velculescu, Luke R G Pike.

Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples, and then validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer, and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a five-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0519
Nat Methods. 2024 Jun 07.

Systematic assessment of long-read RNA-seq methods for transcript identification and quantification.

Francisco J Pardo-Palacios, Dingjie Wang, Fairlie Reese, Mark Diekhans, Sílvia Carbonell-Sala, Brian Williams, Jane E Loveland, Maite De María, Matthew S Adams, Gabriela Balderrama-Gutierrez, Amit K Behera, Jose M Gonzalez Martinez, Toby Hunt, Julien Lagarde, Cindy E Liang, Haoran Li, Marcus Jerryd Meade, David A Moraga Amador, Andrey D Prjibelski, Inanc Birol, Hamed Bostan, Ashley M Brooks, Muhammed Hasan Çelik, Ying Chen, Mei R M Du, Colette Felton, Jonathan Göke, Saber Hafezqorani, Ralf Herwig, Hideya Kawaji, Joseph Lee, Jian-Liang Li, Matthias Lienhard, Alla Mikheenko, Dennis Mulligan, Ka Ming Nip, Mihaela Pertea, Matthew E Ritchie, Andre D Sim, Alison D Tang, Yuk Kei Wan, Changqing Wang, Brandon Y Wong, Chen Yang, If Barnes, Andrew E Berry, Salvador Capella-Gutierrez, Alyssa Cousineau, Namrita Dhillon, Jose M Fernandez-Gonzalez, Luis Ferrández-Peral, Natàlia Garcia-Reyero, Stefan Götz, Carles Hernández-Ferrer, Liudmyla Kondratova, Tianyuan Liu, Alessandra Martinez-Martin, Carlos Menor, Jorge Mestre-Tomás, Jonathan M Mudge, Nedka G Panayotova, Alejandro Paniagua, Dmitry Repchevsky, Xingjie Ren, Eric Rouchka, Brandon Saint-John, Enrique Sapena, Leon Sheynkman, Melissa Laird Smith, Marie-Marthe Suner, Hazuki Takahashi, Ingrid A Youngworth, Piero Carninci, Nancy D Denslow, Roderic Guigó, Margaret E Hunter, Rene Maehr, Yin Shen, Hagen U Tilgner, Barbara J Wold, Christopher Vollmers, Adam Frankish, Kin Fai Au, Gloria M Sheynkman, Ali Mortazavi, Ana Conesa, Angela N Brooks.

The Long-read RNA-Seq Genome Annotation Assessment Project Consortium was formed to evaluate the effectiveness of long-read approaches for transcriptome analysis. Using different protocols and sequencing platforms, the consortium generated over 427 million long-read sequences from complementary DNA and direct RNA datasets, encompassing human, mouse and manatee species. Developers utilized these data to address challenges in transcript isoform detection, quantification and de novo transcript detection. The study revealed that libraries with longer, more accurate sequences produce more accurate transcripts than those with increased read depth, whereas greater read depth improved quantification accuracy. In well-annotated genomes, tools based on reference sequences demonstrated the best performance. Incorporating additional orthogonal data and replicate samples is advised when aiming to detect rare and novel transcripts or using reference-free approaches. This collaborative study offers a benchmark for current practices and provides direction for future method development in transcriptome analysis.

DOI: https://doi.org/10.1038/s41592-024-02298-3