The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers.Science advances • February 19, 2025
Recep Bayraktar, Yitao Tang, Mihnea Dragomir, Cristina Ivan, Xinxin Peng, Linda Fabris, Jianhua Zhang, Alessandro Carugo, Serena Aneli, Jintan Liu, Mei-ju Chen, Sanjana Srinivasan, Iman Sahnoune, Emine Bayraktar, Kadir Akdemir, Meng Chen, Pranav Narayanan, Wilson Huang, Leonie Ott, Agda Eterovic, Oscar Villarreal, Moustaf Mohammad, Michael Peoples, Danielle Walsh, Jon Hernandez, Margaret Morgan, Kenna Shaw, Jennifer Davis, David Menter, Constantine Tam, Paul Yeh, Sarah-jane Dawson, Laura Rassenti, Thomas Kipps, Tanja Kunej, Zeev Estrov, Simon Joosse, Luca Pagani, Catherine Alix Panabières, Klaus Pantel, Alessandra Ferajoli, Andrew Futreal, Ignacio Wistuba, Milan Radovich, Scott Kopetz, Michael Keating, Giulio Draetta, John Mattick, Han Liang, George Calin
The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNAs (ncUCEs), and their functional relevance in cancers remain poorly characterized. Here, we perform a systematic analysis of whole-genome and in-house targeted UCE sequencing datasets from more than 3000 patients with cancer of 13,736 UCEs and demonstrate that ncUCE somatic alterations are common. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly affects cell proliferation. In-depth functional studies in vitro and in vivo further reveal that specific ncUCEs can be enhancers of tumor suppressors (such as ARID1B) and silencers of oncogenic proteins (such as RPS13). Moreover, several miRNAs located in ncUCEs are recurrently mutated. Mutations in miR-142 locus can affect the Drosha-mediated processing of precursor miRNAs, resulting in the down-regulation of the mature transcript. These results provide systematic evidence that specific ncUCEs play diverse regulatory roles in cancer.
Zanubrutinib and Venetoclax for Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma With and Without Del(17p)/TP53 Mutation: SEQUOIA Arm D Results.Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology • May 31, 2025
Mazyar Shadman, Talha Munir, Shuo Ma, Masa Lasica, Monica Tani, Tadeusz Robak, Ian Flinn, Jennifer Brown, Paolo Ghia, Emmanuelle Ferrant, Constantine Tam, Wojciech Janowski, Wojciech Jurczak, Linlin Xu, Tian Tian, Marcus Lefebure, Stephanie Agresti, Jamie Hirata, Alessandra Tedeschi
Objective: Several chronic lymphocytic leukemia (CLL) studies have demonstrated promising efficacy with the combination of BCL2 and Bruton tyrosine kinase inhibitors; however, patients with CLL with del(17p) and/or TP53 mutation (TP53mut) comprised a small percentage of study populations or were excluded entirely. The purpose of the SEQUOIA Arm D cohort was to evaluate the combination of zanubrutinib + venetoclax in treatment-naĂŻve (TN) patients with CLL/small lymphocytic lymphoma (SLL), in a large population of patients with TP53-aberrant disease.
Methods: Arm D is a nonrandomized cohort of patients aged 65 years and older (or 18-64 years with comorbidities). Patients received zanubrutinib from cycle 1 and venetoclax from cycle 4 (ramp-up) to cycle 28, followed by continuous zanubrutinib monotherapy until progressive disease (PD), unacceptable toxicity, or meeting undetectable minimal residual disease (uMRD)-guided stopping criteria.
Results: Between November 2019 and July 2022, 114 patients were enrolled: 66 (58%) with TP53-aberrant disease, 47 (41%) without TP53-aberrant disease, and 1 with missing TP53 results. At a median follow-up of 31.2 months, 85 patients (75%) remained on zanubrutinib monotherapy; 29 patients (25%) discontinued zanubrutinib because of adverse event, uMRD-guided stopping criteria, PD, or other. In the intention-to-treat population, 59% of patients achieved peripheral blood uMRD. The 24-month progression-free survival estimate was 92% (95% CI, 85% to 96%). The most common any-grade treatment-emergent AEs (TEAEs) were COVID-19 (54%), diarrhea (41%), contusion (32%), and nausea (30%). The most common grade ≥3 TEAEs were neutropenia (17%), hypertension (10%), diarrhea (6%), and decreased neutrophil count (6%).
Conclusions: Zanubrutinib + venetoclax demonstrated impressive efficacy and a favorable safety profile in patients with TN CLL/SLL, regardless of the presence of TP53-aberrant disease.
Enhanced Disease Detection of Hairy Cell Leukaemia Through Next-Generation Sequencing Based BRAF V600E and Phased Variant Analysis.EJHaem • March 12, 2025
Simon Wu, Tamia Nguyen, Imogen Caldwell, Sally Hunter, Sushmitha Kannan, Camille Santos, Yan Yap, Clarissa Wilson, Mayani Rawicki, Constantine Tam, Rachel Koldej, David Ritchie, Piers Blombery
Longitudinal disease assessment by molecular techniques is not routine in hairy cell leukaemia (HCL). Combining BRAF V600E and other genomic targets through next-generation sequencing (NGS) with phased variant analysis is a novel approach for disease detection in this setting. BRAF V600E digital droplet PCR of paired peripheral blood and cell-free DNA (cfDNA) specimens detected residual disease in 15/48 and 6/48 specimens respectively from patients with HCL. NGS testing with phased variant analysis improved disease detection in cfDNA specimens, including those with equivocal BRAF V600E results by digital droplet PCR. Through multiple patient-specific genomic targets to improve sensitivity, NGS may potentially improve disease detection in HCL. The authors have confirmed clinical trial registration is not needed for this submission.
International Consensus Statement on Diagnosis, Evaluation, and Research of Richter Transformation: the ERIC Recommendations.Blood • January 17, 2025
Adam Kittai, Monia Marchetti, Othman Al Sawaf, Ohad Benjamini, Alexey Danilov, Matthew Davids, Barbara Eichhorst, Toby Eyre, Anna Frustaci, Michael Hallek, Paul Hampel, Yair Herishanu, Rodney Hicks, Arnon Kater, Rebecca King, JosĂ©-ignacio MartĂn Subero, Carolyn Owen, Erin Parry, Maurilio Ponzoni, Davide Rossi, Tanya Siddiqi, Stephan Stilgenbauer, Constantine Tam, Elisa Ten Hacken, Philip Thompson, William Wierda, Gianluca Gaidano, Jennifer Woyach, Paolo Ghia
Richter transformation (RT) is defined as an aggressive lymphoma emerging in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Despite novel therapeutics developed in CLL, RT is associated with poor outcomes. In light of recent progress regarding the diagnostic procedures and therapeutic concepts of RT, an international group of experts, under the coordination of the European Research Initiative on CLL (ERIC), has developed consensus recommendations for clinical procedures and future research on this disease. Patients with RT typically present with a rapid clinical decline, worsening B-symptoms, elevated LDH, and/or rapidly enlarging lymphadenopathy. Workup should include a PET-CT for patients with suspected RT. An excisional biopsy should be taken from an accessible lesion, preferably with the highest FDG avidity, and analyzed for the presence of aggressive lymphoma. The molecular relationship to the original CLL clone(s) should be defined. As no effective standard treatment for RT exists, patients should be treated in a clinical trial. Response of both RT and CLL should be assessed at an early time point, and survival endpoints should be prioritized in trial design. We hope that these recommendations can help to harmonize clinical and translational research and improve outcomes for patients with RT.
International Consensus Statement on Diagnosis, Evaluation, and Research of Richter Transformation: the ERIC Recommendations.Blood • January 17, 2025
Adam Kittai, Monia Marchetti, Othman Al Sawaf, Ohad Benjamini, Alexey Danilov, Matthew Davids, Barbara Eichhorst, Toby Eyre, Anna Frustaci, Michael Hallek, Paul Hampel, Yair Herishanu, Rodney Hicks, Arnon Kater, Rebecca King, JosĂ©-ignacio MartĂn Subero, Carolyn Owen, Erin Parry, Maurilio Ponzoni, Davide Rossi, Tanya Siddiqi, Stephan Stilgenbauer, Constantine Tam, Elisa Ten Hacken, Philip Thompson, William Wierda, Gianluca Gaidano, Jennifer Woyach, Paolo Ghia
Richter transformation (RT) is defined as an aggressive lymphoma emerging in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Despite novel therapeutics developed in CLL, RT is associated with poor outcomes. In light of recent progress regarding the diagnostic procedures and therapeutic concepts of RT, an international group of experts, under the coordination of the European Research Initiative on CLL (ERIC), has developed consensus recommendations for clinical procedures and future research on this disease. Patients with RT typically present with a rapid clinical decline, worsening B-symptoms, elevated LDH, and/or rapidly enlarging lymphadenopathy. Workup should include a PET-CT for patients with suspected RT. An excisional biopsy should be taken from an accessible lesion, preferably with the highest FDG avidity, and analyzed for the presence of aggressive lymphoma. The molecular relationship to the original CLL clone(s) should be defined. As no effective standard treatment for RT exists, patients should be treated in a clinical trial. Response of both RT and CLL should be assessed at an early time point, and survival endpoints should be prioritized in trial design. We hope that these recommendations can help to harmonize clinical and translational research and improve outcomes for patients with RT.
