Citations 2
Landscape of reversion alterations in homologous recombination genes reveals evolutionary constraints
Decker, Brennan, Sisoudiya, Saumya D. , Thornton, James, Cui, Chenming, Solieva, Shahlo , Shi, Tao, Guintini, Fabio, Fleischmann, Zoe, Hartman, Mark, Bailey, Shannon T., Leibowitz, Jeffrey , Sokol, Ethan S, Schrock, Alexa B. , Couch, Fergus J, Reiss, Kim A, Domchek, Susan M, Sivakumar, Smruthy, Decker, Brennan , Cui, Chenming , Harada, Taku, Madison, Russell W. , Datta, Arindam , Fleischmann, Zoe , Frampton, Garrett M. , Couch, Fergus J. , Reiss, Kim A. , Domchek, Susan M. , Bowman, Gregory R. , Greenberg, Roger A. , Nathanson, Katherine L.
No container title available | May 22, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
ABSTRACT Reversion mutations (REVs) restore homologous recombination repair (HRR) and confer resistance to PARP inhibitors (PARPi) in HR-deficient cancers. Yet, their prevalence, mechanisms, and biological constraints remain undefined. We analyzed genomic profiling of 609,464 tissue and liquid biopsy samples across multiple cancer types to delineate the pan-cancer landscape of REVs. REVs were identified in eight HRR genes, most frequently BRCA2 and BRCA1 and notably never in ATM or CHEK2 . REVs exclusively impacted truncating pathogenic variants, predominantly through large in-frame and exon-level deletions, associated with repetitive sequences. Conserved functional domains are relatively depleted of REVs. Structural modeling and functional studies support that exon-level deletions preserve critical domain architecture and confer PARPi resistance. The study establishes HRR reversion as a structurally permissive, yet evolutionarily constrained, resistance mechanism with implications on response, monitoring, and therapeutic strategy. One Sentence Summary Homologous recombination reversion evolves through structurally tolerated, microhomology-driven alterations that restore DNA repair under therapeutic selection across cancers.
Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference
Kloske, Courtney M. , Blue, Elizabeth , Carrillo, María C. , Chen, Xiaoying , Chiba‐Falek, Ornit , Davis, Albert A. , Paolo, Gilbert Di , Garretti, Francesca , Golden, Lesley R. , Heinecke, Jay W. , Herz, Joachim, Huang, Yadong , Kanekiyo, Takahisa , Khvorova, Anastasia, Hertog, Sascha J. Koppes‐den, Lamb, Bruce T. , Lawler, Paige E. , Litvinchuk, Alexandra , Liu, Chia‐Chen , Michaelson, D. M., Miller, Justin J. , Morganti, Josh M. , Oosthoek, Marlies , Ramachandran, Kapil V. , Ramakrishnan, Abhirami , Robert, Aiko, Sexton, Claire E. , Shah, Nilomi, Shue, Francis , Strickland, Michael R. , TCW, Julia , Thierry, Manon, Tuckey, Ryan A. , Ulrich, Jason D. , Wang, Na , Weninger, Stacie, Zhao, Na , Goate, Alison , Liu, Chia-Chen , Shue, Francis , Zhao, Na , Goate, Alison M , Belloy, Michaël E. , Bowman, Gregory R. , Gate, David M , Iadecola, Costantino , Johnson, Lance A. , Karch, Celeste M. , Khvorova, Anastasia , Hertog, Sascha Koppes-den , Le Guen, Yann , Mahinrad, Simin , Marcora, Edoardo , Mariño, Claudia , Narayan, Priyanka , Naslavsky, Michel Satya , Raulin, Ana‐Caroline , Saleh, Rasha N.M. , Sible, Isabel J. , Soranno, Andrea , Tsai, Li‐Huei , Kant, Rik van der , Wellington, Cheryl L. , Yassine, Hussein N. , Bu, Guojun , Holtzman, David M.
Alzheimer's & Dementia | July 19, 2024 | Volume: 20 | Issue: 9 | Pages: 6590-6605
AbstractINTRODUCTIONThe apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid‐beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex‐dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research.METHODSIn 2023, the Alzheimer's Association convened multidisciplinary researchers at the “AAIC Advancements: APOE” conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE‐targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function.RESULTSThis manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field.DISCUSSIONUnderstanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine.Highlights APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid‐beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.