Citations 2
Timing the onset of homologous recombination deficiency before breast cancer diagnosis
Andreopoulos, Michail , Niu, Muchun , Zhang, Yang, Gulhan, D. , Zong, Chenghang , Gulhan, Doga , Zhang, Yang, Viswanadham, Vinay , Jin, Hu , Batalini, Felipe , Wulf, Gerburg M. , Park, Peter J. , Głodzik, Dominik
No container title available | October 19, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Mutations in BRCA1 and BRCA2 genes, whether inherited or somatically acquired, cause homologous recombination deficiency (HRD) in tumor cells. The timing of HRD onset in the emerging tumor lineage is unknown. Here, we present HRDTimer, an algorithm to infer the onset of HRD-driven mutagenesis prior to cancer diagnosis. We estimate that HRD arises at 34% of SBS1-based molecular time---corresponding to a median of 8.3 years (IQR 7.1--10.4) prior to diagnosis in triple-negative breast cancers, and 15.0 years (IQR 12.0--20.6) in ER-positive breast cancers. Bulk sequencing reveals accelerated SBS1 accumulation following neoplastic transformation compared to normal tissue, influencing the estimated age of HRD onset. Single-cell duplex sequencing confirms SBS1 acceleration in tumors and further shows that non-tumor cells largely lack the HRD signature, indicating that HRD is rare in pre-malignant cells, even in BRCA1/2 mutation carriers. Together, our analysis pinpoints the onset of HRD before diagnosis, defining a window for detection and potential interception.
Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability
Bae, Taejeong , Fasching, Liana , Wang, Yifan , Shin, Joo Heon , Šuvakov, Milovan , Jang, Yeongjun , Norton, Scott , Dias, Caroline , Mariani, Jessica , Jourdon, Alexandre , Wu, Feinan , Panda, Arijit , Pattni, Reenal , Chahine, Yasmine, Yeh, Rebecca C., Roberts, Rosalinda C. , Hüttner, Anita , Straub, Richard E. , Walsh, Christopher A. , Network§, Brain Somatic Mosaicism, Urban, Alexander E. , Weinberger, Daniel R. , Vaccarino, Flora M. , Abyzov, Alexej , Šestan, Nenad , Moran, John V. , Gleeson, Joseph G. , Mathern, Gary W. , Courchesne, Eric, Chess, Andrew , Bizzotto, Sara , D’Gama, Alissa M. , Hill, Robert , Kim, Sonia , Miller, Michael , Borges-Monroy, Rebeca , Bohrson, Craig L. , Galor, Alon , Kwon, Min‐Seok , Luquette, Joe, Sherman, Maxwell A. , Rosenbluh, Chaggai , Cho, Sean, Thorpe, Jeremy , McConnell, Michael J. , Narurkar, Rujuta, Paquola, Apuã C.M. , Shin, Jooheon, Molitor, Cindy, Peters, Mette A. , Linker, Sara B. , Reed, Patrick , Wang, Meiyan , Zhou, Bo , Amero, Aitor Serres, Lobón, Irene , Moruno, Manuel Solis, Pérez, Raquel García, Povolotskaya, Inna , Soriano, Eduardo , Antaki, Danny , Averbuj, Dan, Ball, Laurel, Yang, Xiaoxu , Chung, Changuk , Emery, Sarah B., Flasch, Diane A. , Sun, Chen , Zhao, Xuefang , Zhou, Weichen , Frisbie, Trenton J., Cherskov, Adriana , Pochareddy, Sirisha , Kleinman, Joel E , Hyde, Thomas M , Straub, Richard E , Walsh, Christopher A , Urban, Alexander E , Leckman, James F , Weinberger, Daniel R , Vaccarino, Flora M , Abyzov, Alexej , Shin, Joo Heon , Zhou, Bo , Šuvakov, Milovan , Bae, Taejeong , Wang, Yifan , Jang, Yeongjun , Network§, Brain Somatic Mosaicism, Leckman, James F. , Park, Peter J. , Gage, Fred H , Gleeson, Joseph G. , Courchesne, Eric, Roy, Subhojit , Akbarian, Schahram , Coulter, Michael E. , Ganz, Javier , Hill, Robert, Huang, August Yue , Khoshkhoo, Sattar , Lee, Alice , Lodato, Michael A. , Maury, Eduardo A. , Rodin, Rachel E. , Zhou, Zinan , Chu, Chong , Cortés‐Ciriano, Isidro , Dou, Yanmei , Gulhan, D. , Viswanadham, Vinay , Jones, Attila , Langmead, Ben , Erwin, Jennifer A. , Jaffe, Andrew E. , Zhu, Xiaowei , Juan, David , Marquès‐Bonet, Tomàs , Breuss, Martin W. , Kidd, Jeffrey M. , Kopera, Huira C. , Kwan, Kenneth Y , Mills, Ryan E. , Moldovan, John B. , Scuderi, Soraya
Science | July 28, 2022 | Volume: 377 | Issue: 6605 | Pages: 511-517
We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.