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Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress.
Tomaszowski, Karl-Heinz; Roy, Sunetra; Guerrero, Carolina; Shukla, Poojan; Keshvani, Caezaan; Chen, Yue; Ott, Martina; Wu, Xiaogang; Zhang, Jianhua; DiNardo, Courtney D; Schindler, Detlev; Schlacher, Katharina.
Affiliation
  • Tomaszowski KH; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • Roy S; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • Guerrero C; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • Shukla P; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • Keshvani C; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • Chen Y; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • Ott M; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • Wu X; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • Zhang J; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • DiNardo CD; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • Schindler D; Institut fuer Humangenetik, University of Wuerzburg, Wuerzburg, Germany.
  • Schlacher K; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. kschlacher@mdanderson.org.
Nat Commun ; 14(1): 1333, 2023 03 11.
Article in En | MEDLINE | ID: mdl-36906610
The prototypic cancer-predisposition disease Fanconi Anemia (FA) is identified by biallelic mutations in any one of twenty-three FANC genes. Puzzlingly, inactivation of one Fanc gene alone in mice fails to faithfully model the pleiotropic human disease without additional external stress. Here we find that FA patients frequently display FANC co-mutations. Combining exemplary homozygous hypomorphic Brca2/Fancd1 and Rad51c/Fanco mutations in mice phenocopies human FA with bone marrow failure, rapid death by cancer, cellular cancer-drug hypersensitivity and severe replication instability. These grave phenotypes contrast the unremarkable phenotypes seen in mice with single gene-function inactivation, revealing an unexpected synergism between Fanc mutations. Beyond FA, breast cancer-genome analysis confirms that polygenic FANC tumor-mutations correlate with lower survival, expanding our understanding of FANC genes beyond an epistatic FA-pathway. Collectively, the data establish a polygenic replication stress concept as a testable principle, whereby co-occurrence of a distinct second gene mutation amplifies and drives endogenous replication stress, genome instability and disease.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Breast Neoplasms / Fanconi Anemia Limits: Animals / Female / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2023 Document type: Article Affiliation country: United States Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Breast Neoplasms / Fanconi Anemia Limits: Animals / Female / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2023 Document type: Article Affiliation country: United States Country of publication: United kingdom