RESUMO
Recurrence is a major cause of death among BRCA1/2 mutation carriers with breast (BrCa) and ovarian cancers (OvCa). Herein we perform multi-omic sequencing on 67 paired primary and recurrent BrCa and OvCa from 27 BRCA1/2 mutation carriers to identify potential recurrence-specific drivers. PARP1 amplifications are identified in recurrences (False Discovery Rate q = 0.05), and PARP1 is significantly overexpressed across primary BrCa and recurrent BrCa and OvCa, independent of amplification status. RNA sequencing analysis finds two BRCA2 isoforms, BRCA2-201/Long and BRCA2-001/Short, respectively predicted to be sensitive and insensitive to nonsense-mediated decay. BRCA2-001/Short is expressed more frequently in recurrences and associated with reduced overall survival in breast cancer (87 vs. 121 months; Hazard Ratio = 2.5 [1.18-5.5]). Loss of heterozygosity (LOH) status is discordant in 25% of patient's primary and recurrent tumors, with switching between both LOH and lack of LOH found. Our study reveals multiple potential drivers of recurrent disease in BRCA1/2 mutation-associated cancer, improving our understanding of tumor evolution and suggesting potential biomarkers.
Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Feminino , Humanos , Proteína BRCA2/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Perda de Heterozigosidade/genética , Modelos de Riscos Proporcionais , Proteína BRCA1/genética , Mutação , Mutação em Linhagem GerminativaRESUMO
Recent changes in U.S. immigration policy are adversely affecting biomedical science, at a time when biomedical research is most sorely needed on multiple fronts. Here we discuss the immense contributions of immigrants to cancer research and the adverse impact that current administration policies will have on successful cancer research.
Assuntos
Pesquisa Biomédica/métodos , Diversidade Cultural , Emigrantes e Imigrantes/estatística & dados numéricos , Etnicidade/estatística & dados numéricos , Neoplasias/terapia , Pesquisadores/estatística & dados numéricos , Logro , Emigração e Imigração/legislação & jurisprudência , Emigração e Imigração/estatística & dados numéricos , Humanos , Neoplasias/diagnóstico , Competência Profissional/normas , Competência Profissional/estatística & dados numéricos , Estados UnidosRESUMO
The adenomatous polyposis coli (APC) gene plays, among other things, a crucial role in the regulation of cell proliferation and survival through its ability to regulate canonical Wnt signaling. In this issue of the JCI, Wang et al. provide an intriguing new mechanism for APC function involving the regulation of a novel long noncoding RNA (lncRNA), leading to changes in exosome production. APC signaling via this novel pathway can regulate cell proliferation and invasion as well as angiogenesis. In addition to enhancing our understanding of APC function, this new mechanism is of particular clinical significance, as it may provide additional targets for the treatment of APC-mutated cancers.