RESUMO
During each cell cycle, the process of DNA replication timing is tightly regulated to ensure the accurate duplication of the genome. The extent and significance of alterations in this process during malignant transformation have not been extensively explored. Here, we assess the impact of altered replication timing (ART) on cancer evolution by analysing replication-timing sequencing of cancer and normal cell lines and 952 whole-genome sequenced lung and breast tumours. We find that 6%-18% of the cancer genome exhibits ART, with regions with a change from early to late replication displaying an increased mutation rate and distinct mutational signatures. Whereas regions changing from late to early replication contain genes with increased expression and present a preponderance of APOBEC3-mediated mutation clusters and associated driver mutations. We demonstrate that ART occurs relatively early during cancer evolution and that ART may have a stronger correlation with mutation acquisition than alterations in chromatin structure.
Assuntos
Neoplasias da Mama , Período de Replicação do DNA , Neoplasias Pulmonares , Mutação , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Linhagem Celular Tumoral , Desaminases APOBEC/genética , Desaminases APOBEC/metabolismo , Taxa de Mutação , Replicação do DNA/genética , Genoma HumanoRESUMO
The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.
Assuntos
Instabilidade Cromossômica , Receptores ErbB , Neoplasias Pulmonares , Mutação , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Camundongos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Terapia de Alvo Molecular/métodos , Feminino , Variações do Número de Cópias de DNA , MasculinoRESUMO
Our recent study revealed that APOBEC3B is upregulated during the preinvasive stages of non-small cell lung cancer and breast cancer. In addition to its role in mediating single nucleotide variants, we propose that APOBEC3 promotes copy number intratumor heterogeneity prior to invasion, providing a substrate for cancer evolution.