ABSTRACT
Recurrence risks of cancer patient can change during treatment as a result of treatment-related tumor evolution. However, biomarkers that can monitor these changes are lacking. Here, we investigated whether tracking circulating tumor DNA (ctDNA) dynamics through liquid biopsy can inform real-time recurrence risk. Nasopharyngeal carcinoma (NPC) provides an ideal model where cell-free Epstein-Barr virus (EBV) DNA (cfEBV DNA), a ctDNA, can be sensitively detected. We conducted the EP-SEASON study (NCT03855020) and prospectively recruited 1,000 NPC patients undergoing per-protocol cfEBV DNA assessments at 11 time points and receiving sequential chemo-radiotherapy. Longitudinal cfEBV DNA displayed distinct patterns during neoadjuvant chemotherapy and radiotherapy. Despite the prognostic significance of cfEBV DNA at each time point, real-time recurrence risks changed in sync with cfEBV DNA dynamics. Furthermore, we identified phenotypes of whole-course ctDNA changing dynamics associated with different survival outcomes. In conclusion, tracking longitudinal on-treatment ctDNA can forecast real-time recurrence risk, facilitating risk-adapted, individualized patient management.
Subject(s)
Biomarkers, Tumor , Circulating Tumor DNA , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Neoplasm Recurrence, Local , Humans , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , Male , Female , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Middle Aged , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/blood , Nasopharyngeal Carcinoma/blood , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Carcinoma/virology , Nasopharyngeal Carcinoma/diagnosis , Adult , Nasopharyngeal Neoplasms/blood , Nasopharyngeal Neoplasms/virology , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/diagnosis , Longitudinal Studies , DNA, Viral/blood , Prospective Studies , Aged , Prognosis , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/isolation & purification , Liquid Biopsy/methods , Epstein-Barr Virus Infections/blood , Epstein-Barr Virus Infections/virology , Epstein-Barr Virus Infections/complicationsABSTRACT
BACKGROUND: Nsa cytoplasmic male sterility (CMS) is a novel alloplasmic male sterility system derived from somatic hybridization between Brassica napus and Sinapis arvensis. Identification of the CMS-associated gene is a prerequisite for a better understanding of the origin and molecular mechanism of this CMS. With the development of genome sequencing technology, organelle genomes of Nsa CMS line and its maintainer line were sequenced by pyro-sequencing technology, and comparative analysis of the organelle genomes was carried out to characterize the organelle genome composition of Nsa CMS as well as to identify the candidate Nsa CMS-associated genes. RESULTS: Nsa CMS mitochondrial genome showed a higher collinearity with that of S. arvensis than B. napus, indicating that Nsa CMS mitochondrial genome was mainly derived from S. arvensis. However, mitochondrial genome recombination of parental lines was clearly detected. In contrast, the chloroplast genome of Nsa CMS was highly collinear with its B. napus parent, without any evidence of recombination of the two parental chloroplast genomes or integration from S. arvensis. There were 16 open reading frames (ORFs) specifically existed in Nsa CMS mitochondrial genome, which could not be identified in the maintainer line. Among them, three ORFs (orf224, orf309, orf346) possessing chimeric and transmembrane structure are most likely to be the candidate CMS genes. Sequences of all three candidate CMS genes in Nsa CMS line were found to be 100% identical with those from S. arvensis mitochondrial genome. Phylogenetic and homologous analysis showed that all the mitochondrial genes were highly conserved during evolution. CONCLUSIONS: Nsa CMS contains a recombined mitochondrial genome of its two parental species with the majority form S. arvensis. Three candidate Nsa CMS genes were identified and proven to be derived from S. arvensis other than recombination of its two parental species. Further functional study of the candidate genes will help to identify the gene responsible for the CMS and the underlying molecular mechanism.