Genetic alteration and mutation profiling of circulating cell-free tumor DNA(cfDNA) for diagnosis and targeted therapy of gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs) have been recognized as a biologically distinctive type of tumor,different from smooth muscle and neural tumors of the gastrointestinal tract.The identification of genetic aberrations in proto-oncogenes that drive the growth of GISTs is critical for improving the efficacy of cancer therapy by matching targeted drugs to specific mutations.Research into the oncogenic mechanisms of GISTs has found that these tumors frequently contain activating gene mutations in either platelet-derived growth factor receptor A(PDGFRA) or a receptor tyrosine protein associated with a mast cell growth factor receptor encoded by the KIT gene.Mutant cancer subpopulations have the potential to disrupt durable patient responses to molecularly targeted therapy for GISTs,yet the prevalence and size of subpopulations remain largely unexplored.Detection of the cancer subpopulations that harbor low-frequency mutant alleles of target proto-oncogenes through the use of molecular genetic methods,such as polymerase chain reaction(PCR) target amplification technology,is hampered by the high abundance of wildtype alleles,which limit the sensitivity of detection of these minor mutant alleles.This is especially true in the case of mutant tumor DNA derived "driver" and "drug-resistant" alleles that are present in the circulating cell-free tumor DNA(cfDNA) in the peripheral blood circulation of GIST patients.So-called "liquid biopsy" allows for the dynamic monitoring of the patients' tumor status during treatment using minimally invasive sampling.New methodologies,such as a technology that employs a xenonucleic acid(XNA) clamping probe to block the PCR amplification of wild-type templates,have allowed improved molecular detection of these low-frequency alleles both in tissue biopsy samples and in cfDNA.These new methodologies could be widely applied for minimally invasive molecular testing in the therapeutic management of GISTs.

Evaluating chromosomal segregation in a family where both spouses carry an autosomal translocation

Autosomal reciprocal translocations represent exchanges of chromatin fragments between non-homologous chromosomes.Translocations are facilitated by the creation of quadrivalent structures during the first meiotic division,which are characterized by the length of the translocated and centric segments,asymmetry,and the presence of terminal breakpoints,all of which may impact segregation mode.Here,we report a rare case of multiple reciprocal translocations within a single family.This includes the evaluation of the translocations in each of the spouses and an analysis of their chromosome segregation patterns as determined by the constellation of universal characteristics in each of their quadrivalents.The obtained results will be of interest to fundamental biology,as they will expand the understanding of the factors affecting chromosome segregation during meiosis.