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Simple Summary Most solid tumors share mutations in TP53 that is thus considered one of the main cancer driver genes. Mutations in TP53 occur very early during tumor development, so their identification helps in diagnosing cancer. Furthermore, knowing in advance the TP53 mutation status might help guiding targeted treatments against this gene. However, this analysis is mainly performed in tissue samples, that is, solid biopsies, being an invasive technique. Contrarily, liquid biopsies, consisting of the analysis of blood samples, are non-invasive, can be performed repeatedly, helping in monitoring the patient evolution, and might be useful in early stages when the tumor is not yet detected by other technologies. Here, we review the main studies conducted on two types of liquid biopsies: circulating tumor cells and cell-free DNA. We discuss the main findings regarding TP53 mutation analysis, the clinical utility of this information and some controversies arising from the study of liquid biopsies compared to tissue samples, and we finish by suggesting future directions within this field. Abstract Being minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding TP53 mutation status analysis, liquid biopsies have not yet substituted tissue samples, mainly due to the lack of concordance between the two types of biopsies. This needs to be examined in a study-dependent manner, taking into account the particular type of liquid biopsy analyzed, that is, circulating tumor cells (CTCs) or cell-free DNA (cfDNA), its involvement in the tumor biology and evolution and, finally, the technology used to analyze each biopsy type. Here, we review the main studies analyzing TP53 mutations in either CTCs or cfDNA in the three more prevalent solid tumors: breast, colon and lung cancers. We evaluate the correlation for mutation status between liquid biopsies and tumor tissue, suggesting possible sources of discrepancies, as well as evaluating the clinical utility of using liquid biopsies for the analysis of TP53 mutation status and the future actions that need to be undertaken to make liquid biopsy analysis a reality for the evaluation of TP53 mutations.

Simple Summary: Most solid tumors share mutations in TP53 that is thus considered one of the main cancer driver genes. Mutations in TP53 occur very early during tumor development, so their identification helps in diagnosing cancer. Furthermore, knowing in advance the TP53 mutation status might help guiding targeted treatments against this gene. However, this analysis is mainly performed in tissue samples, that is, solid biopsies, being an invasive technique. Contrarily, liquid biopsies, consisting of the analysis of blood samples, are non-invasive, can be performed repeatedly, helping in monitoring the patient evolution, and might be useful in early stages when the tumor is not yet detected by other technologies. Here, we review the main studies conducted on two types of liquid biopsies: circulating tumor cells and cell-free DNA.We discuss the main findings regarding TP53 mutation analysis, the clinical utility of this information and some controversies arising from the study of liquid biopsies compared to tissue samples, and we finish by suggesting future directions within this field. Abstract: Being minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding TP53 mutation status analysis, liquid biopsies have not yet substituted tissue samples, mainly due to the lack of concordance between the two types of biopsies. This needs to be examined in a study-dependent manner, taking into account the particular type of liquid biopsy analyzed, that is, circulating tumor cells (CTCs) or cell-free DNA (cfDNA), its involvement in the tumor biology and evolution and, finally, the technology used to analyze each biopsy type. Here, we review the main studies analyzing TP53 mutations in either CTCs or cfDNA in the three more prevalent solid tumors: breast, colon and lung cancers. We evaluate the correlation for mutation status between liquid biopsies and tumor tissue, suggesting possible sources of discrepancies, as well as evaluating the clinical utility of using liquid biopsies for the analysis of TP53 mutation status and the future actions that need to be undertaken to make liquid biopsy analysis a reality for the evaluation of TP53 mutations.