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Emerging concepts in liquid biopsies

View Article: PubMed Central - PubMed

ABSTRACT

Characterizing and monitoring tumor genomes with blood samples could achieve significant improvements in precision medicine. As tumors shed parts of themselves into the circulation, analyses of circulating tumor cells, circulating tumor DNA, and tumor-derived exosomes, often referred to as “liquid biopsies”, may enable tumor genome characterization by minimally invasive means. Indeed, multiple studies have described how molecular information about parent tumors can be extracted from these components. Here, we briefly summarize current technologies and then elaborate on emerging novel concepts that may further propel the field. We address normal and detectable mutation levels in the context of our current knowledge regarding the gradual accumulation of mutations during aging and in light of technological limitations. Finally, we discuss whether liquid biopsies are ready to be used in routine clinical practice.

No MeSH data available.


Related in: MedlinePlus

Mutation rate in adult stem cells and their potential consequences. a Correlation of the number of somatic point mutations in adult stem cells derived from colon, small intestine, and liver with age of the donor (adapted from [66]); there is an increase of ~36 mutations/adult stem cell/year. b Summary of the “Three strikes to cancer model” [68] for colorectal cancer, where mutations occur in specific driver genes. In the breakthrough phase, a mutation occurs in APC and results in abnormal division of the respective cell. Subsequently, a mutation in KRAS may follow in the expansion phase and may give rise to a benign tumor. Occurrence of a further mutation in a driver gene in at least one of the listed pathways SMAD4, TP53, PIK3CA, or FBXW7 may enable the tumor to invade surrounding tissues and to initiate the invasive phase with dissemination of tumor cells and formation of metastases [68]. The mutations may be detectable in cfDNA; furthermore, depending on the ctDNA allele frequency and tumor stage, somatic copy number alterations may become visible (shown exemplarily for chromosome 8: blue: lost; green: balanced; and red: gained region). c As the order of driver gene mutations is important, the consequences differ if a TP53 mutation occurs in a colon stem cell before the initiating mutations have taken place. Such a TP53 mutation alone will not be sufficient to cause increased proliferation or even to transform the cell into a tumor cell. However, due to the stem cell’s capacity of self-renewal, cells with this mutation may be propagated in the respective part of the colon. Depending on how many of these cells are removed by apoptosis or other events, ultra-sensitive ctDNA assays may then detect this mutation in the blood; this will usually not be accompanied by copy number alterations (as indicated by the green scatter-plot for chromosome 8)
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Fig1: Mutation rate in adult stem cells and their potential consequences. a Correlation of the number of somatic point mutations in adult stem cells derived from colon, small intestine, and liver with age of the donor (adapted from [66]); there is an increase of ~36 mutations/adult stem cell/year. b Summary of the “Three strikes to cancer model” [68] for colorectal cancer, where mutations occur in specific driver genes. In the breakthrough phase, a mutation occurs in APC and results in abnormal division of the respective cell. Subsequently, a mutation in KRAS may follow in the expansion phase and may give rise to a benign tumor. Occurrence of a further mutation in a driver gene in at least one of the listed pathways SMAD4, TP53, PIK3CA, or FBXW7 may enable the tumor to invade surrounding tissues and to initiate the invasive phase with dissemination of tumor cells and formation of metastases [68]. The mutations may be detectable in cfDNA; furthermore, depending on the ctDNA allele frequency and tumor stage, somatic copy number alterations may become visible (shown exemplarily for chromosome 8: blue: lost; green: balanced; and red: gained region). c As the order of driver gene mutations is important, the consequences differ if a TP53 mutation occurs in a colon stem cell before the initiating mutations have taken place. Such a TP53 mutation alone will not be sufficient to cause increased proliferation or even to transform the cell into a tumor cell. However, due to the stem cell’s capacity of self-renewal, cells with this mutation may be propagated in the respective part of the colon. Depending on how many of these cells are removed by apoptosis or other events, ultra-sensitive ctDNA assays may then detect this mutation in the blood; this will usually not be accompanied by copy number alterations (as indicated by the green scatter-plot for chromosome 8)

Mentions: Measurement of the somatic mutation load in stem cells within various human tissues poses an immense technical problem. Blokzijl et al. [66] addressed this challenge by using cells capable of forming long-term organoid cultures. An organoid can be defined as a cellular structure containing several cell types that have developed from stem cells or organ progenitors that self-organize through cell sorting and spatially restricted lineage commitment [67]. Single adult stem cells from the small intestine, colon, and liver, tissues which differ greatly in proliferation rate and cancer risk, were expanded into epithelial organoids to obtain sufficient DNA for whole-genome sequencing. The donors ranged in age from 3 to 87 years and, not unexpectedly, it was found that stem cells accumulated mutations with age independent of tissue type [66]. The mutation rate, i.e., the increase in the number of somatic point mutations in each stem cell, was in the same range for all assessed tissues, at approximately 36 mutations per year, despite the large variation in cancer incidence among these tissues (Fig. 1a). Importantly, the findings suggested a universal genomic ageing mechanism, i.e., a chemical process acting on DNA molecules, independent of cellular function or proliferation rate. Furthermore, this intrinsic, unavoidable mutational process can cause the same types of mutations as those observed in cancer driver genes [66].Fig. 1


Emerging concepts in liquid biopsies
Mutation rate in adult stem cells and their potential consequences. a Correlation of the number of somatic point mutations in adult stem cells derived from colon, small intestine, and liver with age of the donor (adapted from [66]); there is an increase of ~36 mutations/adult stem cell/year. b Summary of the “Three strikes to cancer model” [68] for colorectal cancer, where mutations occur in specific driver genes. In the breakthrough phase, a mutation occurs in APC and results in abnormal division of the respective cell. Subsequently, a mutation in KRAS may follow in the expansion phase and may give rise to a benign tumor. Occurrence of a further mutation in a driver gene in at least one of the listed pathways SMAD4, TP53, PIK3CA, or FBXW7 may enable the tumor to invade surrounding tissues and to initiate the invasive phase with dissemination of tumor cells and formation of metastases [68]. The mutations may be detectable in cfDNA; furthermore, depending on the ctDNA allele frequency and tumor stage, somatic copy number alterations may become visible (shown exemplarily for chromosome 8: blue: lost; green: balanced; and red: gained region). c As the order of driver gene mutations is important, the consequences differ if a TP53 mutation occurs in a colon stem cell before the initiating mutations have taken place. Such a TP53 mutation alone will not be sufficient to cause increased proliferation or even to transform the cell into a tumor cell. However, due to the stem cell’s capacity of self-renewal, cells with this mutation may be propagated in the respective part of the colon. Depending on how many of these cells are removed by apoptosis or other events, ultra-sensitive ctDNA assays may then detect this mutation in the blood; this will usually not be accompanied by copy number alterations (as indicated by the green scatter-plot for chromosome 8)
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Related In: Results  -  Collection

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Fig1: Mutation rate in adult stem cells and their potential consequences. a Correlation of the number of somatic point mutations in adult stem cells derived from colon, small intestine, and liver with age of the donor (adapted from [66]); there is an increase of ~36 mutations/adult stem cell/year. b Summary of the “Three strikes to cancer model” [68] for colorectal cancer, where mutations occur in specific driver genes. In the breakthrough phase, a mutation occurs in APC and results in abnormal division of the respective cell. Subsequently, a mutation in KRAS may follow in the expansion phase and may give rise to a benign tumor. Occurrence of a further mutation in a driver gene in at least one of the listed pathways SMAD4, TP53, PIK3CA, or FBXW7 may enable the tumor to invade surrounding tissues and to initiate the invasive phase with dissemination of tumor cells and formation of metastases [68]. The mutations may be detectable in cfDNA; furthermore, depending on the ctDNA allele frequency and tumor stage, somatic copy number alterations may become visible (shown exemplarily for chromosome 8: blue: lost; green: balanced; and red: gained region). c As the order of driver gene mutations is important, the consequences differ if a TP53 mutation occurs in a colon stem cell before the initiating mutations have taken place. Such a TP53 mutation alone will not be sufficient to cause increased proliferation or even to transform the cell into a tumor cell. However, due to the stem cell’s capacity of self-renewal, cells with this mutation may be propagated in the respective part of the colon. Depending on how many of these cells are removed by apoptosis or other events, ultra-sensitive ctDNA assays may then detect this mutation in the blood; this will usually not be accompanied by copy number alterations (as indicated by the green scatter-plot for chromosome 8)
Mentions: Measurement of the somatic mutation load in stem cells within various human tissues poses an immense technical problem. Blokzijl et al. [66] addressed this challenge by using cells capable of forming long-term organoid cultures. An organoid can be defined as a cellular structure containing several cell types that have developed from stem cells or organ progenitors that self-organize through cell sorting and spatially restricted lineage commitment [67]. Single adult stem cells from the small intestine, colon, and liver, tissues which differ greatly in proliferation rate and cancer risk, were expanded into epithelial organoids to obtain sufficient DNA for whole-genome sequencing. The donors ranged in age from 3 to 87 years and, not unexpectedly, it was found that stem cells accumulated mutations with age independent of tissue type [66]. The mutation rate, i.e., the increase in the number of somatic point mutations in each stem cell, was in the same range for all assessed tissues, at approximately 36 mutations per year, despite the large variation in cancer incidence among these tissues (Fig. 1a). Importantly, the findings suggested a universal genomic ageing mechanism, i.e., a chemical process acting on DNA molecules, independent of cellular function or proliferation rate. Furthermore, this intrinsic, unavoidable mutational process can cause the same types of mutations as those observed in cancer driver genes [66].Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Characterizing and monitoring tumor genomes with blood samples could achieve significant improvements in precision medicine. As tumors shed parts of themselves into the circulation, analyses of circulating tumor cells, circulating tumor DNA, and tumor-derived exosomes, often referred to as “liquid biopsies”, may enable tumor genome characterization by minimally invasive means. Indeed, multiple studies have described how molecular information about parent tumors can be extracted from these components. Here, we briefly summarize current technologies and then elaborate on emerging novel concepts that may further propel the field. We address normal and detectable mutation levels in the context of our current knowledge regarding the gradual accumulation of mutations during aging and in light of technological limitations. Finally, we discuss whether liquid biopsies are ready to be used in routine clinical practice.

No MeSH data available.


Related in: MedlinePlus