Limits...
Genetic Heterogeneity and Clonal Evolution of Tumor Cells and their Impact on Precision Cancer Medicine.

Sabaawy HE - J Leuk (Los Angel) (2013)

Bottom Line: The efficacy of targeted therapies in leukemias and solid tumors depends upon the accurate detection and sustained targeting of initial and evolving driver mutations and/or aberrations in cancer cells.Tumor clonal evolution of the diverse populations of cancer cells during cancer progression contributes to the longitudinal variations of clonal, morphological, anatomical, and molecular heterogeneity of tumors.Here, I briefly portray tumor cell clonal evolution at the cellular and molecular levels, and present the multiple types of genetic heterogeneity in tumors, with a focus on their impact on the implementation of personalized or precision cancer medicine.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Rutgers-Robert Wood Johnson Medical School, USA ; Department of Cellular and Molecular Pharmacology, Rutgers-Robert Wood Johnson Medical School, USA ; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903-2681, USA.

ABSTRACT
The efficacy of targeted therapies in leukemias and solid tumors depends upon the accurate detection and sustained targeting of initial and evolving driver mutations and/or aberrations in cancer cells. Tumor clonal evolution of the diverse populations of cancer cells during cancer progression contributes to the longitudinal variations of clonal, morphological, anatomical, and molecular heterogeneity of tumors. Moreover, drug-resistant subclones present at initiation of therapy or emerging as a result of targeted therapies represent major challenges for achieving success of personalized therapies in providing meaningful improvement in cancer survival rates. Here, I briefly portray tumor cell clonal evolution at the cellular and molecular levels, and present the multiple types of genetic heterogeneity in tumors, with a focus on their impact on the implementation of personalized or precision cancer medicine.

No MeSH data available.


Related in: MedlinePlus

Tumor intiating cells, tumor cell clonal evolution, and tumor heterogeneityA simplified diagram displaying the different tumor evolution processes under review. Within the tumor microenvironment, Tumor intiating cells (TICs) initiate premalignant clones through the interactions with the niche cells. The premalignant clones may generate frequent sublinical lesions such as carcinoma in situ (or preleukemic conditions) that are either in most cases repaired at the cellular levels through cell death mechanisms, and at the genetic levels through DNA repair of driver genetic mutations. The premalignant clones may alternatively remain harboring quiescent TICs that can then undergo tumor cell differentiation and/or plasticity within the competitive clonal evolution process to compete for space, nutrients, and proximity to vascular supply. Acquisition of secondary genetic and epigenetic changes in TICs or supportive tumor cells that favor enhanced self-renewal and clonal growth allows premalignant lesions to become a clinically diagnosed malignancy. This tumor evolution process can take from weeks to several years or even decades depending on the tumor type and the the host genetic and enviromental exposure factors. TICs are the units of clonal evolution and their diversity seed the recently identified tumor heterogeneity within each tumor (intratumor heterogeneity) (represented by a dominant clone in red, and three additional subclones in green, blue and yellow in the model). I proposed one dominat clone and three subclones for simplicity. Indeed, the frequency of subclones can be unlimited and dependes on the sensetivity of the detection assays. Neverthless, only detectable clones are thought to have clinical implications. Genetic and phenotypic variations are also detected between individuals with the same tumor type (Intertumor heterogeneity), and occur due to the diversity of clones generated during tumor cell clonal evolution. Upon treatment (Rx), relapse might occur from the diagnostic dominant clone that acquired more selective and drug resistance features, or from sublones that have acquired or inherited resistance to therapy. Therefore, detecting clonal heterogeneity and mechanisms of development of therapy resistant clones is critical for tailoring combination therapies for personalized cancer medicine. Solid arrows indicate defined pathways while dashed arrows indicate suggested mechanisms.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3927925&req=5

Figure 1: Tumor intiating cells, tumor cell clonal evolution, and tumor heterogeneityA simplified diagram displaying the different tumor evolution processes under review. Within the tumor microenvironment, Tumor intiating cells (TICs) initiate premalignant clones through the interactions with the niche cells. The premalignant clones may generate frequent sublinical lesions such as carcinoma in situ (or preleukemic conditions) that are either in most cases repaired at the cellular levels through cell death mechanisms, and at the genetic levels through DNA repair of driver genetic mutations. The premalignant clones may alternatively remain harboring quiescent TICs that can then undergo tumor cell differentiation and/or plasticity within the competitive clonal evolution process to compete for space, nutrients, and proximity to vascular supply. Acquisition of secondary genetic and epigenetic changes in TICs or supportive tumor cells that favor enhanced self-renewal and clonal growth allows premalignant lesions to become a clinically diagnosed malignancy. This tumor evolution process can take from weeks to several years or even decades depending on the tumor type and the the host genetic and enviromental exposure factors. TICs are the units of clonal evolution and their diversity seed the recently identified tumor heterogeneity within each tumor (intratumor heterogeneity) (represented by a dominant clone in red, and three additional subclones in green, blue and yellow in the model). I proposed one dominat clone and three subclones for simplicity. Indeed, the frequency of subclones can be unlimited and dependes on the sensetivity of the detection assays. Neverthless, only detectable clones are thought to have clinical implications. Genetic and phenotypic variations are also detected between individuals with the same tumor type (Intertumor heterogeneity), and occur due to the diversity of clones generated during tumor cell clonal evolution. Upon treatment (Rx), relapse might occur from the diagnostic dominant clone that acquired more selective and drug resistance features, or from sublones that have acquired or inherited resistance to therapy. Therefore, detecting clonal heterogeneity and mechanisms of development of therapy resistant clones is critical for tailoring combination therapies for personalized cancer medicine. Solid arrows indicate defined pathways while dashed arrows indicate suggested mechanisms.

Mentions: NGS for cancer samples is now widely accessible, increasingly affordable, and provides a transformative influence on cancer care with a particular insight into the complexity of the cancer genome [2]. With it, we came to realize the true meaning of the statement that cancer is a disease of the genome. Neoplasms in general represent abnormal outgrowth of tumor cells that gain selective advantages in cell growth, survival, and metabolism. Their sustained growth kinetics lead to the formation of dominant neoplastic clones that compete with, and override normal and preneoplastic cells for space, energy, and nutrient requirements utilizing their genetic and non-genetic drivers for selective advantage. Sequencing of genomes from tumor cells within these clones revealed that tumors have partially or fully transformed cells that harbor hundreds to thousands of genetic mutations, chromosomal alterations, and epigenetic aberrations. The majority of these mutations represents neutral (passenger) mutations, while the selection and propagation of dominant clones of tumor cells that ultimately lead to malignant transformation are both successively and may be independently sustained by multiple different combinations of driver mutations. The orchestrated and sustained signaling actions of these driver mutations during the process of clonal evolution provide, at each stage, a selection advantage, and allow dominant tumor cell clones to finally control various interactions with microenvirmental clues at the eminent stages of tumor development (Figure 1) [3,4]. Intrinsic changes in Tumor Initiating Cells (TICs) result partially from ineffective DNA repair mechanisms [5] and deregulated stem cell differentiation signals [6]. The repertoire of these intrinsic changes in preneoplastic TICs confers neoplastic features of uncontrolled proliferation, unlimited self-renewal, sustained angiogenesis, abnormal differentiation, and tissue invasion and metastasis making hallmarks of cancer [3]. These mutations act as drivers for transformation of cells primed with genetic and epigenetic changes to form preleukemic clones. The preleukemic clones proceed in evolution with additional mutations and clonal selection causing occult leukemias and solid tumors [7–9]. Sequencing studies revealed about 140 genes that when altered by intragenic mutations can act as driver mutations during tumorigenesis [10]. A typical tumor contains two to eight driver mutations, while the remaining are passenger mutations that do not directly confer selective advantages [10], but might play critical roles in orchestrating the genetic interactions between driver mutations and the microenvironment towards tumor progression. The numbers of driver and passenger mutations that were revealed by sequencing vary among tumor types and even from patient to patient. Genome sequencing studies have also found that pediatric leukemias harbor on average 9.6 mutations per tumor, while melanomas and lung cancer might harbor more than 200 mutations per tumor [10]. The latter might reflect effects of environmental factors such as smoking and UV radiation that play significant roles in the etiology of lung cancer and melanomas, respectively.


Genetic Heterogeneity and Clonal Evolution of Tumor Cells and their Impact on Precision Cancer Medicine.

Sabaawy HE - J Leuk (Los Angel) (2013)

Tumor intiating cells, tumor cell clonal evolution, and tumor heterogeneityA simplified diagram displaying the different tumor evolution processes under review. Within the tumor microenvironment, Tumor intiating cells (TICs) initiate premalignant clones through the interactions with the niche cells. The premalignant clones may generate frequent sublinical lesions such as carcinoma in situ (or preleukemic conditions) that are either in most cases repaired at the cellular levels through cell death mechanisms, and at the genetic levels through DNA repair of driver genetic mutations. The premalignant clones may alternatively remain harboring quiescent TICs that can then undergo tumor cell differentiation and/or plasticity within the competitive clonal evolution process to compete for space, nutrients, and proximity to vascular supply. Acquisition of secondary genetic and epigenetic changes in TICs or supportive tumor cells that favor enhanced self-renewal and clonal growth allows premalignant lesions to become a clinically diagnosed malignancy. This tumor evolution process can take from weeks to several years or even decades depending on the tumor type and the the host genetic and enviromental exposure factors. TICs are the units of clonal evolution and their diversity seed the recently identified tumor heterogeneity within each tumor (intratumor heterogeneity) (represented by a dominant clone in red, and three additional subclones in green, blue and yellow in the model). I proposed one dominat clone and three subclones for simplicity. Indeed, the frequency of subclones can be unlimited and dependes on the sensetivity of the detection assays. Neverthless, only detectable clones are thought to have clinical implications. Genetic and phenotypic variations are also detected between individuals with the same tumor type (Intertumor heterogeneity), and occur due to the diversity of clones generated during tumor cell clonal evolution. Upon treatment (Rx), relapse might occur from the diagnostic dominant clone that acquired more selective and drug resistance features, or from sublones that have acquired or inherited resistance to therapy. Therefore, detecting clonal heterogeneity and mechanisms of development of therapy resistant clones is critical for tailoring combination therapies for personalized cancer medicine. Solid arrows indicate defined pathways while dashed arrows indicate suggested mechanisms.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927925&req=5

Figure 1: Tumor intiating cells, tumor cell clonal evolution, and tumor heterogeneityA simplified diagram displaying the different tumor evolution processes under review. Within the tumor microenvironment, Tumor intiating cells (TICs) initiate premalignant clones through the interactions with the niche cells. The premalignant clones may generate frequent sublinical lesions such as carcinoma in situ (or preleukemic conditions) that are either in most cases repaired at the cellular levels through cell death mechanisms, and at the genetic levels through DNA repair of driver genetic mutations. The premalignant clones may alternatively remain harboring quiescent TICs that can then undergo tumor cell differentiation and/or plasticity within the competitive clonal evolution process to compete for space, nutrients, and proximity to vascular supply. Acquisition of secondary genetic and epigenetic changes in TICs or supportive tumor cells that favor enhanced self-renewal and clonal growth allows premalignant lesions to become a clinically diagnosed malignancy. This tumor evolution process can take from weeks to several years or even decades depending on the tumor type and the the host genetic and enviromental exposure factors. TICs are the units of clonal evolution and their diversity seed the recently identified tumor heterogeneity within each tumor (intratumor heterogeneity) (represented by a dominant clone in red, and three additional subclones in green, blue and yellow in the model). I proposed one dominat clone and three subclones for simplicity. Indeed, the frequency of subclones can be unlimited and dependes on the sensetivity of the detection assays. Neverthless, only detectable clones are thought to have clinical implications. Genetic and phenotypic variations are also detected between individuals with the same tumor type (Intertumor heterogeneity), and occur due to the diversity of clones generated during tumor cell clonal evolution. Upon treatment (Rx), relapse might occur from the diagnostic dominant clone that acquired more selective and drug resistance features, or from sublones that have acquired or inherited resistance to therapy. Therefore, detecting clonal heterogeneity and mechanisms of development of therapy resistant clones is critical for tailoring combination therapies for personalized cancer medicine. Solid arrows indicate defined pathways while dashed arrows indicate suggested mechanisms.
Mentions: NGS for cancer samples is now widely accessible, increasingly affordable, and provides a transformative influence on cancer care with a particular insight into the complexity of the cancer genome [2]. With it, we came to realize the true meaning of the statement that cancer is a disease of the genome. Neoplasms in general represent abnormal outgrowth of tumor cells that gain selective advantages in cell growth, survival, and metabolism. Their sustained growth kinetics lead to the formation of dominant neoplastic clones that compete with, and override normal and preneoplastic cells for space, energy, and nutrient requirements utilizing their genetic and non-genetic drivers for selective advantage. Sequencing of genomes from tumor cells within these clones revealed that tumors have partially or fully transformed cells that harbor hundreds to thousands of genetic mutations, chromosomal alterations, and epigenetic aberrations. The majority of these mutations represents neutral (passenger) mutations, while the selection and propagation of dominant clones of tumor cells that ultimately lead to malignant transformation are both successively and may be independently sustained by multiple different combinations of driver mutations. The orchestrated and sustained signaling actions of these driver mutations during the process of clonal evolution provide, at each stage, a selection advantage, and allow dominant tumor cell clones to finally control various interactions with microenvirmental clues at the eminent stages of tumor development (Figure 1) [3,4]. Intrinsic changes in Tumor Initiating Cells (TICs) result partially from ineffective DNA repair mechanisms [5] and deregulated stem cell differentiation signals [6]. The repertoire of these intrinsic changes in preneoplastic TICs confers neoplastic features of uncontrolled proliferation, unlimited self-renewal, sustained angiogenesis, abnormal differentiation, and tissue invasion and metastasis making hallmarks of cancer [3]. These mutations act as drivers for transformation of cells primed with genetic and epigenetic changes to form preleukemic clones. The preleukemic clones proceed in evolution with additional mutations and clonal selection causing occult leukemias and solid tumors [7–9]. Sequencing studies revealed about 140 genes that when altered by intragenic mutations can act as driver mutations during tumorigenesis [10]. A typical tumor contains two to eight driver mutations, while the remaining are passenger mutations that do not directly confer selective advantages [10], but might play critical roles in orchestrating the genetic interactions between driver mutations and the microenvironment towards tumor progression. The numbers of driver and passenger mutations that were revealed by sequencing vary among tumor types and even from patient to patient. Genome sequencing studies have also found that pediatric leukemias harbor on average 9.6 mutations per tumor, while melanomas and lung cancer might harbor more than 200 mutations per tumor [10]. The latter might reflect effects of environmental factors such as smoking and UV radiation that play significant roles in the etiology of lung cancer and melanomas, respectively.

Bottom Line: The efficacy of targeted therapies in leukemias and solid tumors depends upon the accurate detection and sustained targeting of initial and evolving driver mutations and/or aberrations in cancer cells.Tumor clonal evolution of the diverse populations of cancer cells during cancer progression contributes to the longitudinal variations of clonal, morphological, anatomical, and molecular heterogeneity of tumors.Here, I briefly portray tumor cell clonal evolution at the cellular and molecular levels, and present the multiple types of genetic heterogeneity in tumors, with a focus on their impact on the implementation of personalized or precision cancer medicine.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Rutgers-Robert Wood Johnson Medical School, USA ; Department of Cellular and Molecular Pharmacology, Rutgers-Robert Wood Johnson Medical School, USA ; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903-2681, USA.

ABSTRACT
The efficacy of targeted therapies in leukemias and solid tumors depends upon the accurate detection and sustained targeting of initial and evolving driver mutations and/or aberrations in cancer cells. Tumor clonal evolution of the diverse populations of cancer cells during cancer progression contributes to the longitudinal variations of clonal, morphological, anatomical, and molecular heterogeneity of tumors. Moreover, drug-resistant subclones present at initiation of therapy or emerging as a result of targeted therapies represent major challenges for achieving success of personalized therapies in providing meaningful improvement in cancer survival rates. Here, I briefly portray tumor cell clonal evolution at the cellular and molecular levels, and present the multiple types of genetic heterogeneity in tumors, with a focus on their impact on the implementation of personalized or precision cancer medicine.

No MeSH data available.


Related in: MedlinePlus