In search of molecular approaches to improving cancer therapy efficacy
The study of genome rearrangement sites using full genome sequences is an important approach to revealing the nature of cancer and finding effective ways for cancer treatment. The progress in DNA sequencing could make the procedure of whole genome reading close to routine procedure of lower cost. T...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2014
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| Cite this: | In search of molecular approaches to improving cancer therapy efficacy / E. Cherepenko, G. Telegeev // Experimental Oncology. — 2014. — Т. 36, № 1. — С. 52-55. — Бібліогр.: 28 назв. — англ. |
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| citation_txt | In search of molecular approaches to improving cancer therapy efficacy / E. Cherepenko, G. Telegeev // Experimental Oncology. — 2014. — Т. 36, № 1. — С. 52-55. — Бібліогр.: 28 назв. — англ. |
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| description | The study of genome rearrangement sites using full genome sequences is an important approach to revealing the nature of cancer and finding effective ways for cancer treatment. The progress in DNA sequencing could make the procedure of whole genome reading close to routine procedure of lower cost. The personal analysis of rearranged ends (PARE) method used for rearrangement study is reviewed. PARE allows identifying of individual cancer biomarkers making personal medicine possible. Also, the progress in “liquid biopsy” technology based on detection of circulating tumor cells in the patient’s blood is shortly summarized. Another important approach is the discovered phenomenon of synthetic lethality causing cancer cell death due to appropriate combination of mutations in different genes or inhibitors of their protein products. Studies of genome rearrangements and synthetic lethality are considered promising for the development of effective cancer treatment approaches. Key Words: PARE, circulating tumor DNA, circulating tumor cells, liquid biopsy, synthetic lethality, cancer cell.
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| first_indexed | 2025-12-07T16:47:40Z |
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52 Experimental Oncology 36, 52–55, 2014 (March)
IN SEARCH OF MOLECULAR APPROACHES TO IMPROVING
CANCER THERAPY EFFICACY
E. Cherepenko*, G. Telegeev
Institute of Molecular Biology and Genetics, NAS of Ukraine, Kyiv, Ukraine
The study of genome rearrangement sites using full genome sequences is an important approach to revealing the nature of cancer
and finding effective ways for cancer treatment. The progress in DNA sequencing could make the procedure of whole genome reading
close to routine procedure of lower cost. The personal analysis of rearranged ends (PARE) method used for rearrangement study
is reviewed. PARE allows identifying of individual cancer biomarkers making personal medicine possible. Also, the progress in
“liquid biopsy” technology based on detection of circulating tumor cells in the patient’s blood is shortly summarized. Another
important approach is the discovered phenomenon of synthetic lethality causing cancer cell death due to appropriate combination
of mutations in different genes or inhibitors of their protein products. Studies of genome rearrangements and synthetic lethality are
considered promising for the development of effective cancer treatment approaches.
Key Words: PARE, circulating tumor DNA, circulating tumor cells, liquid biopsy, synthetic lethality, cancer cell.
Obviously, there comes a time in oncology speaking
in biblical language to “gather stones” and to evaluate
the significance of molecular diversity detected in tumor
cells. Such a feeling may emerge due to the organiza-
tion of the first systemic discussion of numerous results
obtained in individual cancer treatment. Such discussion
was organized by the Ist International Congress on per-
sonalized treatment of cancer (Controversies in Persona-
lized Oncology Treatment) that took place in Barce-
lona on 7–10 March, 2013 [1]. Prospects of personalized
medicine are mostly based on advances in the study
of the individual characteristics of tumor DNA sequences.
DNA sequences rearrangements especially frequent
in cancer genome could currently be localized allowing
the construction of individual patient’s oncomaps. Another
important approach is the discovered possibility of the so-
called synthetic lethality. This term is related to tumor cell
killing with the use of individual molecular combinations
targeting activity of special enzymes or induction of muta-
tions. These novel approaches can be somewhat simpli-
fied using the so-called “liquid biopsy” as the recently
discovered possibility of manipulating with cancer patient
DNA and separate circulating tumor cells (CTC) present
in blood and possibly in other fluids of the organism. Here
we discuss some of the molecular approaches that could
improve treatment of cancer patients
The study of the individual characteristics of DNA
in cancer patients is becoming easier due to new technolo-
gies: comparable genome hybridization (CGH) and DNA
sequencing called New Generation Sequencing (NGS).
Possibility of full genome sequencing allows detecting dif-
ferences in genetic texts of cancer patients in comparison
with the genome of healthy individuals. Such a healthy
genome for the comparison purposes is called reference
genome or reference assembly using the DNA sequencing
data from a number of healthy donors. Useful information
can currently be obtained by comparison of a) nucleotide
sequences of healthy and cancer genomes of different
individuals, b) genomes of normal and malignant cells
of the same organism, and c) nucleotide sequences of tu-
mors of different histological types. Thus, the develo ped
technologies opened a powerful way for the genetic map-
ping [2]. Analysis of oncomaps allowed separate the genes
carrying cancer-related mutations into two groups: driver
and passenger as to whether they do or do not influence
the malignant cell reproduction rate and hence the growth
of the tumor [3]. Interesting, could the genomic rearrange-
ments present in cancer patient be divided alike?
The opened possibilities to study sequence
alterations in full cancer genomes draw attention
to genome rearrangements. Until recently the main
efforts in tumor DNA studies were focused mainly on two
things. The first is single nucleotide polymorphism (SNP)
presented by different point mutations and the so-
called indel mutations (associated with insert or loss
of nucleotides-deletion). And the second one is mainly
due to the processes of nucleotide loss or conversely
amplification that change the number of gene copies
in genome. Previously it was called CNV — copy number
variation, and later a new term aCGH (array comparative
genome hybridization) appeared. Numerous sequence
alterations found in cancer patient DNA are currently
covered by specially developed databases. As an example
954,247 mutations in 2680 exomes of 14 cancer types
could be studied [4]. These databases include The Cancer
Genome Atlas — TCGA data; COSMIC — Cancer Gene
Census; CRAVAT — Cancer-Related Analysis of VArients
Toolkit, and others that are comprehensively summarized
in the work [4 and references therein].
In recent years the genetic rearrangements in cancer
cell genomes and their functional role are of particular
interest in connection with the previously established
fact of aneuploidy in tumor cells [5–9]. Aneuploidy
Received: July 30, 2013.
*Correspondence: E-mail: cherepenko@mail.ru
Abbreviations used: aCGH — array comparative genome hybridiza-
tion; CGH — comparable genome hybridization; CNV — copy num-
ber variation; CTC — circulating tumor cells; DSB — double strand
brake; DTC — disseminating tumor cells; LCM — laser capture
microdissection; NGS — New Generation Sequencing; PARE —
personal analysis of rearranged ends; SNP — single nucleotide
polymorphism; SSB — single strand brake.
Exp Oncol 2014
36, 1, 52–55
POINT OF VIEW
Experimental Oncology 36, 52–55, 2014 (March) 53
is characteristic to cancer cell as well as the inherent insta-
bility of cell cancer genome leading to numerous genomic
rearrangements and chromosomal chaos [5–7]. Many
authors have addressed a question how aneuploidy and
genome instability may be associated [3, 10]. In the study
[10] there have been compared the results of cancer
cells study at the level of karyotypic changes and that
of individual genes mutability, without going into details
on the genes being drivers or passengers. The most
informative name of a novel approach is the classic one
“Whole genome vs selected gene panel approach” [11].
The possibility of full genome sequencing and detec-
tion of genomic rearrangement sites allows experimental
studies of deregulation of cancer cell work as a functional
single system. Study of genome rearrangements may
deepen insights on cell organization.
Study of genomic rearrangements using
PARE method. Development of high-tech methods
of sequencing, extremely optimized and less expensive for
reading full genome texts, even very large and complex,
provided the possibility of detecting various reorganiza-
tions of the genome, in particular, changes in nucleotide
sequences resulted from formation of different gap(s)
and illegitimate reunion of different genome fragments.
An efficacious method to study the genomic rear-
rangements in cancer cells is a method called PARE
(personalized analysis of rearranged ends) [12]. We briefly
describe here this technology.
It is clear that full genome sequences could be com-
pared in the manner base by base. However, because
the patient genome size is about 3 billion nucleotides,
the work would be too expensive and unjustified for
clinical use. At the same time, simultaneous examination
of only short sequences at both ends of the same DNA
molecule of fragmented genome is the way to simplifica-
tion. The known distance apart both DNA molecule ends
allows getting rid of the nucleotide content between
the two ends. The identification of these end sequences
occurs as if in paired form, in the form of these ends ma-
ting (mate-paired ends). Then mapping of these ends
to fully sequenced genome significantly simplifies and
reduces the cost of finding rearranged sites in genome.
Using this approach, it is possible to consider the influence
of repeated and amplified sequence first of all when com-
paring molecules belonging respectively to the genomes
of normal and malignant cells. So, this technique account-
ing nucleotide changes at sites of repeated and ampli-
fied sequences, allows identifying such a combination
of nucleotide text in the molecules of cancer genome that
is not detected in the molecules of a fragmented genome
of normal cells. Detection of molecules that carry such
a nucleotide combination indicates that these molecules
come from genome sites where rearrangement via both
intra- and interchromosomal translocations occurs.
To characterize the logic of an approach to study
genetic rearrangements using PARE we briefly describe
one example. Genomic DNA is fragmented using me-
chanical efforts and ends of molecules obtained are
repaired using biotin label. Then such molecules are
circulated and cleared of noncircular DNA using nuclease
digestion. Circular molecules obtained are fragmented
again, and catching biotin label using magnetic beads
with the streptavidin allows obtaining of fragments of uni-
form size that contain only the end sequence of the same
original mole cule. The ends of the DNA molecules obtained
in such a manner are also repaired and are surrounded
by the sequences of special adaptors and primers that allow
sequencing 25 nucleotide end tags. Performing emulsion
PCR allows landing on a magnetic bead of only one DNA
molecule. In this manner the library of end sequences can
be obtained and fixed on a hard surface for sequencing
in the form of amplicons, or DNA colonies, or using new
terminology DNA clusters. In the resulting mate-paired end
library, different molecules of the genome are sequenced.
Modern equipment and methods allow simultaneous se-
quencing up to 500 000 of such mo lecules (massive parallel
sequencing) per a sequencer run. Currently, nucleotide
sequencing exploits two principles: sequencing by using
template synthesis, classical Sanger sequencing and se-
quencing by oligonucleotide ligation [13]. There has been
great progress in the development of equipment, analyzing
signals produced by both types of sequencing.
The success of the molecular approach to finding
individual tumor markers based on the PARE method
and its practical use in medicine has been demonstrated
in the work by V. Velculescu et al. [12]. In the referred
work the pair ends study approach originally designed
by Applied Biosystems SOLiD system was used. Using
the reference genome, studying the genome of solid can-
cers compared respectively to the patient healthy tissue
genome, the authors analyzed the short end sequence for
each DNA sample of roughly 40 million reads. The posi-
tions of these reads at the reference genome were defined
exactly. The total nucleotide number of analyzed end
sequences was increased by the value of nucleotides be-
tween the ends of the studied molecules. Considering the
study of the number of mate-paired end tags molecules
represented in the library, the performed sequencing
resulted in 18-fold physical coverage of the human ge-
nome, i.e. with very high probability this analysis covered
the whole genome completely.
The detection of individual cancer biomarkers.
An important result of the work [12] was the demon-
stration of the discovery of an individual oncomarker
in a colon cancer patient and the detection in the blood
plasma (possibly in other body fluids) of tumor mutant
DNA with modifications that distinguish it from normal cell
DNA. The possibility of manipulations with the cancer cell
DNA circulating in the patient’s blood was convincingly
demonstrated.
It turned out that the mutant DNA, identified only
in the tumor cells of a studied patient is characterized
by a translocation of sequences between 4 and 8 chromo-
somes — 4: 8 translocation. Two methods were used to find
it. According to one of them mo lecules that contained
sequences belonging to diffe rent chromosomes have
been selected from the end tag libraries and the genome
text was studied at the distance between end tags equal
to 1 kb. If an unusual combination of nucleotides has been
detected in this group of molecules at least 5 times, such
54 Experimental Oncology 36, 52–55, 2014 (March)
carriers have been chosen to further research using PCR
primer specific for translocation breakpoints. In the case
of healthy DNA corresponding PCR products were not
found, by they were identified in case of the cancer DNA.
The second method for search of rearranged sequenc-
es in cancer cells using mate-paired end sequencing
approach allows distinguishing between real transloca-
tion breakpoints from those that appear due to genome
repetitive and amplified sequences. In this case, the work
with tags was carried out on the 3 kb genome sequences.
Determination of tags density occurrence on a single
molecule and on the total number of mo lecules of this
group allows determining which sites found are related
to genome amplification processes and which are real
rearranged sequences of a cancer cell. Studying in this
manner DNA from 5 different cancer patients, the translo-
cation 4: 8 was identified only in one of them. The particular
value of this result is that no comparison of the cancer
and normal cell genomes is needed. This halves the cost
of the analysis making the price acceptable to the broader
range of patients.
Identification of 4: 8 marker in a cancer cell genome has
enabled to determine the sensitivity of the measurement
in the presence of various DNA impurities originated from
healthy tissues. It turned out that using a primer annealing
to 4: 8 rearrangement breakpoint allows revealing a cancer
cell genome equivalent in the presence of 390 000 normal
genome equivalents. So, in the plasma of a patient blood the
presence of tumor DNA can be detected at the concentra-
tion less than 0.001% of the content of all DNA in the sample.
The capability to detect the circulation of the mutant DNA
in the body simplifies, accelerates and diversifies the ap-
proaches to various cancer research. It is clear that this
identified rearrangement of sequences could be exploited
not only as a personal biomarker but also allows studying
biochemical and physiological changes induced in the cell
due to such rearrangement.
Moreover, an individual 4: 8 chromosome translocation
biomarker simplifies the study of the efficacy of chemo-
therapy because it improves monitoring of the marker
in blood samples. It opens the prospect for an individual
cancer therapy. However, this approach may face certain
limitations due to malignant cells heterogeneity observed
in the same tumor that is associated with the cancer ge-
nome instability. The tumor cells at any given moment are
presented in the form of different clones, as well as their
different subclones. In the work [14] it has been shown that
the study of genomic polymorphism of fully sequenced
tumor DNA exons allows comparing the level of clonal
heterogeneity and their proliferation rates.
We note here also that the heterogeneity of tumor cells
stimulates developing the technology that allows the se-
lection of a single cell; an accurate characterization of DNA
from such a cell improves characterization of the studied
clone and its different subclones. Obtaining of such
cells is possible using with the aid of a laser technique,
so-called Laser Capture Microdissection — LCM [15].
The DNA obtained in this way contains sequences of a full
genome. By means of amplification and fragmentation
it could be used for preparing a library of molecules ready
for the mate-paired ends sequencing and identification
of rearrangement sites.
Circulating tumor cells. The study of CTC in peri-
pheral blood of patients with solid tumors of epithelial origin
is also currently an area of intense studies [16]. Moreover,
it was found that tumor progression is accompanied
by appearance of disseminating tumor cells (DTC) homing
mainly in the bone marrow where they can stay dormant
for years due to yet undisclosed reasons [17–19].
Various sensitive methods of isolation of CTC from
blood including the “liquid biopsy” are developed.
Methods are based on different principles: the use of dif-
ferences in physical properties (cell density, their size),
differences in gene expression profile (the cells express
the marker proteins like adhesion molecule of epithelial
cells — EpCAM and proteins of cytoske leton filaments —
cytokeratin). The status of these markers can be evaluated
by immunostaining, proper results of RT-PCR reactions
and special EPISPOT analysis [20].
Synthetic lethality. The distinctive feature of cancer
cell is its genome instability and emerging repair defects
that make highly probable the mutagenesis processes.
High levels of mutagenesis in tumor cell can decrease
the efficacy of targeted therapy. Therefore, the success
of chemotherapy depends on the ability to inhibit muta-
genesis processes.
The studies of different gene mutation effects showed
that when mutations in some genes are induced in cells
separately there are no large biological effects, except
minor phenotypic changes. However, the simultaneous
mutations in few different genes may result in cancer cell
death that is called synthetic lethality.
A phenomenon called metabolic bypass is related
to cell survival in the conditions of the loss of a gene leading
to total absence of an enzyme activity [21]. It means
an existence of some biochemical compensating mecha-
nisms buffering the possible effects of emerging genetic
changes. A special review [22] is dedicated to the prin-
ciples for the work of such buffer mechanisms. Moreover,
in a chapter of the book [21] we have shown that an ef-
ficacious approach to the study of the cellular potential
buffer mechanisms might be the study of artifacts revealed
during gene cloning using genetic complementation
methods. Interestingly, these artifacts may belong quite
to different metabolic pathways.
So, if the synthetic lethality can be an efficient method
for cancer cells elimination from the body, the search
of such possible combinations is perspective. Here
we present some results of studies in the field of synthetic
lethality.
Simultaneously the two groups of researchers have
found that treatment of breast cancer cell cultures
with a target inhibitor of poly-ADP-ribose polymerase
(PARP) resulted in massive cell death [23]. PARP is in-
volved in the reparation processes, in particular, in repair
of single strand breaks — SSB using base excision repair
BER. When PARP “senses” SSB it undergoes structural
change, interacts with coenzyme nicotinamide adenin
dinucleotide (NAD+) and cleaves it producing nicotina mide
and ADP-ribose that PARP polymerises to highly negative
Experimental Oncology 36, 52–55, 2014 (March) 55
chains — PAR. As a result of this reaction, a reparative
active protein complex containing PAR-PARP is formed
at the site of DNA reparation. Interestigly, when PARP
binds its inhibitor, the enzyme interacts with DNA, but
can’t dissociate from it what makes DNA replication im-
possible [24]. It was studied why breast cancer cells unlike
healthy cells die when they were treated using the inhibitor
that competes with NAD+ for binding with the PARP and
thus disabling the enzyme of capacity to repair DNA
strands breaks. It turned out that genome reparation is car-
ried out through various mechanisms, and some of them
are overlapping. It is known that in breast cancer patients
there is malfunction of BRCA 1 and BRCA2 genes. The first
gene is involved in repair of double strand breaks — DSB
and the second one is responsible for homologous re-
combination. However, if these genes do not function
in breast cancer cells because of mutations induced then
PARP begins to fulfill their work. Clearly, the PARP inhibitor
deprives the cell of the last chance to maintain its genome
intact and emerged in this case synthetic lethality dooms
cell to death. Currently the role of synthetic lethality po-
tential in conjunction with that of the reparation processes
for the successful treatment of breast cancer is intensely
studied [25–27].
The repair processes and synthetic lethality in the case
of solid tumors is thought to be influenced by tumor mi-
croenvironment. Using model cell culture experiments
it has been shown that in condition of hypoxia the genes
coding for proteins involved in homologous recombination
are not expressed and no DSB reparation occurs. If PARP
inhibitor is used, the massive cell death is observed [28].
So, the original technology of possible reading
the large arrays of DNA sequences known as New Gene-
ration Sequencing allows working with the full genome
sequences reliably finding the places of genomic rear-
rangements. Study of genome reorganizations raises
many questions for fundamental research. Currently, new
opportunities, namely, the study of circulating tumor DNA
and CTC in the manner of “liquid biopsy” have appeared.
High levels of mutagenesis observed in cancer cell due
to many intrinsic factors (for example induction of APOBEC
mutagenase, imbalance in synthesis of DNA precursors)
speaking philosophically represent both evil and good.
The first is frequent loss of cancer cell sensitivity to target
drugs. The second is the possibility of creating lethal com-
bination of mutations leading to possible synthetic lethality
of the cell. The important task is learning how to do this
probability useful and effective for clinical purposes.
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Copyright © Experimental Oncology, 2014
|
| id | nasplib_isofts_kiev_ua-123456789-145331 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-07T16:47:40Z |
| publishDate | 2014 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Cherepenko, E. Telegeev, G. 2019-01-20T11:15:40Z 2019-01-20T11:15:40Z 2014 In search of molecular approaches to improving cancer therapy efficacy / E. Cherepenko, G. Telegeev // Experimental Oncology. — 2014. — Т. 36, № 1. — С. 52-55. — Бібліогр.: 28 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145331 The study of genome rearrangement sites using full genome sequences is an important approach to revealing the nature of cancer and finding effective ways for cancer treatment. The progress in DNA sequencing could make the procedure of whole genome reading close to routine procedure of lower cost. The personal analysis of rearranged ends (PARE) method used for rearrangement study is reviewed. PARE allows identifying of individual cancer biomarkers making personal medicine possible. Also, the progress in “liquid biopsy” technology based on detection of circulating tumor cells in the patient’s blood is shortly summarized. Another important approach is the discovered phenomenon of synthetic lethality causing cancer cell death due to appropriate combination of mutations in different genes or inhibitors of their protein products. Studies of genome rearrangements and synthetic lethality are considered promising for the development of effective cancer treatment approaches. Key Words: PARE, circulating tumor DNA, circulating tumor cells, liquid biopsy, synthetic lethality, cancer cell. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Point of view In search of molecular approaches to improving cancer therapy efficacy Article published earlier |
| spellingShingle | In search of molecular approaches to improving cancer therapy efficacy Cherepenko, E. Telegeev, G. Point of view |
| title | In search of molecular approaches to improving cancer therapy efficacy |
| title_full | In search of molecular approaches to improving cancer therapy efficacy |
| title_fullStr | In search of molecular approaches to improving cancer therapy efficacy |
| title_full_unstemmed | In search of molecular approaches to improving cancer therapy efficacy |
| title_short | In search of molecular approaches to improving cancer therapy efficacy |
| title_sort | in search of molecular approaches to improving cancer therapy efficacy |
| topic | Point of view |
| topic_facet | Point of view |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/145331 |
| work_keys_str_mv | AT cherepenkoe insearchofmolecularapproachestoimprovingcancertherapyefficacy AT telegeevg insearchofmolecularapproachestoimprovingcancertherapyefficacy |