Review Article :
Micronuclei (MN) formation has been observed
(cancer and pre-cancerous lesions) of the oral cavity among betel quid chewers.
Micronuclei
act as a cancer biomarker which is related with smokeless tobacco associated
genetic mutations. Micronuclei are a sensitive indicator of genetic damage.
These are small, extra nuclear bodies that are formed during mitosis from
lagging chromosomes. The test is used as a tool for genotoxicity and easily
detectable without affecting the cancer patients. The present review focuses on
the various types of cancer of the human body with micronuclei study. A
biological marker is most useful for identification of various hazards and risk
assessment. Many biological markers have been developed to estimate exposure
and to assess the risk of adverse effects. In general, micronucleus analysis is
utilized in both genotoxicity testing with its exposure which effects in human
population. These MN assay allows the detection of both aneugenic agents
(numerical chromosome alterations) and clastogenic
agents (chromosome breakage). Micronuclei can be measured by the feulgen
reaction, giemsa or fluorescence dyes. History of Micronuclei In the early 1970s, micronucleus was first
suggested by Boller and Schmidt. Heddle showed that it is a easy method to
detect genotoxic potential of mutagens
using bone marrow erythrocytes of animals [1,2]. Stich and co-workers developed
a protocol for micronucleus assay with exfoliated human epithelial cells about
25 years ago [3]. A few years later, Countryman & Heddle showed that
peripheral blood lymphocytes could be used for micronucleus approach and they
both recommended using micronuclei as a biomarker in testing purpose. T.
Boveri observed abnormal nuclear morphologies which is mainly found in cancer.
Micronuclei are also referred to Howell-Jolly bodies; discovered by
hematologists William Henry Howell and Justin Marie Jolly in erythrocytes.
Micronucleus induction by a chemical (which is mainly treated with colchicine)
was first reported in Ehrlich on ascites tumor cells. This results in parts of
the chromatids or chromosomes being broken off and developed as an extra
nucleus in one of the daughter cells. This is the process by which micronuclei
are formed. Relationship with Micronuclei with
Different Types of Cancer Liver Cancer with MN: Liver cancer is one of the
important cancers of human body. The final event in a cascade of genetic
changes having their phenotypic counterpart in a spectrum of morphological
alterations such as Cirrhotic
Nodules (CN); Large Regenerative Nodules (LRN); Low-Grade Dysplastic
Nodules (LG-DN); High-Grade Dysplastic Nodules (HG-DN) and full-blown
Hepatocellular Carcinoma (HCC) [4-7]. Chromosome instability, including
structural chromosome anomalies and allele loss or gain, has been demonstrated
in HCC and found to be closely associated with hepatitis B virus [8-11].
Micronuclei are chromosomal fragments left out of the daughter nuclei during
nuclear division [12,13]. Chromosome
breakage and mitotic apparatus dysfunctions are involved in the morphogenesis
of MN, closely associated with chromosome instability [14]. MN has been
demonstrated in every stages of liver carcinogenesis in an experimental model
[15-17]. MN may activate the p53-mediated cell cycle checkpoint [18]. Micro
nucleated hepatocytes were consistently found in significantly lower
numbers in normal liver than in any of the types of non-neoplastic and
neoplastic liver nodules; a frequency of ≤ 4.50, 0.76 MN/1,000 hepatocytes
unequivocally identified normal liver tissue. MN (markers of chromosome
instability) progressively increases over the course of human liver
carcinogenesis. Colorectal Cancer
with MN: Genetic
instability with chromosomal instability, microsatellite instability, and
abnormal DNA methylation as the mayor path described for Colorectal
Cancer (CRC) [19]. The
diagnosis of CRC at early stages is one of the proven strategies resulting in a
higher cure rate [20]. Micronucleus frequency in (PBL) Peripheral Blood
Lymphocytes has emerged as one of the most reliable biomarkers for cancer risk
assessment, including CRC [21]. MN frequency has the potential to be a
sensitive and non-invasive biomarker for CRC risk assessment which is highly
effective for research purpose. Kidney Cancer
with MN: Chronic
Kidney Disease (CKD) is a major public health problem in recent years [22].
Significantly increases in MN frequencies and basal DNA damage (determined by
comet assay) in peripheral blood lymphocytes of children with CKD. Frequencies
of MN and other nuclear anomalies, such as Nuclear Buds (NBs), Binucleated
Cells (BN), Condensed Chromatin (CC), Karyorrhectic (KR) and Pyknotic (PK)
cells in Buccal Epithelial Cells (BEC) in children with CKD. In
each CKD subgroup, either the MN frequency or the micronucleated cell frequency
in BEC was significantly (5 to 7 fold) elevated than control. Scoring MN and
other nuclear anomalies such as nuclear buds (for DNA damage), Binucleated
Cells (for cytokinetic defects), condensed chromatin, and karyorrhectic and
pyknotic (for cell death) cells in BEC, known as the cytome approach, has also
been found to be associated with down syndrome and Alzheimer s disease [23].
Limited number of studies on nuclear anomalies other than the MN frequency, it
has been suggested that the predictive value of the MN assay in BEC is most
important [24]. Retinoblastoma
(RB) with MN: Formation
of micronuclei caused by aneugenic events leading to chromosome loss, likely
originating from erroneous kinetochore attachment, and not spindle assembly
checkpoint dysfunctions are the trigger for aneuploidy in (pRb) Retinoblastoma
Protein depleted primary human fibroblasts. Micronuclei are considered a
marker of chromosome damage (chromosome loss or chromosome breakage events)
formed during mitosis and identified in interphase as small bodies of extra
chromatin in the cytoplasm of mammalian cells. MN
might originate by the presence of lagging chromosomes observed during anaphase
in human fibroblasts after RB acute loss. MN, which remains separate from the
nucleus after nuclear division, might be the most likely way by which pRb-depleted
cells become hypo diploid. MN is considered a possible cause of chromosome
loss during mitosis resulting in the generation of hypodiploid cells that lack
few chromosomes. Indeed immunofluorescence microscopy performed in pRb-depleted
cells and in RB/AURORA-A and RB/PLK1 knockdown cells showed the presence of
micronuclei containing whole chromosomes. An
alternative hypothesis might be that micronuclei originate in RB silenced cells
by defects in kinetochore
assembling that generates dysfunctional centromere unable to contact correctly
mitotic microtubules. Altered expression and dosage of some centromere
components by promoting defects in kinetochore assembling could trigger
micronuclei generation resulting in unfaithful chromosome segregation during
mitosis. pRb plays a critical role in regulating chromosome stability in human
primary fibroblasts and its deficiency triggers defects in chromosome
segregation via micronuclei formation. Thus, micronuclei could represent a
mechanism underlying chromosome instability following RB acute loss [25]. Blood Cancer with
MN: Micronucleus
is formed from acentric chromosome fragments or whole chromosomes during
metaphase or anaphase phase of cell division [26]. They reflect chromosome
damage and may thus provide a marker of early-stage carcinogenesis [27-29]. A
number of studies have been designed to evaluate the potential influence of
factors such as gender, age, smoking habit, alcohol, genotoxic agents, chemical
substances and radiation had a remarkable effect on the frequency of MN [28,30].
MN test can be performed for different cell types such as lymphocytes,
fibroblast and epithelial cells to check any abnormalities [31]. Consequently,
MN formation is a reliable biomarker
of exposure to radiation [32-34]. In our study, the MN frequency was also
compared with WBC count. The MN frequency showed an increase during RT. MN
level was showed greater frequency in the elderly control group (non-smokers)
with a mean age of 52.6 ± 2.9 years than the young controls with a mean age of
23.5 ± 1.3 years (non-smokers). MN formation was not observed in the young
controls, but a low frequency of MN (0.05%) was determined in the elderly
controls. The
observation of MN in these healthy persons without Radiotherapy (RT) and
chemotherapy clearly indicates that MN formation is related to donors age. These findings suggest that age can
influence the formation of MN in WBC. The effect of aging on spontaneous MN
frequency has been reported by various authors [30,31,33,35-37]. Higher
frequencies of MN have previously been reported in females than in males [38].
Anna, et al. investigated the level of cytogenetic damage in peripheral blood
lymphocytes of patients undergoing chemotherapy
[39]. As a result, it has been showed that highest level of cytogenetic damage
was observed at the end of therapy. They determined the frequencies of increased
MN during the first half of therapy and declined thereafter. Moreover, they
observed the leukocyte count strongly decreased at the beginning of therapy
with an upward trend at the end. Boreham, et al. reported the relationship
between radiation dose and radiation-induced the apoptosis and MN formation
[40]. They
found that apoptosis and the MN frequency decreased in low dose rate of
radiation, but apoptosis
and the MN frequency in binuclear cells increased with increasing of applied
radiation dose. Hubert, et al. used MN test to determine the effects of
radiation on 99 workers studied in Belgium Doel Nuclear Center [41]. They
reported an increase in the frequency of MN with increase in the annual
exposure to radiation. In another study, MN formation and cell proliferation in
human lymphocytes exposed to 50 Hz magnetic fields for 72 h was investigated.
As a result, 50 Hz magnetic fields have no effect on MN formation, and a
significant increase in cell proliferation was not observed [42]. Widel, et al.
investigated the frequency of MN in peripheral blood samples were taken before
and after RT in patients with cervical cancer [43]. As
a result, they reported a significant increase in the MN frequency compared
with the controls. Maes, et al. reported effect of 2450 MHz microwave on the MN
frequency in human blood lymphocytes in vitro where they stated an increase in
the MN frequency with increasing of exposure duration of microwave [44]. Breast Cancer
(BC) with MN: Breast
Cancer is the most frequently diagnosed form of cancer and the leading cause of
cancer-related
deaths among females in the world. It is leading cause of cancer-related
deaths among females in the world, accounting for 23% (1.38 million) of the
total new cancer cases and 14% (458,400 subjects) of the total cancer deaths in
2008 [45]. In Mexico, the incidence and mortality of BC have risen in the last
years. Results
of several studies showed that the frequencies of MN in the lymphocytes of BC
patients are significantly increased compared with healthy women [46-49]. A
minimally invasive and potentially useful method for monitoring genetic damage
in humans is the MN assay in exfoliated buccal mucosa cells [50,51]. MN and
Broken Eggs (BE) phenomenon are considered as genotoxic events, BN as a spindle
disturbance (aneugenic effects) and Condensed Chromatin (CC), KR, Karyolysis
(KL) and pyknosis as acute cytotoxic effects [50]. Bonassi, et al. analyzed all
the data concerning MN assay in buccal cells of cancer patients and postulated
that a diagnosis of cancer significantly increased MN and other endpoints
frequencies [52]. Especially
high correlation was found for oro-pharyngeal cancers, respiratory system
cancers, and for all the other cancers pooled together. Two Indian research
groups also reported about increased number of MNi in oral mucosa cells of BC
patients compared with healthy controls and patients with benign breast
lesions. Hence, several groups of investigators reported increased
frequencies of MNi in buccal mucosa cells of BC patients. We also investigated
possible differences of nuclear anomalies between BC patients with stage I and
II and healthy females. It can be noted that all parameters (reflecting both
genotoxicity and cytotoxicity) in cells of stage I BC patients were higher
compared to controls. It
is also noteworthy that 72% of fragile site are coincidental with oncogene loci
on human chromosomes. Highly significant differences were found between BC
patients with stages I, II and III and the control subjects in the numbers of
lymphocytes with MN. Defective DNA repair leads to genetic instability which
appears in the elevation of MN in somatic (epithelial) cells Increase in MN
radiation induced in small groups of healthy women carrying a BRCA 1/2 mutation
compared with matched control groups suggested a close relationship between the
presence of these mutations and the MN induction by ionizing radiations [53-55]. It
has showed an increased MN frequency associated to in vitro radiation exposure
in sporadic BC patients [56]. MN frequency was higher in cases than in
controls. Overall, in the BRCA-negative group, there was a difference of 52.8
MN/1000. The MNT has been evaluating the chromosomal instability in selected
groups of patients affected by cancer or degenerative
diseases, compared with control [57-59]. Urinary Cancer
with MN: Biomarkers
used in health studies of human are generally divided into threeclasses: · Biomarkers of
exposure · Biomarkers of
effect · Biomarkers of
susceptibility [60,61]. In
human bio monitoring the most commonly used materials are blood and urine. Now
a day s epithelial cells are becoming more and more popular as they may be
obtained from the oral cavity, bladder or nose in a noninvasive way [62,63].
Potential carcinogens enter the body through dermal penetration, ingestion
and/or inhalation. Thus, epithelial cells are usually the first and the most
significant barrier to absorption of exogenous factors [64]. Micronucleus assay
conducted on buccal cells and urothelial
cells detected biomarkers of early biological effects. Higher micronuclei
frequency was recorded in the group of male smokers from Indian population aged
41 years and above, smoking for more than 20 years [65]. In
other studies a statistically higher frequency of micronuclei in urothelial
cells was detected in male smokers in comparison to nonsmokers [66,67].
Bonassi, et al. (2011) based on the project HUMNxl results, concluded that the
significant increase of micronuclei in buccal cells was associated with heavy
smoking exceeding 40 cigarettes per day [68]. Cervical Cancer
with MN: Cervical
cancer is the third most common cancer among women worldwide and the second
cause of cancer mortality in Brazilian female [69,70]. Cervical cancer has some
of the best prospects in terms of prevention and cure, when diagnosed early,
cervical cancer has up to a 100% chance of cure. About 80% of cervical cancer
cases occur in developing countries, where neither population-based screening
nor optimal treatment is available to treat this cancer [71]. Complementary
methods aimed at increasing the sensitivity of screening for cervical cancer
have been described, including high-risk HPV testing and MN identification
[72-74]. The presence of MN is a biomarker, used to screen populations at risk
of cervical
cancer [75]. Evolution
from CIN I to CIN III is accompanied by enhanced genetic instability, the
presence of MN has been used, in combination with cytological findings, as a
biomarker of the risk of cervical cancer [76,77]. MN screening was done in all
selected Cyto
Pathological (CP) smears by counting 1,000 cervical squamous cells with a
light microscope at a magnification of 1000x [78]. The MN frequencies observed
here were significantly higher in the groups with cellular changes compared to
the control group, in agreement with previous case-control studies [79,80]. Brain Cancer with
MN: Induction
of micronucleus formation (cytogenetic damage) in brain cancer cells upon
exposure of Dielectric
Barrier Discharge (DBD) plasma [81]. The effect of DBD plasma on
micronucleus formation in brain cancer cells has not been described by
scientific community yet. Therefore, major purpose of our present study is to
investigate the effect of DBD plasma on the genetic material for different
types of cell lines. In the recent years, the in vitro micronucleus assay has
become an attractive tool for measuring genotoxicity because of its capacity to
detect clastogenic and aneugenic events, simplicity of scoring, accuracy,
multipotentiality, and wide applicability [82,83]. Brain
tumors represent one of the most treatment refractory forms of cancer. These
include different kind of intracranial malignancies, malignant gliomas Grade
IV, anaplastic astrocytoma (Grade III), and different types of anaplastic
tumors of mixed origins, such as oligoastrocytoma
and oligodendroglioma [84]. These are the most common brain tumors in adults
and third leading cause of cancer-induced deaths in the age group of 15 to 34
year with 20-25 per cent of pediatric neoplasms [85-87]. Post irradiation
presence of LND significantly increased micronuclei formation, particularly in
the cells that had been pre-sensitized by 5-Bromo-2-deoxy-Uridine [88]. The
efficacy of temozolomide treatment is limited to tumors with relatively lower
levels of the enzyme MGMT, and the presence of an intact MMR pathway. Total
311 subjects screened from different regions of Eastern & North Eastern
India and also from RKMSP and ESI Hospital, Kolkata. Out of 311 subjects more
than 60% persons chew betel quid. In our study we checked that after black tea
supplementation, micronuclei percentages are lower than previous one. It is
seen that 5 folds increase MN% than normal, in oral cancer cases who mainly
chew betel quid, which is highly statistically significant (p<0.0001*). The
authors thank the Prof (Dr.) Madhusnata De (PhD. Guide), Secretary of
Ramakrishna Mission Seva Pratishthan, for kind permission to use the laboratory
for this work and Department of Maxillofacial and ENT Department of RKMSP
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Micronuclei (MN), an important cancer biomarker (2019) Edelweiss Cancer OA 1:
37-42. Micronuclei, Oral Cancer, Cancer Biomarker.Micronuclei (MN), an Important Cancer Biomarker
Abstract
Full-Text
Introduction
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Acknowledgements
References
Keywords
