Clinical implications of p53 alterations in oral cancer progression: a review from India
p53 plays a central role in prevention of normal cell from the development of the malignant phenotype. Somatic alterations (mutations, loss of heterozygosity, deletions) in p53 are a hallmark of most human cancers and cause defects in normal p53 function. However, in the tumors harboring wild-type p...
Gespeichert in:
| Datum: | 2018 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | English |
| Veröffentlicht: |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2018
|
| Schriftenreihe: | Experimental Oncology |
| Schlagworte: | |
| Online Zugang: | https://nasplib.isofts.kiev.ua/handle/123456789/139242 |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Zitieren: | Clinical implications of p53 alterations in oral cancer progression: a review from India / K.R. Patel, B.N. Vajaria, R.D. Singh, R. Begum, P.S. Patel // Experimental Oncology. — 2018 — Т. 40, № 1. — С. 10–18. — Бібліогр.: 90 назв. — англ. |
Institution
Digital Library of Periodicals of National Academy of Sciences of Ukraine| id |
nasplib_isofts_kiev_ua-123456789-139242 |
|---|---|
| record_format |
dspace |
| spelling |
nasplib_isofts_kiev_ua-123456789-1392422025-02-23T19:02:54Z Clinical implications of p53 alterations in oral cancer progression: a review from India Patel, K.R. Vajaria, B.N. Singh, R.D. Begum, R. Patel, P.S. Reviews p53 plays a central role in prevention of normal cell from the development of the malignant phenotype. Somatic alterations (mutations, loss of heterozygosity, deletions) in p53 are a hallmark of most human cancers and cause defects in normal p53 function. However, in the tumors harboring wild-type p53, there are alterations in the regulation of the p53. Thus, understanding why p53 is unable to perform its role as a tumor suppressor in these wild-type tumors is very crucial. Germ-line polymorphisms in p53 are also anticipated to cause measurable disturbance in p53 function. Over-expression as well as polymorphic variants of MDM2 might have effects on cancer development. In addition, degradation of p53 by E6 protein of high risk human papillomavirus is also suggested as one of the mechanisms which attenuate p53 responses in oral carcinogenesis. p53 has also been demonstrated to mediate cellular responses upon various DNA damaging cancer therapies, importantly, apoptosis. These responses have been implicated in an individual’s ability to respond to these cancer therapies. Thus, exploring mechanisms by which normal function of p53 is affected in the comprehensive way in oral cancer might aid in the identification of tumor characteristics, prognosis and thus in the development of a new approach to treat the oral cancer. 2018 Article Clinical implications of p53 alterations in oral cancer progression: a review from India / K.R. Patel, B.N. Vajaria, R.D. Singh, R. Begum, P.S. Patel // Experimental Oncology. — 2018 — Т. 40, № 1. — С. 10–18. — Бібліогр.: 90 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/139242 en Experimental Oncology application/pdf Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| language |
English |
| topic |
Reviews Reviews |
| spellingShingle |
Reviews Reviews Patel, K.R. Vajaria, B.N. Singh, R.D. Begum, R. Patel, P.S. Clinical implications of p53 alterations in oral cancer progression: a review from India Experimental Oncology |
| description |
p53 plays a central role in prevention of normal cell from the development of the malignant phenotype. Somatic alterations (mutations, loss of heterozygosity, deletions) in p53 are a hallmark of most human cancers and cause defects in normal p53 function. However, in the tumors harboring wild-type p53, there are alterations in the regulation of the p53. Thus, understanding why p53 is unable to perform its role as a tumor suppressor in these wild-type tumors is very crucial. Germ-line polymorphisms in p53 are also anticipated to cause measurable disturbance in p53 function. Over-expression as well as polymorphic variants of MDM2 might have effects on cancer development. In addition, degradation of p53 by E6 protein of high risk human papillomavirus is also suggested as one of the mechanisms which attenuate p53 responses in oral carcinogenesis. p53 has also been demonstrated to mediate cellular responses upon various DNA damaging cancer therapies, importantly, apoptosis. These responses have been implicated in an individual’s ability to respond to these cancer therapies. Thus, exploring mechanisms by which normal function of p53 is affected in the comprehensive way in oral cancer might aid in the identification of tumor characteristics, prognosis and thus in the development of a new approach to treat the oral cancer. |
| format |
Article |
| author |
Patel, K.R. Vajaria, B.N. Singh, R.D. Begum, R. Patel, P.S. |
| author_facet |
Patel, K.R. Vajaria, B.N. Singh, R.D. Begum, R. Patel, P.S. |
| author_sort |
Patel, K.R. |
| title |
Clinical implications of p53 alterations in oral cancer progression: a review from India |
| title_short |
Clinical implications of p53 alterations in oral cancer progression: a review from India |
| title_full |
Clinical implications of p53 alterations in oral cancer progression: a review from India |
| title_fullStr |
Clinical implications of p53 alterations in oral cancer progression: a review from India |
| title_full_unstemmed |
Clinical implications of p53 alterations in oral cancer progression: a review from India |
| title_sort |
clinical implications of p53 alterations in oral cancer progression: a review from india |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2018 |
| topic_facet |
Reviews |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/139242 |
| citation_txt |
Clinical implications of p53 alterations in oral cancer progression: a review from India / K.R. Patel, B.N. Vajaria, R.D. Singh, R. Begum, P.S. Patel // Experimental Oncology. — 2018 — Т. 40, № 1. — С. 10–18. — Бібліогр.: 90 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
AT patelkr clinicalimplicationsofp53alterationsinoralcancerprogressionareviewfromindia AT vajariabn clinicalimplicationsofp53alterationsinoralcancerprogressionareviewfromindia AT singhrd clinicalimplicationsofp53alterationsinoralcancerprogressionareviewfromindia AT begumr clinicalimplicationsofp53alterationsinoralcancerprogressionareviewfromindia AT patelps clinicalimplicationsofp53alterationsinoralcancerprogressionareviewfromindia |
| first_indexed |
2025-11-24T15:03:43Z |
| last_indexed |
2025-11-24T15:03:43Z |
| _version_ |
1849684523240914944 |
| fulltext |
10 Experimental Oncology 40, 10–18, 2018 (March)
CLINICAL IMPLICATIONS OF p53 ALTERATIONS IN ORAL CANCER
PROGRESSION: A REVIEW FROM INDIA
K.R. Patel1, B.N. Vajaria1, R.D. Singh1, R. Begum2, P.S. Patel1, *
1Biochemistry Research Division, Gujarat Cancer & Research Institute, Asarwa,
Ahmedabad 380016, Gujarat, India
2Department of Biochemistry, M.S. University of Baroda, Vadodara 390002, Gujarat, India
p53 plays a central role in prevention of normal cell from the development of the malignant phenotype. Somatic alterations (mutations,
loss of heterozygosity, deletions) in p53 are a hallmark of most human cancers and cause defects in normal p53 function. However,
in the tumors harboring wild-type p53, there are alterations in the regulation of the p53. Thus, understanding why p53 is unable
to perform its role as a tumor suppressor in these wild-type tumors is very crucial. Germ-line polymorphisms in p53 are also an-
ticipated to cause measurable disturbance in p53 function. Over-expression as well as polymorphic variants of MDM2 might have
effects on cancer development. In addition, degradation of p53 by E6 protein of high risk human papillomavirus is also suggested
as one of the mechanisms which attenuate p53 responses in oral carcinogenesis. p53 has also been demonstrated to mediate cellular
responses upon various DNA damaging cancer therapies, importantly, apoptosis. These responses have been implicated in an indi-
vidual’s ability to respond to these cancer therapies. Thus, exploring mechanisms by which normal function of p53 is affected in the
comprehensive way in oral cancer might aid in the identification of tumor characteristics, prognosis and thus in the development
of a new approach to treat the oral cancer.
Key Words: p53 mutations, p53 polymorphisms, MDM2, HPV, oral cancer.
One third world burden of oral cancer cases is re-
ported from India [1]. Though, tobacco usage is an es-
tablished risk factor for oral cancer development, the
role of high-risk human papillomavirus (HR-HPV)
in etiopathogenesis of oral cancer has come up in most
of the epidemiological studies [2, 3]. It has been re-
ported that the clinico-pathological and molecular
pathological profile of tobacco-smoking and alcohol
associated oral cancers in the western countries were
different from tobacco-chewing associated oral can-
cers, mainly in the Indian subcontinent [4]. Further,
human papillomavirus (HPV) positive oral cancer
patients show different molecular properties and are
considered as a distinct clinical-pathological entity
with different outcomes and response to treatment
as compared to HPV negative oral cancer patients [5].
Beside the above mentioned exogenous risk factors,
inherited genetic factors also make an individual sus-
ceptible to oral cancer development.
Cancer develops through the accumulation
of genetic alterations in genes involved in cell cycle
regulation, angiogenesis, apoptosis, DNA repair,
etc [6]. Oral cancer occurs as a consequence of vari-
ous molecular events that collectively develop from
an exposure to carcinogens present in the environment
and an individual’s genetic susceptibility [7]. This leads
to damage of individual genes or portions of genetic
materials. Most of these alterations involve activa-
tion of proto-oncogenes and/or inactivation of tumor
suppressor genes. Many investigators have evaluated
a range of molecular markers involved in the oral car-
cinogenesis, including molecules involved in the cell
cycle regulation, DNA repair, apoptosis, angiogenesis
and extracellular matrix degradation. However, the ex-
isting data about the role of molecular markers in oral
cancer development are still unclear and inconclusive.
p53, a tumor suppressor gene has come up to the
forefront of cancer research because it is commonly
mutated in human cancer. Curiosity in the p53 has
generated a large amount of information regarding
the complexity of its function and regulation in carci-
nogenesis.
The p53 gene is located on the short arm of chro-
mosome 17 with 11 exons, of which 10 are coding.
The p53 protein is comprised of 393 amino acids and
divided into five domains with each domain having
a different structure and function. The most important
role of p53 is to integrate signals emerging from a wide
range of cellular stresses, including stresses due to en-
vironmental carcinogen exposure. p53 induces adap-
tive and protective cellular responses through trigger-
ing the transcription of specific genes which prevent
erroneous cell proliferation, by inducing growth arrest
at the stage of cell cycle followed by DNA damage
or apoptosis, if the damage is not repairable. Thus,
it preserves the integrity of the genome (Fig. 1). These
functions of p53 make this protein as the “guardian
of the genome” [8].
Disturbance in the p53 is an almost frequent event
in cancerous tumors. Somatic mutations in p53 with
the aim of absence or dysfunction in p53 protein
is one of the most universal mechanisms by which
the p53 pathway is damaged during carcinogenesis.
These mutations are mainly single base substitutions
that result in amino acid substitution [9]. Importantly,
Submitted: August 03, 2017.
*Correspondence: E-mail: prabhudas_p@hotmail.com
Fax: 079-2268 5490
Abbreviations used: GOF — gain of function; HPV — human papil-
lomavirus; HR-HPV — high-risk human papillomavirus; LOH — loss
of heterozygosity; LR-HPV — low risk human papillomavirus;
MDM2 — mouse double minute 2.
Exp Oncol 2018
40, 1, 10–18
Experimental Oncology 40, 10–18, 2018 (March)40, 10–18, 2018 (March) (March) 11
these missense mutations in p53 gene are usually
followed by loss of heterozygosity (LOH), suggesting
that there is a selective advantage conferred by losing
the remaining wild-type p53, even after one allele has
been mutated [10]. It was also reported that p53 LOH
is a critical prerequisite for missense mutant p53 stabi-
lization and gain of function (GOF) in vivo [11]. Further,
it was also observed that deletion at 17p13.1 locus
of TP53 gene was among the most common altera-
tions found in primary solid tumors [12]. Unlike these
somatic alterations, the majority of polymorphisms
in the p53 gene are also expected to be associated
with cancer risk by compromising the normal ac-
tivities of p53 [9]. The levels of p53 in normal cell are
tightly controlled. Under normal conditions, mouse
double minute 2 (MDM2), a key negative regulator
of p53 binds to its transactivation domain and ubiquity-
lates, targeting it for degradation [13]. Since p53 tran-
scriptionally activates MDM2, the expression levels
of p53 and MDM2 are balanced through a feedback
negative loop. This balance is altered in stresses such
as DNA damage which leads to increased p53 levels
[14]. Underlying this crucial role of MDM2 in the con-
trol of p53 functions suggested that polymorphisms
in the MDM2 gene may be responsible for probable
alterations in p53 functions. Moreover, degradation
of p53 by E6 protein of HR-HPV is also one of the
mechanism by which normal function of p53 is altered
in HPV associated oral carcinogenesis [3]. Together,
all of above mentioned mechanisms leads to altera-
tions in p53 responses in cancer cell (Fig. 2). Thus,
exploring mechanisms by which p53 responses are
affected in the comprehensive way might aid in the
identification of tumor characteristics, prognosis and
thus in the development of a new approach to treat
cancer. The present review aims to summarize ad-
vances in p53 research, especially in oral cancer with
special emphasis on somatic mutations and germ-line
polymorphisms in the p53 gene.
p53 MUTATIONS IN ORAL CANCER
Approximately, 10% (hematopoietic malignan-
cies) to 50–70% of all other human cancers are found
to have somatic mutations in the p53 gene [15]. The
frequency of p53 mutations also varies according
to the tumor type [16]. Wide variations in the frequency
of p53 mutations have been reported between differ-
ent studies of the same tumor type, probably reflecting
methodological and geographic differences [17]. Also
the frequency of p53 mutations has been also ob-
served to vary between groups which differ in ethnicity
or nationality for some cancer types [18]. This may
be due to specific carcinogen exposure or inherited
features in those populations.
Cancer-associated mutations in p53 are primarily
missense substitutions non-randomly distributed along
the molecule, particularly in the central DNA binding
domain [15]. These single amino acid changes affect
Fig. 1. Tumor suppressor gene p53; guardian of the genome
Fig. 2. Mechanisms that lead to alteration in p53 responses
12 Experimental Oncology 40, 10–18, 2018 (March)
transcriptional activity of p53 to various degrees. How-
ever, all mutations do not have an equal deleterious
effect on p53 function, and some missense mutants
may even acquire new functions [15, 19]. Different
mutations have different effect on the function of the
p53 protein. Evidences also have suggested that mutant
p53 not only loses its tumor suppressive function, but
also has dominant negative effect on the remaining wild-
type allele [20]. Moreover, mutant p53 has also ability
to transcriptionally activate genes involved in increased
proliferation, inhibition of apoptosis, limitless replica-
tion, angiogenesis, invasion and metastasis, etc [10,
16]. Thus, mutant p53 promotes tumorigenesis through
many different aspects of oncogenetic processes and
hence, mutant p53 may play a central role in tumori-
genesis, almost in all the “hallmarks of cancer” (Fig. 3).
However, how different forms of mutant p53 affect
tumorigenesis is still unclear.
Fig. 3. Mutant p53 contributes to tumorigenesis
In head and neck tumors, the prevalence of p53 mu-
tation varies from 30% to 70%, depending on the
metho dologies used to assess p53 mutations, types
of the tumor material and heterogeneity of the tu-
mor sites examined [18]. The other reason for these
wide variations could be different levels of exposure
to risk factors like, tobacco and alcohol in the studied
populations as mentioned earlier. There are reports
on p53 mutation profile in oral cancers from various
regions of India also. Reports from Southern India
showed p53 mutations in 17% and 21% of oral cancer
cases [21, 22]. Studies from Western and Northern
region also reported that 17% of oral cancer patients
harbor p53 mutations [23, 24]. In contrast, no p53 mu-
tations were reported in the study from Orissa, the
Eastern region of India [25].
It was suggested that the incidence of p53 mutations
in oral cancer patients was associated with a history
of tobacco use [26, 27]. However, there are the studies
which have reported no association of p53 mutation with
smoking [28]. Further, it was observed that the p53 mu-
tation frequency in betel quid/tobacco-associated
Asian oral cancer (15%) was significantly different from
worldwide oral cancers, i.e. 46% [29]. There are reports
which suggested that p53 mutation pattern also differ
in group of having different type of tobacco habits [30,
31]. Recently, we observed different type of base pair
changes and the multiple mutations in p53 gene in oral
cancer patients which suggest DNA insults by several
different carcinogens which are present in smokeless
tobacco. Our results on p53 mutation spectrum strongly
support the notion that ethnic/geographic and dif-
ferences in tobacco consuming habits are the major
cause of variations in the p53 mutations [32]. Thus,
the p53 mutational pattern has been recommended
to be a clinically appropriate “molecular sensor” for
genotoxic exposure to carcinogens present in the en-
vironment and endogenous mutagens [33].
p53 POLYMORPHISMS IN ORAL CANCER
Several sequence variations are present in the
p53 gene. Most of these variations are intronic and
have no cancer related biological consequenc-
es [9]. The International Agency for Research
on Cancer (IARC) TP53 mutation database lists
29 common polymorphisms in the non-coding
region of TP53 [34]. However, of which, two in-
tronic polymorphisms in p53 gene; 16 bp duplication
in intron 3 (rs17878362) and G>A transition in intron
6 (rs1625895) have been suggested to affect the
levels of p53 gene expression as well as its func-
tions [35]. Also, it is important to mention that the
functional role of these two intronic polymorphisms
of p53 in cancer risk remains uncertain which is dis-
cussed in detail in our previous article [36]. Very few
studies have reported the association between these
two intronic polymorphisms and oral cancer risk. Galli
et al. [37] have reported that intron 3 polymorphism
was associated with increased oral cancer risk.
However, the same study also suggested that intron
6 polymorphism was associated with reduced oral
cancer risk in Italian population. From India, only one
study has analyzed the association between these
two polymorphisms and oral cancer risk. The results
revealed no association between intron 3 polymor-
phism and oral cancer risk; however, a variant allele
at intron 6 was protective for oral cancer development
in population from east region of India [38]. However,
in our study, none of this intronic polymorphism was
significantly associated with oral cancer risk in popu-
lation from West India [36].
Of the 19 exonic polymorphisms, 11 polymor-
phisms in p53 are non-synonymous, resulting
in an amino-acid change and only four of these
have been validated. Out of these, there are suf-
ficient molecular evidences for two polymorphisms
(Pro47Ser and Arg72Pro) suggesting their role
in functional change of the p53 protein. The rest two
polymorphisms (V217M and G360A) have not been
associated with an altered cancer risk till date [9]. The
codon 47 polymorphism resulting in proline to ser-
ine substitution is rare whereas arginine to proline
substitution in codon 72 is common [39, 40]. It was
reported that Arg to Pro polymorphism at codon
72 in exon 4 affects the structure of p53 protein and
its biochemical and biological activities [41]. In our
previous article, we have discussed various studies,
which have reported how this polymorphism affects
various important functions of p53 such as cell cycle
regulation, apoptosis, transcriptional trans-activation
capacity and senescence (Fig. 4) [36].
Experimental Oncology 40, 10–18, 2018 (March)40, 10–18, 2018 (March) (March) 13
Fig. 4. p53 Arg72Pro polymorphism and its influence
on p53 functions
It was also observed that the p53 protein harbor-
ing Arg allele was more susceptible to degradation
by HPV E6 protein and had a significantly higher fre-
quency of p53 mutations [42, 43]. Moreover, it was
also reported that there is a tissue specific influence
of Arg72Pro polymorphism on apoptosis [44]. Recent-
ly, Hu et al. [45] observed that Pro form of p53 gene has
significantly higher levels of BPDE induced apoptotic
index compared to Arg form in primary lymphocytes.
Moreover, the Arg form of p53 gene was associated
with poor apoptosis in head and neck tumors [46].
Such tissue specific function of this polymorphism
may explain why most of the epidemiological studies
remain inconclusive.
We have discussed various studies from India in our
previous research article and observed that no signifi-
cant association of Arg72Pro polymorphism with oral
cancer risk was observed in most of studies [36]. Fur-
ther, it was suggested that the association of Arg72Pro
polymorphism with cancer risk was modulated by eth-
nicity, allelic frequency, histological and anatomical
sites of tumors [47]. However, recent meta-analysis
of Arg72Pro polymorphism of p53 suggests no as-
sociation of this polymorphism with oral cancer risk
as even after stratifying by ethnicity [48]. Also, a recent
meta-analysis by Mandal et al. [49] suggested that
Arg72Pro polymorphism may not be an independent
risk factor for cancer in Indian population. However,
still to provide conclusive results, all the intronic and
exonic polymorphisms should be considered simulta-
neously. Our recent study considering all these three
polymorphisms simultaneously suggested that carri-
ers of absence of 16 bp duplication allele at intron 3,
proline allele at exon 4 and G allele at intron 6 were
protected from oral cancer development [36].
p53 can also be inactivated by alternative mecha-
nisms other than somatic mutations and germ-line
polymorphisms. Here we summarize two important
events that alternatively inactivate p53: (1) Polymor-
phisms in MDM2 gene and (2) HPV infections.
MDM2 AND ITS ASSOCIATION WITH p53
Because MDM2 is a key negative regulator
of p53 activity, over-expression of MDM2 inhibits the
p53 responses. Hence, in order to activate p53, euka-
ryotic cells have to develop mechanisms to block this
negative feedback regulation in response to variety
of stress. These mechanisms include posttranslational
modification of either p53 or MDM2 such as acetyla-
tion, phosphorylation and protein-protein interaction.
However, cancers often take advantages of this feed-
back loop to promote their growth as various tumors
express high levels of MDM2 through distinct mecha-
nisms without p53 mutations [50]. It has been reported
that MDM2 transgenic mice expressing higher levels
of MDM2 in various tissues, develop spontaneous
tumors compared to non-transgenic mice [13]. Thus,
over-expression of MDM2 has an effect on tumor
susceptibility in mice. In fact, reports suggest that
over-expression of MDM2 commonly occurs in oral
cancer [51, 52]. Recently, novel MDM2 splice variants
were identified in oral cancer at a high frequency and
were found to be significantly associated with oral
cancer development [53]. Taken together, MDM2 may
play a significant role in oral carcinogenesis. Therefore,
it is biologically plausible that functional genetic vari-
ants in the MDM2 gene may have an effect on cancer
development in the general population.
It has been reported that one intronic polymor-
phism (T>G in the Sp1-binding site within the intronic
promoter region, rs2279744) of MDM2 may increase
the affinity of the Sp1 transcriptional factor, which re-
sults in higher MDM2 mRNA and protein levels. Thus,
the presence of this polymorphism may attenuate
the p53 responses, hence increasing cancer sus-
ceptibility [9, 54]. There are very few studies, which
have investigated the association of this MDM2 poly-
morphism with oral cancer risk. Two risk association
studies highlighted that MDM2 polymorphism did not
alter the risk of oral cancer, but may influence the age
of disease onset [13, 55]. A study on MDM2 polymor-
phism and oral cancer risk from India suggested that
this polymorphism could not modify the risk of oral
cancer independently [56]. However, authors sug-
gested that this polymorphism may modulate cancer
risk in combination with p53 and p73 polymorphisms.
More interestingly, a recent meta-analysis by Zhuo
et al. [57] also suggested that homozygote GG alleles
of MDM2 SNP309 may be a low-penetrant risk factor
for HNC, and G allele may confer nasopharyngeal
cancer susceptibility.
HPV INFECTION AND ITS ASSOCIATION
WITH p53 PROTEIN
The participation of HPV in oral carcinogenesis
was first proposed by Syrjanen et al. in 1983 [58].
HPVs have been divided into two groups: (1) High
Risk HPV (HR-HPV) and (2) Low Risk (LR-HPV). HR-
HPVs are mainly associated with potentially malignant
lesions, e.g. HPV 16 and 18, whereas LR-HPVs are
more commonly associated with benign diseases, e.g.
14 Experimental Oncology 40, 10–18, 2018 (March)
HPV 6 and 11 [3]. The molecular mechanisms by which
HPVs disrupt key cellular elements responsible for cell
cycle regulation and apoptosis have been identified.
HPV E6 oncoprotein degrades p53 protein. Thus, cells
that contain damaged DNA enter aberrantly into mito-
sis, sustain proliferative ability and may eventually con-
tribute to the propagation of structural chromosomal
abnormalities in HR-HPV associated cancer [59].
Various investigators have reported prevalence
of HPV infection in oral cancer worldwide [60–63].
However, results show large variations from low preva-
lence to high prevalence. Also several reports from
Bangladesh, various countries from central Europe
and Latin America did not find HPV infection in oral
cancer [64–67]. There are large regional and time
trend variations in prevalence rates of HPV in oral
cancers [68]. Recent reviews suggest that separa-
tion of oral carcinoma from the heterogeneous group
of head and neck carcinomas is very essential to gain
valid results of HPV prevalence in oral cancers [60, 62].
Prevalence of HR-HPV type 16 and 18 infections
in oral cancers varies widely across the different geo-
graphical regions of India. Prevalence of HPV 16 infec-
tion is reported to vary from 6% to 45.8%, whereas HPV
18 infection from 0% to 54.2% of oral cancers from
India which was reviewed in our previous article [69].
HPV positive oral cancers are highest from Southern
India, while the Western part of the country (Mumbai)
exhibits low HPV positive oral cancers [69]. Recently,
we have reported absence of HPV16 and 18 infections
in oral cancer patients in population from Gujarat, West
India [69].
p53 ALTERATIONS
AND CLINICOPATHOLOGICAL
CHARACTERISTICS
The prognostic value of p53 in oral cancer has
long been debated. Contradictory results have been
published about the presence or absence of p53 gene
mutations and the outcome in oral cancer. Yamazaki
et al. [70] suggested that mutations within the DNA
binding domain of p53 could be important prognostic
factors for locoregional failure, lymph node metastasis
and the occurrence of subsequent distant metastasis
in oral cancers. It was also reported that a dominant
negative mutation in p53 may be a good predictor
of early recurrence in oral cancer patients [71]. How-
ever, Tsurusako et al. [72] suggested that p53 muta-
tions may not be strongly involved in the development
of well differentiated tongue cancers. In a recent study,
faster tumor growth, higher frequency of metastasis
in cervical lymph node and shorter survival was ob-
served in mice injected with cells harboring disruptive
p53 mutations as compared to mice injected with cells
lacking these mutations [73]. Also the results of our
study strongly suggest that evaluation of p53 muta-
tion status could be useful for predicting loco-regional
recurrence at early stage among oral cancer patients.
Further, detection of p53 mutation in apparently nor-
mal adjacent mucosa along with mutation with tumor
tissues should be done for prognostication. p53 muta-
tions also affect the survival rate as cases with truncat-
ing and transcriptionally non-active p53 mutations had
poor disease free as well as overall survival [32]. How-
ever, the results of a recent meta-analysis by Tandon
et al. [74] highlights that the existing data regarding the
prognostic importance of p53 are indecisive and there
is a great heterogeneity observed in various studies.
It was also observed that MDM2 GG genotype and
p53 mutations were associated with poor disease-
free survival in both early and lymph node positive
advanced stage oral cancer patients [75]. In a multi-
centeric study by the IARC, an inverse association was
observed between the incidence of p53 mutations and
HPV 16 positivity in oral cancer patients [76]. However,
Kozomara et al. [77] suggested that p53 mutations
in combination with HPV infections were associated
with an increased risk of recurrence and worse progno-
sis in oral cancer patients. The HPV positive oral cancer
had improved outcome [5, 63, 78]. Further, it was
suggested that inactivation of p53 protein by HPV
is not as harmful as the mutations induced by other
carcinogens present in environment [2]. It may be be-
cause the wild type p53, which escape HPV mediated
degradation, might trigger cellular apoptosis following
cancer therapy.
ASSOCIATION OF p53 ALTERATIONS
WITH TREATMENT OUTCOME
The most used line of treatment for oral cancers
is surgery followed by radiotherapy and/or chemo-
therapy. Multitasking of p53 is essential for the sup-
pression of tumor, as well as for activating the cellular
responses to DNA damage inducing cancer therapies
such as radiotherapy and chemotherapy [79]. It was
reported that p53 mutations in the DNA binding do-
main might be useful to predict the radioresistance
in oral cancer patients [80]. Yasumoto et al. [81] sug-
gested that the X-ray sensitivity of wild type p53 cells
may come from the expression of genes involved
in apoptosis. Moreover, Tu et al. [82] suggested that
both MDM2 T>G and p53 Arg72Pro polymorphisms
could be useful for evaluating the outcome of ad-
vanced oral cancers treated with adjuvant radiation.
Interest in cisplatin-based neoadjuvant chemo-
therapy has recently emerged due to its survival
benefits in patients with locally advanced oral can-
cer. Recently, Perrone et al. [83] suggested that
the mutant p53 proteins with loss of function may
predict a significant low pathologic complete re-
mission rate and suboptimal response to cisplatin-
based neoadjuvant chemotherapy in patients with
oral cancer. Moreover, sensitivity to cisplatin was
positively associated with the presence of functional
p53 in 60 human tumor cell lines of a National Cancer
Institute (NCI) panel [84]. In addition, tumor cell lines
that harbor non-functional p53 were more resistant
to cisplatin than those harboring functional p53, but
can be sensitized when reconstituted with wild-type
p53 [85]. However, the association of p53 status and
Experimental Oncology 40, 10–18, 2018 (March)40, 10–18, 2018 (March) (March) 15
cisplatin cytotoxicity depends on several other fac-
tors, like types of tumor cells, the presence of other
genetic alterations etc. Further studies on such
genetic alterations are required to determine the
role of p53 in cisplatin cytotoxicity. Proteins that are
involved in p53 pathways can also modulate p53 re-
sponses as mentioned above and thus, cisplatin
cytotoxicity. It was suggested that MDM2 overex-
pression affects the p53 responses under stress
conditions, even in the presence of wild type p53 and
results in to faster cancer progression and resis-
tance to therapy in some tumor types [53]. Further,
emerging evidence in the literature recommend that
p53 (Arg72Pro) and MDM2 (T>G) and p53 protein
degradation by HR-HPV as mentioned earlier could
also determine the patients’ ability to induce p53 re-
sponses to DNA damaging therapies [79].
Various studies have confirmed that Arg72Pro
polymorphism can affect the levels of apoptosis both
in the context of wild type p53 and mutant p53. Wild
type p53 in combination with Arg allele mediates the
p53 dependent apoptotic response more efficiently.
Interestingly, with mutant p53 protein, Pro allele
could be associated with higher levels of apoptosis
(Fig. 5) [79]. Also this observation was supported
by two studies on advanced head and neck squamous
cell carcinomas that received cisplatin based chemo-
radiotherapy. The authors observed that patients
harboring wild type p53 and Arg genotype as well
as patients with mutant p53 in combination with Pro
genotypes had better response rates as well as overall
and progression-free survival [79]. Further studies are
recommended to understand these differences in the
apoptotic response of p53 [86].
Fig. 5. p53 Arg72Pro polymorphism and mutation in combination
affect its apoptotic function
Hence, knowledge of p53 somatic mutational sta-
tus as well as the p53 Arg72Pro genotype of the patient
could help to delineate the patient populations that
will respond to chemo-radiotherapies. However, the
utility of p53 Arg72Pro polymorphism as a predictive
biomarker requires mutational analysis of p53. A re-
cent study suggests that MDM2 T>G polymorphism
is an independent predictive biomarker for selection
of patients who respond to radical chemo-radiothe-
rapy [87]. Together, these studies of p53 Arg72Pro
and MDM2 T>G indicated that high frequency
SNPs in p53 pathway genes could affect the activity
of p53 in cancer cells and thereby influences thera-
peutic responses.
In addition to this, p53-MDM2 pathway presents
many molecular targets for screening small molecules
as potential therapies for tumors harbouring wild type
p53. A number of new small molecules have been
identified to target MDM2 in the past decades and
have entered Phase I clinical trials [50]. One of these
compounds, Nutlin-3, binds with MDM2, dislodges
p53 from MDM2 inducing p53-mediated apoptosis
in leukemias, and is under phase I clinical trial for
leukemia and solid tumors [88]. Further, a small
molecule named JNJ-26854165 was shown to bind
the RING domain of MDM2 and prevent the interac-
tion of the MDM2-p53 complex with the proteasome.
This molecule has been put on phase I clinical trial
for advanced solid tumors [88, 89]. Various others
small molecule inhibitors of E3 ubiquitin ligase activity
of MDM2 as well as the MDM2-p53 interaction have
been revealed later and are currently under pre-clinical
development [50]. More interestingly, some of natu-
rally derived molecules have been shown to decrease
MDM2 expression and activity in vitro and in vivo,
hence, inhibit the p53-MDM2 interaction [90]. In ad-
dition to the direct inhibitors, indirectly interrupting the
MDM2-p53 negative feedback loop, which prevents
MDM2-mediated degradation of p53, are also been
explored for the development of molecule-targeted
therapy for cancers [50]. Moreover, several miRNA
have been identified that suppress MDM2, hence,
miRNAs have become a new but important component
of the p53 signaling pathway through regulating the
p53/MDM2 feedback loop [91].
CONCLUSION
In nutshell, it can be suggested that incorporating
information of the inherited genetic polymorphisms
of the p53 pathway along with the somatic muta-
tions in p53, patient populations can be stratified and
therapies could be better targeted. These data support
a hypothesis that individuals could develop cancer
that retains wild type p53, but still have an attenu-
ated p53 response because they may harbor genetic
polymorphisms either in p53 gene or in MDM2 gene
or HPV infection. Thus, comprehensive analysis of all
the mechanisms by which p53 response is attenu-
ated in oral cancer, is very essential to improve our
understanding of oral cancer pathogenesis. Further,
this knowledge will aid in improving prognosis and
treatment of oral cancer.
REFERENCES
1. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN
2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC
Cancer Base No. 11 [Internet]. Lyon, France: IARС; 2013.
Available from: http://globocan.iarc.fr, accessed on 19/11/2014.
2. Chocolatewala NM, Chaturvedi P. Role of human
papilloma virus in the oral carcinogenesis: an Indian
perspective. J Cancer Res Ther 2009; 5: 71–7.
3. Campisi G, Panzarella V, Giuliani M, et al. Human
papillomavirus: its identity and controversial role in oral
oncogenesis, premalignant and malignant lesions. Int J Oncol
2007; 30: 813–23.
4. Paterson IC, Eveson JW, Prime SS. Molecular changes
in oral cancer may reflect aetiology and ethnic origin. Eur
J Cancer B Oral Oncol 1996; 32B: 150–3.
16 Experimental Oncology 40, 10–18, 2018 (March)
5. Chen SF, Yu FS, Chang YC, et al. Role of human
papillomavirus infection in carcinogenesis of oral squamous
cell carcinoma with evidences of prognostic association. J Oral
Pathol Med 2012; 41: 9–15.
6. Leemans CR, Braakhuis BJ, Brakenhoff RH. The
molecular biology of head and neck cancer. Nat Rev Cancer
2011; 11: 9–22.
7. Choi S, Myers JN. Molecular pathogenesis of oral
squamous cell carcinoma: implications for therapy. J Dent
Res 2008; 87: 14–32.
8. Partridge M, Costea DE, Huang X. The changing
face of p53 in head and neck cancer. Int J Oral Maxillofac
Surg 2007; 36: 1123–38.
9. Whibley C, Pharoah PD, Hollstein M. p53 polymor-
phisms: cancer implications. Nat Rev Cancer 2009; 9: 95–107.
10. Freed-Pastor WA, Prives C. Mutant p53: one name,
many proteins. Genes Dev 2012; 26: 1268–86.
11. Alexandrova EM, Mirza SA, Xu S, et al. p53 loss-of-
heterozygosity is a necessary prerequisite for mutant p53 stabili-
zation and gain-of-function in vivo. Cell Death Dis 2017; 8: e2661.
12. Herrera JC, Isaza LF, Ramírez JL, et al. Detec-
tion of chromosome 17 aneuplody and TP53 gene deletion
in a broad variety of solid tumors by dual-color fluorescence
in situ hybridization (FISH). Biomedica 2010; 30: 390–400.
13. Yu H, Huang YJ, Liu Z, et al. Effects of MDM2 pro-
moter polymorphisms and p53 codon 72 polymorphism on risk
and age at onset of squamous cell carcinoma of the head and
neck. Mol Carcinog 2011; 50: 697–706.
14. Tang Y, Zhao W, Chen Y, et al. Acetylation is indispens-
able for p53 activation. Cell 2008; 133: 612–26.
15. Suzuki K, Matsubara H. Recent advances in p53 re-
search and cancer treatment. J Biomed Biotechnol 2011;
2011: 978312.
16. Muller PA, Vousden KH. Mutant p53 in cancer: new
functions and therapeutic opportunities. Cancer Cell 2014;
25: 304–17.
17. Royds JA, Iacopetta B. p53 and disease: when the
guardian angel fails. Cell Death Differ 2006; 13: 1017–26.
18. Chitra G, Chandramouli A, Chanchal C. p53 muta-
tions in head and neck squamous cell carcinoma. Int J Pharm
Biomed Res 2010; 1: 117–21.
19. Petitjean A, Mathe E, Kato S, et al. Impact of mutant
p53 functional properties on TP53 mutation patterns and
tumor phenotype: lessons from recent developments in the
IARC TP53 database. Hum Mutat 2007; 28: 622–9.
20. Hong B, van den Heuvel AP, Prabhu VV, et al. Target-
ing tumor suppressor p53 for cancer therapy: strategies, chal-
lenges and opportunities. Curr Drug Targets 2014; 15: 80–9.
21. Heinzel PA, Balaram P, Bernard HU. Mutations and
polymorphisms in the p53, p21 and p16 genes in oral carcino-
mas of Indian betel quid chewers. Int J Cancer 1996; 68: 420–3.
22. Munirajan AK, Tutsumi-Ishii Y, Mohanprasad BK,
et al. p53 gene mutations in oral carcinomas from India. Int
J Cancer 1996; 66: 297–300.
23. Saranath D, Tandle AT, Teni TR, et al. p53 inactivation
in chewing tobacco-induced oral cancers and leukoplakias
from India. Oral Oncol 1999; 35: 242–50.
24. Ralhan R, Agarwal S, Nath N, et al. Correlation
between p53 gene mutations and circulating antibodies in be-
tel- and tobacco-consuming North Indian population. Oral
Oncol 2001; 37: 243–50.
25. Patnaik S, Nayak BK, Das BR. Genetic alteration
of p53 in oral tumors. In: AK Varma, ed. Oral Oncology, Vol.
VI. New Delhi, India: Macmillan India Limited, 1999: 87–92.
26. Lazarus P, Stern J, Zwiebel N, et al. Relationship
between p53 mutation incidence in oral cavity squamous cell
carcinomas and patient tobacco use. Carcinogenesis 1996;
17: 733–9.
27. Sorensen DM, Lewark TM, Haney JL, et al. Absence
of p53 mutations in squamous carcinomas of the tongue
in nonsmoking and nondrinking patients younger than
40 years. Arch Otolaryngol Head Neck Surg 1997; 123: 503–6.
28. Chaves AC, Cherubini K, Herter N, et al. Character-
ization of p53 gene mutations in a Brazilian population with
oral squamous cell carcinomas. Int J Oncol 2004; 24: 295–303.
29. Wong YK, Liu TY, Chang KW, et al. p53 alterations
in betel quid- and tobacco-associated oral squamous cell
carcinomas from Taiwan. J Oral Pathol Med 1998; 27: 243–8.
30. Thongsuksai P, Boonyaphiphat P, Sriplung H, et al.
p53 mutations in betel-associated oral cancer from Thailand.
Cancer Lett 2003; 201: 1–7.
31. Hsieh LL, Wang PF, Chen IH, et al. Characteristics
of mutations in the p53 gene in oral squamous cell carcinoma
associated with betel quid chewing and cigarette smoking
in Taiwanese. Carcinogenesis 2001; 22: 1497–503.
32. Singh RD, Patel KR, Patel PS. p53 mutation spectrum
and its role in prognosis of oral cancer patients: A study from
Gujarat, West India. Mutat Res 2016; 783: 15–26.
33. Peltonen JK, Helppi HM, Pääkkö P, et al. p53 in head
and neck cancer: functional consequences and environmental
implications of TP53 mutations. Head Neck Oncol 2010; 2: 36.
34. Hrstka R, Coates PJ, Vojtesek B. Polymorphisms
in p53 and the p53 pathway: roles in cancer susceptibility and
response to treatment. J Cell Mol Med 2009; 13: 440–53.
35. Pietsch EC, Humbey O, Murphy ME. Polymorphisms
in the p53 pathway. Oncogene 2006; 25: 1602–11.
36. Patel KR, Vajaria BN, Begum R, et al. Association
between p53 gene variants and oral cancer susceptibility
in population from Gujarat, West India. Asian Pac J Cancer
Prev 2013; 14: 1093–100.
37. Gallì P, Cadoni G, Volante M, et al. A case-control
study on the combined effects of p53 and p73 polymorphisms
on head and neck cancer risk in an Italian population. BMC
Cancer 2009; 9: 137.
38. Mitra S, Sikdar N, Misra C, et al. Risk assessment
of p53 genotypes and haplotypes in tobacco-associated leuko-
plakia and oral cancer patients from eastern India. Int J Cancer
2005; 117: 786–93.
39. Felley-Bosco E, Weston A, Cawley HM, et al. Func-
tional studies of a germ-line polymorphism at codon 47 within
the p53 gene. Am J Hum Genet 1993; 53: 752–9.
40. Beckman G, Birgander R, Själander A, et al.
Is p53 polymorphism maintained by natural selection? Hum
Hered 1994; 44: 266–70.
41. Ozeki C, Sawai Y, Shibata T, et al. Cancer susceptibility
polymorphism of p53 at codon 72 affects phosphorylation and
degradation of p53 protein. J Biol Chem 2011; 286: 18251–60.
42. Storey A, Thomas M, Kalita A, et al. Role of a p53 poly-
morphism in the development of human papillomavirus-
associated cancer. Nature 1998; 393: 229–34.
43. Hsieh LL, Huang TH, Chen IH, et al. p53 polymor-
phisms associated with mutations in and loss of heterozygosity
of the p53 gene in male oral squamous cell carcinomas in Tai-
wan. Br J Cancer 2005; 92: 30–5.
44. Azzam GA, Frank AK, Hollstein M, et al. Tissue-
specific apoptotic effects of the p53 codon 72 polymorphism
in a mouse model. Cell Cycle 2011; 10: 1352–5.
45. Hu Z, Li C, Chen K, et al. Single nucleotide poly-
morphisms in selected apoptotic genes and BPDE-induced
apoptotic capacity in apparently normal primary lympho-
cytes: a genotype-phenotype correlation analysis. J Cancer
Epidemiol 2008; 2008: 147905.
Experimental Oncology 40, 10–18, 2018 (March)40, 10–18, 2018 (March) (March) 17
46. Schneider-Stock R, Mawrin C, Motsch C, et al. Reten-
tion of the arginine allele in codon 72 of the p53 gene correlates
with poor apoptosis in head and neck cancer. Am J Pathol
2004; 164: 1233–41.
47. Francisco G, Menezes PR, Eluf-Neto J, et al. Arg72Pro
TP53 polymorphism and cancer susceptibility: a comprehen-
sive meta-analysis of 302 case-control studies. Int J Cancer
2011; 129: 920–30.
48. Jiang N, Pan J, Wang L, et al. No significant associa-
tion between p53 codon 72 Arg/Pro polymorphism and risk
of oral cancer. Tumour Biol 2013; 34: 587–96.
49. Mandal RK, Yadav SS, Panda AK. No evidence of cor-
relation between p53 codon 72 G > C gene polymorphism and
cancer risk in Indian population: a meta-analysis. Tumour
Biol 2014; 35: 8607–13.
50. Zhang Q, Zeng SX, Lu H. Targeting p53-MDM2-
MDMX loop for cancer therapy. Subcell Biochem 2014;
85: 281–319.
51. Shwe M, Chiguchi G, Yamada S, et al. P53 and
MDM2 co-expression in tobacco and betel chewing-asso-
ciated oral squamous cell carcinomas. J Med Dent Sci 2001;
48: 113–9.
52. Lim KP, Sharifah H, Lau SH, et al. Alterations of the
p14ARF-p53-MDM2 pathway in oral squamous cell carci-
noma: MDM2 overexpression is a common event. Oncol Rep
2005; 14: 963–8.
53. Sam KK, Gan CP, Yee PS, et al. Novel MDM2 splice
variants identified from oral squamous cell carcinoma. Oral
Oncol 2012; 48: 1128–35.
54. Bond GL, Hu W, Bond EE, et al. A single nucleotide
polymorphism in the MDM2 promoter attenuates the p53 tu-
mor suppressor pathway and accelerates tumor formation
in humans. Cell 2004; 119: 591–602.
55. Hamid S, Yang YH, Peng KN, et al. MDM2 SNP309 does
not confer an increased risk to oral squamous cell carcinoma
but may modulate the age of disease onset. Oral Oncol 2009;
45: 496–500.
56. Misra C, Majumder M, Bajaj S, et al. Polymorphisms
at p53, p73, and MDM2 loci modulate the risk of tobacco
associated leukoplakia and oral cancer. Mol Carcinog 2009;
48: 790–800.
57. Zhuo X, Ye H, Li Q, et al. Is MDM2 SNP309 variation
a risk factor for head and neck carcinoma? An updated meta-
analysis based on 11,552 individuals. Medicine (Baltimore),
2016; 95: e2948.
58. Syrjänen S, Lamberg M, Pyrhönen S, et al. Morpho-
logical and immunohistochemical evidence suggesting human
papillomavirus (HPV) involvement in oral squamous cell
carcinogenesis. Int J Oral Surg 1983; 12: 418–24.
59. Korzeniewski N, Spardy N, Duensing A, et al. Ge-
nomic instability and cancer: lessons learned from human
papillomaviruses. Cancer Lett 2011; 305: 113–22.
60. Termine N, Panzarella V, Falaschini S, et al. HPV
in oral squamous cell carcinoma vs head and neck squamous
cell carcinoma biopsies: a meta-analysis (1988–2007). Ann
Oncol 2008; 19: 1681–90.
61. Isayeva T, Li Y, Maswahu D, et al. Human papillomavi-
rus in non-oropharyngeal head and neck cancers: a systematic
literature review. Head Neck Pathol 2012; 6: S104–20.
62. Kansy K, Thiele O, Freier K. The role of human papil-
lomavirus in oral squamous cell carcinoma: myth and reality.
Oral Maxillofac Surg 2014; 18: 165–72.
63. Bychkov VA, Nikitina EG, Ibragimova MK, et al.
Comprehensive meta-analytical summary on human papil-
lomavirus association with head and neck cancer. Exp Oncol
2016; 38: 68–72.
64. El-Mofty SK, Lu DW. Prevalence of human papilloma-
virus type 16 DNA in squamous cell carcinoma of the palatine
tonsil, and not the oral cavity, in young patients: a distinct
clinicopathologic and molecular disease entity. Am J Surg
Pathol 2003; 27: 1463–70.
65. Ribeiro KB, Levi JE, Pawlita M, et al. Low human
papillomavirus prevalence in head and neck cancer: results
from two large case-control studies in high-incidence regions.
Int J Epidemiol 2011; 40: 489–502.
66. de Spíndula-Filho JV, da Cruz AD, Oton-Leite AF,
et al. Oral squamous cell carcinoma versus oral verrucous
carcinoma: an approach to cellular proliferation and negative
relation to human papillomavirus (HPV). Tumour Biol 2011;
32: 409–16.
67. Akhter M, Ali L, Hassan Z, et al. Association of human
papilloma virus infection and oral squamous cell carcinoma
in Bangladesh. J Health Popul Nutr 2013; 31: 65–9.
68. Choi S, Myers JN. Molecular pathogenesis of oral
squamous cell carcinoma: implications for therapy. J Dent
Res 2008; 87: 14–32.
69. Patel KR, Vajaria BN, Begum R, et al. Prevalence
of high-risk human papillomavirus type 16 and 18 in oral and
cervical cancers in population from Gujarat, West India. J Oral
Pathol Med 2014; 43: 293–7.
70. Yamazaki Y, Chiba I, Hirai A, et al. Radioresistance
in oral squamous cell carcinoma with p53 DNA contact muta-
tion. Am J Clin Oncol 2003; 26: e124–9.
71. Hassan NM, Tada M, Hamada J, et al. Presence
of dominant negative mutation of TP53 is a risk of early recur-
rence in oral cancer. Cancer Lett 2008; 270: 108–19.
72. Tsurusako S, Tanaka H, Hayashi Y, et al. Low inci-
dence of p53 mutations in well-differentiated tongue squamous
cell carcinoma in Japan. Jpn J Clin Oncol 2002; 32: 327–31.
73. Sano D, Xie TX, Ow TJ, et al. Disruptive TP53 mu-
tation is associated with aggressive disease characteristics
in an orthotopic murine model of oral tongue cancer. Clin
Cancer Res 2011; 17: 6658–70.
74. Tandon S, Tudur-Smith C, Riley RD, et al. A system-
atic review of p53 as a prognostic factor of survival in squamous
cell carcinoma of the four main anatomical subsites of the
head and neck. Cancer Epidemiol Biomarkers Prev 2010;
19: 574–87.
75. Huang SF, Chen IH, Liao CT, et al. Combined effects
of MDM2 SNP 309 and p53 mutation on oral squamous cell
carcinomas associated with areca quid chewing. Oral Oncol
2009; 45: 16–22.
76. Dai M, Clifford GM, le Calvez F, et al. Human papil-
lomavirus type 16 and TP53 mutation in oral cancer: matched
analysis of the IARC multicenter study. Cancer Res 2004;
64: 468–71.
77. Kozomara RJ, Brankovic-Magic MV, Jovic NR, et al.
Prognostic significance of TP53 mutations in oral squamous
cell carcinoma with human papilloma virus infection. Int J Biol
Markers 2007; 22: 252–7.
78. O’Rorke MA, Ellison MV, Murray LJ, et al. Human
papillomavirus related head and neck cancer survival: a system-
atic review and meta-analysis. Oral Oncol 2012; 48: 1191–201.
79. Vazquez A, Bond EE, Levine AJ, et al. The genetics
of the p53 pathway, apoptosis and cancer therapy. Nat Rev
Drug Discov 2008; 7: 979–87.
80. Yamazaki Y, Chiba I, Hirai A, et al. Specific
p53 mutations predict poor prognosis in oral squamous cell
carcinoma. Oral Oncol 2003; 39: 163–9.
81. Yasumoto J, Imai Y, Takahashi A, et al. Analysis
of apoptosis-related gene expression after X-ray irradiation
18 Experimental Oncology 40, 10–18, 2018 (March)
in human tongue squamous cell carcinoma cells harboring
wild-type or mutated p53 gene. J Radiat Res 2003; 44: 41–5.
82. Tu HF, Chen HW, Kao SY, et al. MDM2 SNP 309 and
p53 codon 72 polymorphisms are associated with the outcome
of oral carcinoma patients receiving postoperative irradiation.
Radiother Oncol 2008; 87: 243–52.
83. Perrone F, Bossi P, Cortelazzi B, et al. TP53 mutations
and pathologic complete response to neoadjuvant cisplatin and
fluorouracil chemotherapy in resected oral cavity squamous
cell carcinoma. J Clin Oncol 2010; 28: 761–6.
84. Vekris A, Meynard D, Haaz MC, et al. Molecular
determinants of the cytotoxicity of platinum compounds: the
contribution of in silico research. Cancer Res 2004; 64: 356–62.
85. Wang D, Lippard SJ. Cellular processing of platinum
anticancer drugs. Nat Rev Drug Discov 2005; 4: 307–20.
86. Vikhanskaya F, Siddique MM, Kei Lee M, et al. Evalu-
ation of the combined effect of p53 codon 72 polymorphism
and hotspot mutations in response to anticancer drugs. Clin
Cancer Res 2005; 11: 4348–56.
87. Vivenza D, Gasco M, Monteverde M, et al.
MDM2 309 polymorphism predicts outcome in platinum-
treated locally advanced head and neck cancer. Oral Oncol
2012; 48: 602–7.
88. Kojima K, Burks JK, Arts J, et al. The novel tryptamine
derivative JNJ-26854165 induces wild-type p53- and E2F1-
mediated apoptosis in acute myeloid and lymphoid leukemias.
Mol Cancer Ther 2010; 9: 2545–57.
89. Yang Y, Ludwig RL, Jensen JP, et al. Small molecule
inhibitors of HDM2 ubiquitin ligase activity stabilize and
activate p53 in cells. Cancer Cell 2005; 7: 547–59.
90. Qin JJ, Nag S, Voruganti S, et al. Natural product
MDM2 inhibitors: anticancer activity and mechanisms of ac-
tion. Curr Med Chem 2012; 19: 5705–25.
Copyright © Experimental Oncology, 2018
|