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Journal ArticleDOI

Risk genes in head and neck cancer: A systematic review and meta-analysis of last 5 years

01 Mar 2014-Oral Oncology (Pergamon)-Vol. 50, Iss: 3, pp 178-188

TL;DR: The aim of this work was to identify risk genes related to the development and progression of squamous cell carcinoma head and neck (SCCHN) and do a meta-analysis of available estimates, showing no significant association between different allelic variants of Arg72Pro rs1042522 and SCCHN risk.
Abstract: Summary The aim of this work was to identify risk genes related to the development and progression of squamous cell carcinoma head and neck (SCCHN) and do a meta-analysis of available estimates. Eligible gene/polymorphism studies were identified by electronic searches. Individual participant data of 8540 patients with HNC and 9844 controls from 19 genetic studies were analyzed, yielding adjusted (tobacco, gender, age and alcohol) odds ratios (OR) and 95% confidence intervals (CIs) comparing cases with controls. A meta-analysis was done on the studies that applied fixed and random models. People have an increase of polymorphism expression related to inflammation (NFKB1-294-ATTG, TNFα308-A2A2/A2A1, and TNFβ252- B2B2/B2B1) or carcinogenic metabolism (GSTM1 null, and CYP1A1 m1/m1), representative of malignancy development. Furthermore, the increased expression of genes associated with the stabilization and repair of the cellular (OGG1-Asp267Asn, Ser279Gly Ile253Phe, 1578A > T, 1582C > T Ala399Glu (1542C > A) 1582insG 1543_1544delCT), and genes associated with the regulation of proliferation, apoptosis or tumor survival (miRNA499-CT/CC, CRYABC802G-CG/GG) are considered as risk factors. In this scheme, only the polymorphisms of ADH7A92G-GG and DEC1606-T/C genes are protective against malignancy transformation. The TP53, GSTM1 and CYPA1genes have been evaluated in more than one study and analyzed for homogeneity in each genotype. The meta-analysis showed no significant association between different allelic variants of Arg72Pro rs1042522 and SCCHN risk. In a model of tumorigenesis, an increased risk of SCCHN is associated with DNA repair and DNA stabilization genes. In addition, the polymorphisms involved in inflammation and carcinogenic metabolism processes represent an increased risk of SCCHN.
Topics: Odds ratio (52%)

Summary (2 min read)

INTRODUCTION

  • Head and Neck Carcinoma (HNC), of which the majority are squamous cell carcinomas of the head and neck , is the sixth most prevalent cancers in mankind and, presents high morbidity and low rates of survival.
  • It is known that the apoptotic and proliferation genes are involved in cancer development and these could be useful as a biomarker of this pathology.
  • Systematic reviews and meta-analysis allow stronger and more generalized conclusions for identifying some models of risk markers.
  • This has led to the production of an enormous number of epidemiologic papers about the relationship between genetic polymorphism and disease.
  • Focused on the microenvironment (focal proliferative lesions precede cancer) or morphostasis theory (morphostatic fields maintain the normal behavior of the cell and its tissue micro-architecture), also known as There are two subtypes.

METHODS

  • This study was made according to the PRISMA reporting items for systematic reviews and metaanalysis guidelines.
  • The search strategy included the following keywords (variably combined): “oral cancer”, “oral cancer polymorphism”, “oncogene”, “tumor suppressor gene”, “squamous cell carcinoma”, “head and neck cancer”.
  • Abstracts and titles of all the identified papers obtained by the electronic search were evaluated.
  • All studies which met the inclusion criteria (presence/absence of mutation and/or polymorphism by PCR, Odd Ratios (OR) adjusted for alcohol and tobacco, 95% Confidence Intervals (CIs) were assessed in order to establish their validity and subsequent data extraction.
  • The meta package of R software 2.15.3 (March 2013) was used.

Role of the funding source

  • The funders had no role in study design, data collection, analysis or interpretation of data, preparation of the report, or the decision to publish.
  • All members of the analysis and writing committee had access to the raw data and are responsible for the final submission for publication.

RESULTS

  • Nineteen original reports were retrieved from 2285 potential reports that addressed the issue of DNA gene / polymorphisms and risk of SCCHN.
  • Twelve of the studies were of unpaired casecontrol design, 6 studies were matched case-control, and 1 nested case-control (Table 1).
  • TP53, GSTM1, and CYPA1were described in four, three, and two studies respectively, which were considered for meta-analysis.
  • No study reported a significant association between this polymorphism and SCCHN risk.
  • For the positive genotype (I 2 =87.4%, Qtest=15.87, p-value=0.0004) and null genotype (I 2 =84%, Q-test=12.53, p-value=0.0019), heterogeneity was significant.

DISCUSSION

  • There are still numerous points that are unclear or unknown.
  • 57 The ADH7A92G 23 polymorphism has been described as associated with diminished SCCHN risk.
  • As well as smoking, alcohol consumption is another known cancer risk factor.
  • This gene is related to an increase of tumor survival because it promotes angiogenesis and inhibits apoptosis.
  • The model proposed in this work shows the genetic composition of individuals that could be at risk or protected against malignancy transformation.

ACKNOWLEDGMENTS

  • The authors received financial support from the Secretaria de Ciencia y Técnica of the Universidad Nacional de Córdoba (Res SECYT, UNC – N° 214/10).

2010; 31(10):1703-9.

  • IARC monographs on the evaluation of the carcinogenic risk of chemicals to man: some miscellaneous pharmaceutical substances.

1977; 13, 1–255.

  • Incidence curves for childhood and adult tumors, also known as Two-event models for carcinogenesis.
  • Su CH, Liu LC, Hsieh YH, Wang HC, Tsai CW, Chang WS, Ho CY, Wu CI, Lin CH, Lane HY, Bau DT.

Contributors

  • MB conceived and coordinated the project, made all the analyses, and wrote the report.
  • All authors contributed individual patient data from trials and commented on the initial surrogate-end point protocol and on drafts of the report.

Genotype wt/wt

  • Yu et al. (2011)26 USA CC matched SCCHN 1083 The University of Texas M. D. Anderson Cancer Center 1090 Cases 269 (24.8) F 814 (75.2)M Controls 258(23.7)F 832(76.3) M Cases 57.1 Controls 56.7 NFKB1 Lin et al. Mahjabeenet al.(2011)19 Pakistan CC matched SCCHN 300 National Oncology Radiotherapy Institute (NORI) Pakistan Institute of Medical Sciences (PIMS).
  • 1.51 0.94-2.43 96 81 Huang et al.(2010) 24 USA SCCHN DEC1 -1628 G>C (rs1591420) GG 1.00a 1008 1021 CG 0.33 0.03-3.16 1 4 CG+CC 1.00 0.73-1.37 90 94 DEC1 -606 T>C (rs4978620) TT 1.00a 529 537 CT 0.87 0.66-1.44 144 177 TT+CT 0.82 0.64-1.05 925 928 DEC1G>A (rs3750505) GG 1.00a 859 882 AG.

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RISK GENES IN HEAD AND NECK CANCER: A SYSTEMATIC REVIEW AND
META-ANALYSIS OF LAST 5 YEARS
Brunoo M
1
, Zarate AM
1
, Bono A
2
, Barra JL
3
, Berra S
4
1
Departamento de Bioloa Bucal;
2
Departamento de Patoloa Bucal, Facultad de Odontología, Universidad Nacional de Córdoba.
3
CIQUIBIC, UNC-CONICET, Departamento de Química Biológica, Facultad Ciencias Químicas, Universidad Nacional de Córdoba.
4
Instuto de Invesgaciones en Ciencias de la Salud (INICSA-CONICET),Universidad Nacional de Córdoba.
Corresponding author:
Dr. Mabel N. Brunoo
tedra Biología Celular, Facultad de Odontología,
Universidad Nacional de rdoba,
Haya de La Torre s/n, Pabellón Argenna,
Ciudad Universitaria, CP 5000, Córdoba-Argenna.
Cita del documento:
Brunoo, M, Zarate, A.M, Bono, A, Barra, J.L, Berra, S. Risk genes in head and neck cancer: a systemac review and
meta-analysis of last 5 years. Oral Oncol. 2014;3(50): 178-188.
Disponible en: hps://rdu.unc.edu.ar/handle/11086/5502
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Versión nal publicada en:
Oral Oncol. 2014 Mar;50(3):178-88. doi: 10.1016/j.oraloncology.2013.12.007

2
INTRODUCTION
Head and Neck Carcinoma (HNC), of which the majority are squamous cell carcinomas of the head
and neck (SCCHN), is the sixth most prevalent cancers in mankind and, presents high morbidity and
low rates of survival.
1
It is known that the apoptotic and proliferation genes are involved in cancer
development and these could be useful as a biomarker of this pathology. Systematic reviews and
meta-analysis allow stronger and more generalized conclusions for identifying some models of risk
markers. These models may help in screening, early diagnosis and/or therapy in the clinic.
2-5
In recent decades, there has been increased interest in genetic predisposition studies in complex
disease. This has led to the production of an enormous number of epidemiologic papers about the
relationship between genetic polymorphism and disease. However, the magnitude of association
between specific polymorphism and disease is still not established. The identification of a predictive
model of risk polymorphisms could help in early diagnosis, and in understanding disease recurrence
and/or progression in the subset of patients.
Vineis et al.
6
summarizedfive proposed models in the history of cancer research as follows: -
Mutational: carcinogenic compounds such as tobacco produce mutations in the genes related to cell
cycle regulation
7
;Genome Instability: based on the tumor suppressor genes hypothesis and DNA
repair (mismatch repair), and microsatellite instability
8
; Non-Genotoxic: based on modulators of
cancer risk (epigenetic events) such as diet, obesity, hormones, etc.
9
; Darwinian: based on Darwin’s
theory and the work of researchers such as Greaves, 2007
10
. This model considers a clonally
selection of cells that acquire advantages over others rather than mutations, but places the emphasis
on the role of the macro- and micro-environment; Tissue Organization: focuses on the local micro-
environment around the precancerous cells. There are two subtypes: focused on the micro-
environment (focal proliferative lesions precede cancer) or morphostasis theory (morphostatic fields
maintain the normal behavior of the cell and its tissue micro-architecture).
11
The aim of this work was to identify risk genes related to the development and progression of
squamous cell carcinoma head and neck (SCCHN) and do a meta-analysis of available estimates.
METHODS
Search strategy and selection criteria
This study was made according to the PRISMA reporting items for systematic reviews and meta-
analysis guidelines. We conducted a systematic review and meta-analysis of case-control studies
from the MEDLINE, Scopus, Cochrane, and CancerLit databases between January 2007 and
January 2013. Language is not restricted. The search strategy included the following keywords

3
(variably combined): oral cancer, oral cancer polymorphism, oncogene, tumor suppressor
gene, squamous cell carcinoma, head and neck cancer”.
Data extraction
Data was collected of adult patients of both genders, with diagnosis of head and neck carcinoma
according to the criteria of ICD-10C00-C14 WHO or another specific source, in whom genetic
polymorphisms were identified. Original published papers that did not report genotyping by PCR
(polymerase chain reaction), or studies of patients with systemic diseases or with syndromes,
pregnancy or with indication of long-term medication were excluded.
Abstracts and titles of all the identified papers obtained by the electronic search were evaluated. All
studies which met the inclusion criteria (presence/absence of mutation and/or polymorphism by
PCR, Odd Ratios (OR) adjusted for alcohol and tobacco, 95% Confidence Intervals (CIs) were
assessed in order to establish their validity and subsequent data extraction.
Evaluation of Quality of Studies
The case-control studies guidelines of the Scottish Intercollegiate Guidelines Network and MOOSE
are followed. Two members of the team (AB, AMZ) evaluated complete articles independently and
double-blinded, to establish their quality. Disagreements were resolved by reiteration, discussion
and consensus with the participation of a third member (JLB).The papers were encoded and
delivered independently to each reviewer. A search was made of combined electronic databases,
and the bibliographies of all selected papers were searched to identify grey literature.
Statistical Analysis
Since the included polymorphisms are diallelic SNPs, odds ratios (ORs) and corresponding 95%
confidence intervals (CIs) were used to assess the strength of association between each gene variant
and HNC risk, based on meta-analysis of molecular association studies.
12
Meta-analysis was performed using the random-effects (DerSimonian Laird) model, based on
whether the homogeneity characteristics of the studies allowed us to assume that the effect size
(HCN risk) varies between studies (studies represent a population of true effects), and the fixed
effects by the Mantel Haenszel method (assumes that all studies belong to a common population,
and that the effect size is not significantly different between studies.) To this end, heterogeneity was
formally investigated by the Q-test and the I
2
statistic
2
100%
Q df
Ix
Q



.
13
The meta package of R
software 2.15.3 (March 2013) was used.

4
Role of the funding source
The funders had no role in study design, data collection, analysis or interpretation of data,
preparation of the report, or the decision to publish. All members of the analysis and writing
committee had access to the raw data and are responsible for the final submission for publication.
RESULTS
Nineteen original reports were retrieved from 2285 potential reports that addressed the issue of
DNA gene / polymorphisms and risk of SCCHN. Twelve of the studies were of unpaired case-
control design, 6 studies were matched case-control, and 1 nested case-control (Table 1). All studies
were adjusted for tobacco and alcohol. Clinical trials, chromosomal alterations or in vitro cell
culture studies were not included. ORs and 95%CIs were estimated between case-control and
presence/absence of SCCHN. Other aspects were also studied that are not included in this paper
because they are not homogenous.
A hundred and eight genotypes of 40 polymorphism/genes (Table 2) related to proliferation,
apoptosis, carcinogenic metabolism, inflammatory and progression pathways were analyzed. The
total number was 8540 cases and 9844 controls (Table 2). The number of males was higher than
females. The average age range was between 50 and 60 years old, but the age ranged from 20 to 80,
and was similar in both cases and controls. In two studies only males were enrolled.
14,15
The following genes/polymorphisms were seen to have significant association with increased risk of
SCCHN: miRNA499
15
, TNFα
16
, TNFβ
16
, NFKB1
17
, NFKBIA
17
, CRYAB (Alpha B-Crystalline)
18
,
OGG1
19
, CYP1B1
20
, and GSTM1.
21,22
In contrast, the ADH7A92G
23
, and DEC1
24
polymorphisms
are associated with a diminished risk of SCCHN.TP53, GSTM1, and CYPA1were described in
four, three, and two studies respectively, which were considered for meta-analysis.
The suppressor tumor gene TP53, Arg72Pro, rs1042522 (CC, GG, CG) polymorphism was
evaluated in four studies for CC / GG genotypes, and in three studies for the CG genotype
24-27
. No
study reported a significant association between this polymorphism and SCCHN risk. The studies
reporting the genotype data were homogenous for the CC genotype (I
2
=40.1%, Q-test=5.01, p-
value=0.1714), GG genotype (I
2
=0%, Q-test=2.69, p-value=0.447), and CG genotype (I
2
=0%, Q-
test=0.66, p-value=0.7171). For each genotype pooled, the OR observed was: CC genotype1.14,
CIs95% [0.9195; 1.4208], p-value=0.2285; GG genotype 0.97, CIs95% [0.8837; 1.0707], p-
value=0.5723; GC genotype 0.91, CIs95% [0.8191; 1.0058], p-value=0.0645.The meta-analysis
showed no significant association between different allelic variants of Arg72Pro rs1042522 and
SCCHN risk (Figure 1).

5
The GSTM1 polymorphism was evaluated in three studies
21,22,28
. No study reported a significant
association between this polymorphism and SCCHN risk. For the positive genotype (I
2
=87.4%, Q-
test=15.87, p-value=0.0004) and null genotype (I
2
=84%, Q-test=12.53, p-value=0.0019),
heterogeneity was significant. Accordingly, there was no indication to meta-analyze the data.
The CYPA1 polymorphism was evaluated in two studies
21,28
. No single study reported a significant
association between this polymorphism and SCCHN risk. The genotype data were homogenous for
wilt/wilt genotype (I
2
=73.3%, Q-test=3.74, p-value=0.0531) and wilt/m1 genotype (I
2
=70.3%, Q-
test=3.37, p-value=0.0665) (Figure 2). For the m1/m1 genotype (I
2
=86.9%, Q-test=7.64, p-
value=0.0057) heterogeneity was significant, which prevented meta-analyzing the data.
DISCUSSION
Despite the great molecular advances made in understanding the mechanism of SCCHN
tumorigenesis, there are still numerous points that are unclear or unknown. The evaluation of
diagnostic markers such as symptoms and genetic tests helps to increase the sensitivity or
specificity of the determination of the presence/absence of malignancy.
2, 3,29
Cancer is a complex pathology, and its incidence and survival index are closely related to social,
cultural and socio-economic determinants of health.
Most of studies included in this paper are from the United States, but Europe, Asia and South
America are also represented. Nonetheless, it is not possible to compare the prevalence of HNC
among the countries, because this is influenced by variables such as ethnicity, geographic latitude
and individual genetic background which are not included in all the studies.
1
Generally, low-income
countries are more exposed to environmental risk factors such as, infections, tobacco, alcohol,
unhealthy diet plus, in many situations, little access to health systems and health education.
30
Genes
related to pathways of cell cycle regulation (proliferation, apoptosis, differentiation, proliferation,
epigenetic) were included in this review and meta-analysis.
The p53, Mdm2, p73, and miRNA proteins are involved in proliferation control and cellular
apoptosis. In this review, there was no reported significant association of TP53, Mdm2, and p73
polymorphisms with SCCHN.
24-27
It is known that the p53 suppressor tumor gene has a key role in
stress cellular response, to preserve genome stability, and it is universally recognized as a human
cancer marker when it is mutated.
2, 31-34
Actually, there is a TP53 polymorphism that produces a
protein with an amino acid (arginine or proline) located at position72.
35
Cellular functions of this polymorphism were studied in in vitro culture, and it was observed that
the protein variant codon72 arginine (R72) has a suppressor function of malignancy and induces an
increase in apoptotic activity in relation to the variant 72 proline (P72).
36,37
Authors such as Sarkar

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Journal ArticleDOI
03 Feb 2003-Nature Genetics
TL;DR: It is found that in cell lines containing inducible versions of alleles encoding the Pro72 and Arg72 variants, and in cells with endogenous p53, the Arg72 variant induces apoptosis markedly better than does the Pro 72 variant.
Abstract: The gene TP53, encoding p53, has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. This polymorphism occurs in the proline-rich domain of p53, which is necessary for the protein to fully induce apoptosis. We found that in cell lines containing inducible versions of alleles encoding the Pro72 and Arg72 variants, and in cells with endogenous p53, the Arg72 variant induces apoptosis markedly better than does the Pro72 variant. Our data indicate that at least one source of this enhanced apoptotic potential is the greater ability of the Arg72 variant to localize to the mitochondria; this localization is accompanied by release of cytochrome c into the cytosol. These data indicate that the two polymorphic variants of p53 are functionally distinct, and these differences may influence cancer risk or treatment.

1,194 citations


"Risk genes in head and neck cancer:..." refers background in this paper

  • ...Cellular functions of this polymorphism were studied in in vitro culture, and it was observed that the protein variant codon72 arginine (R72) has a suppressor function of malignancy and induces an increase in apoptotic activity in relation to the variant 72 proline (P72) [36,37]....

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Journal ArticleDOI
31 Oct 2010-Current Genomics
TL;DR: The P-body model outlines microRNA sorting and shuttling between specialized P- body compartments that house enzymes required for slicer –dependent and –independent silencing, addressing the reversibility of these silencing mechanisms.
Abstract: MicroRNAs are small, highly conserved non-coding RNA molecules involved in the regulation of gene expression. MicroRNAs are transcribed by RNA polymerases II and III, generating precursors that undergo a series of cleavage events to form mature microRNA. The conventional biogenesis pathway consists of two cleavage events, one nuclear and one cytoplasmic. However, alternative biogenesis pathways exist that differ in the number of cleavage events and enzymes responsible. How microRNA precursors are sorted to the different pathways is unclear but appears to be determined by the site of origin of the microRNA, its sequence and thermodynamic stability. The regulatory functions of microRNAs are accomplished through the RNA-induced silencing complex (RISC). MicroRNA assembles into RISC, activating the complex to target messenger RNA (mRNA) specified by the microRNA. Various RISC assembly models have been proposed and research continues to explore the mechanism(s) of RISC loading and activation. The degree and nature of the complementarity between the microRNA and target determine the gene silencing mechanism, slicer-dependent mRNA degradation or slicer-independent translation inhibition. Recent evidence indicates that P-bodies are essential for microRNA-mediated gene silencing and that RISC assembly and silencing occurs primarily within P-bodies. The P-body model outlines microRNA sorting and shuttling between specialized P-body compartments that house enzymes required for slicer –dependent and –independent silencing, addressing the reversibility of these silencing mechanisms. Detailed knowledge of the microRNA pathways is essential for understanding their physiological role and the implications associated with dysfunction and dysregulation.

1,052 citations


"Risk genes in head and neck cancer:..." refers background in this paper

  • ...The miRNA are small portions of RNA, approximately 20–22 nucleotides, which may target a specific messenger RNA and generate feedback of its translation efficiency and stability [41–45]....

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