Next Article in Journal
Multidisciplinary Team Care in Pituitary Tumours
Previous Article in Journal
False Liver Metastasis by Positron Emission Tomography/Computed Tomography Scan after Chemoradiotherapy for Esophageal Cancer—Potential Overstaged Pitfalls of Treatment
Previous Article in Special Issue
Preoperative CT-Based Skeletal Muscle Mass Depletion and Outcomes after Total Laryngectomy
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 16
Issue 5
10.3390/cancers16050949
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Single Nucleotide Polymorphisms as Biomarker Predictors of Oral Mucositis Severity in Head and Neck Cancer Patients Submitted to Combined Radiation Therapy and Chemotherapy: A Systematic Review

by
Ronaldo Cavalieri
1,2,
Harley Francisco de Oliveira
3,
Thais Louvain de Souza
4 and
Milton Masahiko Kanashiro
1,*
1
Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, Brazil
2
Centro de Radioterapia, Grupo OncoBeda, Campos dos Goytacazes 28010-140, Brazil
3
Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto 14015-010, Brazil
4
Faculdade de Medicina de Campos, Campos dos Goytacazes, Rio de Janeiro 28035-581, Brazil
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(5), 949; https://doi.org/10.3390/cancers16050949
Submission received: 27 December 2023 / Revised: 8 February 2024 / Accepted: 20 February 2024 / Published: 27 February 2024
(This article belongs to the Special Issue Approaches to Improve the Prognosis of Head-and-Neck Cancer)
Browse Figures
Review Reports Versions Notes

Abstract

:

Simple Summary

Single Nucleotide Polymorphisms (SNPs) are the most common type of genetic variation found in an individual’s DNA sequences. SNPs can occur in both coding and non-coding regions of the genome and can affect gene expression, protein function, and disease susceptibility. In this systematic review, we evaluate the potential of SNPs as biomarkers in the assessment of oral mucositis (OM) severity in head and neck cancer (HNC) patients treated with concomitant chemoradiation (CRT). This systematic review demonstrates that SNPs in different biological pathways have the potential to be biomarkers and to function as predictors of patients who will develop severe mucositis. The most studied biological pathway was that involving DNA damage repair genes. However, considering the involvement of cytokines and inflammatory pathways in the pathophysiology of mucositis, we believe that this is a promising area in the study of the prediction of this condition. We conclude that SNPs can be used as possible biomarkers for the assessment of OM intensity in HNC patients, and further research is needed to explore the potential of SNPs in personalized medicine for HNC treatment.

Abstract

Single Nucleotide Polymorphisms (SNPs) are the most common type of genetic variation found in an individual’s DNA sequences. SNPs can occur in both coding and non-coding regions of the genome and can affect gene expression, protein function, and disease susceptibility. In this systematic review, we evaluate the potential of SNPs as biomarkers in the assessment of oral mucositis (OM) severity in head and neck cancer (HNC) patients treated with concomitant chemoradiation (CRT). The study selection process involved screening 66 articles from different platforms, and after removing duplicates and excluding articles that did not meet the eligibility criteria, 23 articles were included for full-text evaluation. Among them, genes from several pathways were analyzed. The DNA damage repair pathways had the highest number of genes studied. The most frequently analyzed gene was XRCC1. The proinflammatory cytokine pathways evaluated were TNF, with three articles, and NF-κB, with one article. Most included studies showed a potential association between certain SNPs and high-grade mucositis. We conclude that SNPs can be used as possible biomarkers for the assessment of OM intensity in HNC patients, and further research is needed to explore the potential of SNPs in personalized medicine for HNC treatment.

1. Introduction

Head and neck cancer (HNC) represents a heterogeneous group of malignancies located in an anatomical region containing delicate structures with close relationships to each other and involved in critical functions such as feeding and breathing. In addition, the natural history of the disease and the adverse effects of treatment can directly impact the patient’s appearance, verbal expression, and social interaction [1]. It originates from epithelial or glandular tissue lining the aero-digestive tract, and it can involve the oral cavity, pharynx, nasal cavity, larynx, thyroid, and salivary glands. HNC is a relatively common cancer worldwide, with approximately 950,000 new cases and 470,000 deaths per year across all subsites, and the global incidence is estimated to increase by 34% by 2030 [2]. Until the early 1990s, local curative treatment was primarily based on surgery with or without postoperative radiotherapy (RT). Later on, several publications started to demonstrate the possibility of organ preservation without loss of overall survival in selected groups of patients treated with CRT, making combined treatment a viable option [3,4]. However, conservative treatment with concurrent chemotherapy (CT) has altered and intensified some of the already known toxicity patterns of RT [5].
Mucositis is a frequent and acute complication, occurring regularly in patients receiving CRT. The patient may develop, to varying degrees, dysphagia, odynophagia, dehydration, and weight loss, and it is often necessary to temporarily interrupt RT or reduce the dose of CT, affecting outcomes and increasing frequency, duration, and costs of hospitalization and antibiotic therapy [5]. Worsening severity of mucositis is related to declining levels of quality of life [6]. Classically, it was described exclusively as a direct and local effect of radiation damage to the DNA of basal layer cells, influencing their multiplication and replacement of mucosal surface cells. Radiation-induced mucositis was classically recognized as an “outside-in” process. The concept of mucosal injury as a biological and multifactorial process is relatively new [6,7].
In 2004, Sonis et al. published a study describing aspects of the development of mucositis as a dynamic process involving the activation of different pathways, described in a model of distinct phases [7]. The complexity of its pathogenesis, with description of distinct biological pathways and associated systemic factors, has been increasingly explored [8].
Previous data have reported a possible association between genetic polymorphisms in different pathways and the development of mucositis, acting as potential biomarkers of severity [9]. The most common type of polymorphism is one involving a single nucleotide, called single nucleotide polymorphism (SNP) [10].
The early identification, through the analysis of molecular aspects, of patients who are possibly more likely to develop mucositis, as well as its intensity, represents a promising area and the possibility of a new approach to this frequent complication. Individuals identified early on with a greater probability of developing this debilitating toxicity can be approached differently with the preemptive implementation of preventive measures and aggressive supportive care before and during radiotherapy. The purpose of this systematic review is to identify studies that evaluated SNPs in different pathways as predictive biomarkers of mucositis intensity in head and neck cancer patients submitted to combined radiotherapy and chemotherapy.

2. Methods

This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [11] and registered as 10.17605/OSF.IO/VQJPA.

2.1. Eligibility Criteria

Articles were included that addressed the relationship between SNPs in different biological pathways as biomarkers of the severity of oral mucositis (OM) in HNC patients receiving RT or CRT. The treatments had to be curative and RT could be used as a radical or postoperative treatment.
Articles were excluded because of the following reasons: evaluated patients with other types of cancer; HNC treatment without CRT; no correlation of the SNP with the severity of mucositis; reviews, letters, personal opinions, book chapters, and conference abstracts; association between biomarkers and OM in experimental studies (clinical trials, in vitro or in vivo animal studies); and language restrictions.

2.2. Information Sources and Search Strategies

An exhaustive search was carried out in the main databases used as research tools—PubMed, LILACS, Science Direct, and Cochrane. A search was also carried out on Google Scholar in order to detect any publications in addition to those already listed. Search strategies included the use of the following terms: “head and neck cancer OR head and neck carcinoma” AND “radiation therapy OR radiotherapy OR chemotherapy OR chemoradiation” AND “mucositis OR oral mucositis” AND “single nucleotide polymorphisms OR SNPs OR SNP OR gene polymorphism”.
Articles published between January 2009 and September 2022 were included for analysis. All duplicate articles were removed. In addition, the references of the included articles were reviewed to detect publications that were not identified in the search process.

2.3. Study Selection and Data Collection Process

In the first phase, the articles were listed in the databases and all the titles and abstracts were reviewed by two independent authors (RC and HO), who made the primary selection. The second phase consisted of reading the full text and retrieving those that met the inclusion criteria. This stage was also carried out by the same two authors (RC and HO). In the event of disagreement, a third author (MK) decided whether or not to include the reference. The references of the articles were reviewed by the first author (RC).
For all the articles included, the following information was recorded: authors, year of publication, country, number of patients, RT dose, treatment modalities, pathways of the polymorphisms studied, type of study, and main conclusions.

2.4. Study Risk of Bias and Quality Assessment

The quality and possible sources of bias of the selected studies were assessed using the Newcastle Ottawa Scale (NOS) tool, specific to observational studies. Three quality parameters (selection, comparability, and results), divided into eight specific items, were assessed. Each item on the scale was scored out of one point, except comparability, which was scored out of two points. The maximum for each study was nine, and references with less than five points were identified as representing a considerable risk of bias [12].
Two authors independently verified the parameters (RC and TL). A third author (HO) decided in case of disagreement.

3. Results

3.1. Study Selection

After the terms were restricted, we found a total of 66 articles on different platforms. Duplicated articles were removed, leaving 53 articles. The titles and abstracts of all of them were subsequently analyzed comprehensively. Twenty-seven articles were selected for full-text review. Three additional articles were found from the references of the selected articles. Finally, 23 articles were selected for final analysis (Scheme 1 From PRISMA, http://www.prisma-statement.org/?AspxAutoDetectCookieSupport=1 (accessed on 30 October 2023)).

3.2. Study Characteristics

The countries where the studies were conducted were China (10), Poland (04), India (03), Japan (01), Belgium (01), Italy (01), Spain (01), France (01), and the USA (01).
All articles were published in English, between 2009 and 2021.
The total of individuals from the published articles was 4977. Genome-wide association studies contributed to most of them. Sample size ranged from 24 to 1467 patients with HNC. All patients received RT with or without CT. Two articles included surgery as an option.
All articles used genomic DNA extracted from blood samples, except one that used tumor samples stored in liquid nitrogen from diagnostic biopsies.
Table 1 summarizes the main characteristics and findings of the selected articles.

3.3. Synthesis of Results

3.3.1. Mucositis SNP-Associated Non-Proinflammatory Mediator-Regulated Genes

Among the 23 included articles, genes from several pathways were analyzed.
Eight studies assessed the relationship between acute toxicities and polymorphisms in genes related to DNA damage repair (Figure 1). The most frequently analyzed gene was XRCC1 (Figure 1 and Figure 2). The DNA damage repair pathways had the highest number of genes studied (Figure 3). One article found no substantial association between SNPs in DNA repair genes and mucositis [13].
Three groups analyzed and established the relationship of an SNP at codon 399 of the XRCC1 gene [23,30,34]. Chen et al. observed no significant difference in the severity of acute OM damage during RT between patients with different genotypes [19]. However, in one article there was a significant correlation (p = 0.011) [24] and in another a marginal correlation (p = 0.065) [15].
Three articles published results on the relationship between the Arg194Trp polymorphism in the XRCC1 gene and clinical outcomes in patients with head and neck tumors. Li et al. showed the polymorphism was associated with a decreased incidence of grade 3 acute OM compared with the Arg/Arg allele, but with no statistical significance [15]. The other two articles concluded that the presence of SNP was significantly related to mucositis, p = 0.023 [25] and p = 0.01 [34].
Seven SNPs of four genes of the Wnt/β-catenin pathway were investigated. The rs454886 polymorphism of the adenomatous polyposis coli gene was correlated with grade 3–4 OM (p = 0.045) [17].
Additional studies have found a relationship between mucositis and SNPs in non-coding RNA pathways, in genes encoding ghrelin [26], in the ABCC1 gene pathway [28], and in autophagy-related genes [29].
Four studies performed a genome-wide association analysis. They were included as they found a link between the occurrence of different polymorphisms and the potential risk of developing mucositis. One study was on the CCHCR1 gene [35], the others on the TNKSK [33], ZNF24 [21], and RB1 [23] pathways.

3.3.2. Mucositis SNP-Associated Proinflammatory Mediator-Regulated Genes

Previous data have established the association of inflammatory cytokines and their pathways in the development, maintenance, and intensity of acute mucositis. Clinical inflammatory conditions are preceded by increased levels of these cytokines. Four articles evaluated the relationship between SNPs in inflammatory cytokine pathways and mucositis (Figure 2).
The cytokine pathways evaluated were TNF, with three articles, and NF-κB, with one article. The TNF receptor, TNFR1, when activated, regulates an apoptotic pathway and may be involved in the development of mucositis. Two articles assessed SNPs in the promoter region of the gene encoding the receptor protein, TNFRSF1A, and showed a significant increase in the likelihood of grade 3 mucositis in the last weeks of RT in CC, TT, or GT genotype carriers [27,31]. The other article addressing the TNF pathway assessed the relationship between the SNP (-1211 T>C, rs1799964) in the TNF-α gene itself and the occurrence and intensity of OM [32].
Guo et al. chose five SNPs in the NF-κB pathway to determine whether they related to the likelihood of acute toxicity. There was no relationship between the polymorphisms and mucositis. However, in the same article, the authors also evaluated SNPs in cyclins, cell cycle regulatory proteins. CCND1 rs9344 was associated with grade 3–4 radiation-induced acute OM [20].

3.4. Study Risk of Bias and Quality Assessment

All the references were individually assessed using the NOS tool, with a maximum score of nine. A total of 9 articles (39.1%) obtained a score of six, 11 (47.8%) a score of five. Three (13%) articles scored four, and only these were considered to be of fair quality (Supplementary Table S1).

4. Discussion

In recent years, much progress has been made in understanding the molecular pathways associated with the pathophysiology of diseases, as well as treatments and their adverse effects. In oncology, it is no different; several signaling pathways have been described, and the personalization of the diagnostic and therapeutic approach is a remarkable advance. The treatment of HNC based on RT combined with CT represents a possible cure for certain diseases that previously did not have curative surgical approaches, in addition to offering a chance of organ preservation in an anatomical region very sensitive to these changes [4]. One of the most common and debilitating toxicities, with the potential to compromise therapeutic outcomes related to this strategy, is mucositis [6].
Mucositis is a common and often debilitating side effect of cancer treatment that involves damage to the mucous membranes lining the gastrointestinal tract, particularly in the oral and oropharyngeal regions. It can be caused by CT, radiation therapy, or a combination of both, and can lead to a range of clinical and symptomatic manifestations, including erythema, ulceration, pain, and difficulty eating and drinking [36]. Mucositis can also increase the risk of infection and other complications [37]
Historically, mucositis was seen as a result of a direct action of RT or CT on the cells of the basal epithelial layer. However, this simple picture could not explain the complex interactions that started to be described in the submucosal layer. The concept that mucosal injury is a biological and multifactorial process is relatively new [6,7].
In 2004, Sonis et al. published a study describing the aspects of mucositis development as a dynamic process divided into phases, initially involving the generation of free radicals by direct action of RT and/or CT [7]. Their research showed that local damage triggers an inflammatory response, activating several biological pathways, including nuclear factor kappa-B (NF-kB). This transcription factor, which can also be directly activated by RT and/or CT, induces gene expression of proinflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α), which are apparently increased in mucositis. TNF-α may engage in a positive feedback mechanism with NF-kB, increasing its concentration, and eventually producing a massive release of cytokines (proinflammatory cytokine storm), amplifying the process. The clinical condition then develops with the onset of disease-related signs and symptoms, such as ulcers. At this point, the patient is more susceptible to infections, which can prolong mucositis as the activation of macrophages can release more inflammatory cytokines [7].
Recent advances in molecular and cell biology have provided targets for mechanism-based interventions to prevent and treat mucositis. Normando et al. evaluated several biomarkers for their association with the development of OM, including epidermal growth factor, C-reactive protein, genetic polymorphisms, tumor necrosis factor alpha (TNF-α), erythrocyte sedimentation rate, growth factors, acute-phase inflammatory markers, cytokines, general proteins, plasma antioxidants, apoptotic proteins, and cells. The meta-analysis showed an expression of polymorphisms in XRCC1, XRCC3, and RAD51 genes, as well as an expression of protein biomarkers, in patients with an increased risk of developing OM. However, the effectiveness of these biomarkers in predicting mucositis risk and guiding treatment decisions is still under investigation [9].
Genetic polymorphisms can influence gene expression by affecting various regulatory elements within the genome. Among genetic polymorphisms, SNPs are the most common type of genetic variation in the human genome [10]. Several groups have studied the relationship between SNPs and different clinical outcomes. The development of the disease, the different responses to the therapies implemented, and the development of more intense adverse effects to the treatments may be related to the occurrence of specific SNPs. Searching for and establishing this relationship represents an area of study that could alter and personalize approaches to a wide range of conditions in different areas.
Recently, several studies have explored the relationship between SNPs and susceptibility to mucositis in cancer patients. In this systematic review, we analyzed the non-proinflammatory and proinflammatory genes regulated by SNPs in HNC patients undergoing RT and CT.
Proinflammatory cytokines play a decisive role in the development of mucositis [38]. The presence of polymorphisms in genes that code for proinflammatory proteins can lead to alterations, causing an increase in the release of cytokines and intensification of mucositis. Despite the preponderant role of inflammatory cytokines in the development of mucositis, to date few studies have been published demonstrating a relationship between SNPs in these pathways and this adverse effect. In our review, four publications studied SNPs in these pathways.
In the case of TNF, the process of apoptosis is regulated through the TNFR1 receptor. SNPs in the gene that codes for the receptor can alter its expression and function and be linked to adverse events [39]. Brzozowska et al. showed that the presence of the T allele in the TNFRSF1A gene is associated with an increased risk of manifestation of grade 3 OM in patients with HNC undergoing RT. The study found that patients with TT or GT genotypes demonstrated a higher risk of grade 3 OM manifestation at week five of RTH compared to GG carriers. The results indicate an association between the TNFRSF1A gene SNP (rs4149570) and the risk of more severe RT-related OM in patients with HNC [27].
In their work, Mlak et al. (2020) showed that the CC genotype of the TNFRSF1 A gene is associated with a more severe course of OM [31]. The SNP identified in this study is located in the regulatory region of the TNFRSF1 A gene. Specifically, it is the SNP (rs767455) that has been found to be involved in the regulation of TNFR1 protein expression and may potentially modulate the risk of OM in HNC patients treated with RT, and it is an independent prognostic factor of poor overall survival in HNC patients undergoing intensity-modulated radiation therapy. The TT genotype, in contrast, had an inverse protective effect. However, due to the limitations of the study, further research is needed to confirm these results.
Another inflammatory pathway studied was the NFKB transcription factor, which when activated causes up-regulation of genes that result in increased cytokine production. The κB kinase inhibitor gene IKBKB rs12676482 was related to grade 3–4 radiation-induced acute myelosuppression, but not to mucositis [18].
In the studies that have evaluated SNPs in non-inflammatory pathways, the most investigated have been alterations in DNA damage repair genes. DNA damage repair is a mechanism which is related to radiosensitivity in both tumor response and treatment-related adverse effects [40]. Normal tissues depend on this mechanism to recover between RT sessions from damage caused by RT, and alterations in this mechanism can exacerbate toxicities, increasing variability between individuals receiving the same treatment. The included articles evaluated polymorphisms in candidate genes previously related to radiosensitivity. The most common gene studied was XRCC1, which is associated with the ability to detect and repair three of the most common DNA errors: single-strand breaks; double-strand breaks, which have greater biological significance; and base excision repair [40]. The most frequently searched SNP was c1196A>G p.Gln399Arg [15,19,24].
The risk of bias and the quality of the articles were assessed using the NOS tool, which establishes points for pre-established criteria [12]. The articles generally have a similar design, reducing the possibility of bias. In general, the articles were considered to be of good quality and to have a low risk of bias, since most of them scored five or more. In all the publications, the control groups were not patients who had not been exposed to the treatment, but patients with milder toxicities, which is a characteristic of the study design. However, according to the NOS scale, it is not possible to score them in this respect. Another issue that is not specified in most references is the demonstration that the main outcome, mucositis, is not present at the start of the studies. It is understood that mucositis was not present before the start of RT, but when this is not specified, it cannot be scored using the scale.
This systematic review demonstrates that SNPs in different biological pathways have the potential to be biomarkers and to function as predictors of patients who will develop severe mucositis. The most studied biological pathway was that involving DNA damage repair genes. However, considering the involvement of cytokines and inflammatory pathways in the pathophysiology of mucositis, we believe that this is a promising area in the study of the prediction of this condition. As studies collect more robust data on biomarkers in different pathways, we will be closer to developing a more personalized treatment strategy for a clinical condition that is costly for healthcare systems and so debilitating for patients who already have a very challenging type of cancer.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers16050949/s1, Table S1: Risk of bias assessment.

Author Contributions

Conceptualization, M.M.K. and H.F.d.O.; methodology, M.M.K. and R.C.; software, R.C.; validation, R.C., H.F.d.O. and M.M.K.; formal analysis, R.C. and T.L.d.S.; investigation, R.C.; resources, M.M.K.; data curation, M.M.K.; writing—original draft preparation, R.C.; writing—review and editing, R.C., H.F.d.O. and M.M.K.; visualization, R.C.; supervision, M.M.K. and H.F.d.O.; project administration, M.M.K.; funding acquisition, M.M.K. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by FAPERJ (Fundação de 1 Amparo à Pesquisa do Estado do Rio de Janeiro E-26/211.221/2021).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Mody, M.; Rocco, J.; Yom, S.; Haddad, R.; Saba, N. Head and neck cancer. Lancet 2021, 398, 2289–2299. [Google Scholar] [CrossRef]
  2. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  3. Wolf, G.; Fisher, S.; Hong, W.; Hilman, R.; Spaulding, M.; Laramore, G. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N. Engl. J. Med. 1991, 324, 1685–1690. [Google Scholar] [PubMed]
  4. Pignon, J.; Maillard, E.; Bourhis, J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother. Oncol. 2009, 92, 4–14. [Google Scholar] [CrossRef] [PubMed]
  5. Elting, L.S.; Cooksley, C.D.; Chambers, M.S.; Garden, A.S. Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int. J. Radiat. Oncol. Biol. Phys. 2007, 68, 1110–1120. [Google Scholar] [CrossRef] [PubMed]
  6. Murphy, B.A.; Ridner, S.; Wells, N.; Dietrich, M. Quality of life research in head and neck cancer: A review of the current state of the science. Crit. Rev. Oncol./Hematol. 2007, 62, 251–267. [Google Scholar] [CrossRef]
  7. Sonis, S.T. The pathobiology of mucositis. Nat. Rev. Cancer 2004, 4, 277–284. [Google Scholar] [CrossRef]
  8. Villa, A.; Sonis, S.T. Mucositis. Curr. Opin. Oncol. 2015, 27, 159–164. [Google Scholar] [CrossRef]
  9. Normando, A.G.C.; Rocha, C.L.; de Toledo, I.P.; de Souza Figueiredo, P.T.; dos Reis, P.E.D.; De Luca Canto, G.; Guerra, E.N.S. Biomarkers in the assessment of oral mucositis in head and neck cancer patients: A systematic review and meta-analysis. Support. Care Cancer 2017, 25, 2969–2988. [Google Scholar] [CrossRef]
  10. Kruglyak, L.; Nickerson, D.A. Variation is the spice of life. Nat. Genet. 2001, 27, 234–236. [Google Scholar] [CrossRef]
  11. Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulow, C.; Gotzsche, P.C.; Aloamidis, J.P.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. Br. Med. J. 2009, 339, b2700. [Google Scholar] [CrossRef]
  12. Luchini, C.; Stubbs, B.; Solmi, M.; Veronese, N. Assessing the quality of studies in meta-analyses: Advantages and limitations of the Newcastle Ottawa Scale. World J. Meta-Anal. 2017, 5, 4. [Google Scholar] [CrossRef]
  13. Werbrouck, J.; De Ruyck, K.; Duprez, F.; Veldeman, L.; Claes, K.; Van Eijkeren, M.; Boterberg, T.; Willems, P.; Vral, A.; De Neve, W.; et al. Acute Normal Tissue Reactions in Head-and-Neck Cancer Patients Treated With IMRT: Influence of Dose and Association with Genetic Polymorphisms in DNA DSB Repair Genes. Int. J. Radiat. Oncol. Biol. Phys. 2009, 73, 1187–1195. [Google Scholar] [CrossRef]
  14. Pratesi, N.; Mangoni, M.; Mancini, I.; Paiar, F.; Simi, L.; Livi, L.; Cassani, S.; Buglione, M.; Grisanti, S.; Almici, C.; et al. Association between single nucleotide polymorphisms in the XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck câncer. Radiother. Oncol. 2011, 99, 356–361. [Google Scholar] [CrossRef]
  15. Li, H.; You, Y.; Lin, C.; Zheng, M.; Hong, C.; Chen, J.; Li, D.; Au, W.W.; Chen, Z. XRCC1 codon 399Gln polymorphism is associated with radiotherapy-induced acute dermatitis and mucositis in nasopharyngeal carcinoma patients. Radiat. Oncol. 2013, 8. [Google Scholar] [CrossRef]
  16. Venkatesh, G.H.; Manjunath, V.B.; Mumbrekar, K.D.; Negi, H.; Fernandes, D.J.; Sharan, K.; Banerjee, S.; Sadashiva, S.R.B. Polymorphisms in Radio-Responsive Genes and Its Association with Acute Toxicity among Head and Neck Cancer Patients. PLoS ONE 2014, 9, e89079. [Google Scholar] [CrossRef] [PubMed]
  17. Yu, J.; Huang, Y.; Liu, L.; Wang, J.; Yin, J.; Huang, L.; Chen, S.; Li, J.; Yuan, H.; Yang, G.; et al. Genetic polymorphisms of Wnt/β-catenin pathway genes are associated with the efficacy and toxicities of radiotherapy in patients with nasopharyngeal carcinoma. Oncotarget 2016, 7, 82528–82537. [Google Scholar] [CrossRef]
  18. Yu, J.; Huang, Y.; Liu, L.; Wang, J.; Yin, J.; Huang, L.; Chen, S.; Li, J.; Yuan, H.; Yang, G.; et al. Genetic polymorphisms of long non-coding RNA GAS5 predict platinum-based concurrent chemoradiotherapy response in nasopharyngeal carcinoma patients. Oncotarget 2017, 8, 62286–62297. [Google Scholar]
  19. Chen, H.; Wu, M.; Li, G.; Hua, L.; Chen, S.; Huang, H. Association between XRCC1 single-nucleotide polymorphism and acute radiation reaction in patients with nasopharyngeal carcinoma A cohort study. Medicine 2017, 96, e8202. [Google Scholar] [CrossRef]
  20. Guo, C.; Huang, Y.; Yu, J.; Liu, L.; Gong, X.; Huang, M.; Jiang, C.; Liao, Y.; Huang, L.; Yang, G.; et al. The impacts of single nucleotide polymorphisms in genes of cell cycle and NF-κB pathways on the efficacy and acute toxicities of radiotherapy in patients with nasopharyngeal carcinoma. Oncotarget 2017, 8, 25334–25344. [Google Scholar] [CrossRef]
  21. Le, Z.; Niu, X.; Chen, Y.; Ou, X.; Zhao, G.; Liu, Q.; Tu, W.; Hu, C.; Kong, L.; Liu, Y. Predictive single nucleotide polymorphism markers for acute oral mucositis in patients with nasopharyngeal carcinoma treated with radiotherapy. Oncotarget 2017, 8, 63026–63037. [Google Scholar] [CrossRef]
  22. Ma, W.L.; Liu, R.; Huang, L.H.; Zou, C.; Huang, J.; Wang, J.; Chen, S.J.; Meng, X.G.; Yang, J.K.; Li, H.; et al. Impact of polymorphisms in angiogenesis-related genes on clinical outcomes of radiotherapy in patients with nasopharyngeal carcinoma. Clin. Exp. Pharmacol. Physiol. 2017, 44, 539–548. [Google Scholar] [CrossRef]
  23. Reyes-Gibby, C.C.; Melkonian, S.C.; Wang, J.; Yu, R.K.; Shelburne, S.A.; Lu, C.; Gunn, G.B.; Chambers, M.S.; Hanna, E.Y.; Yeung, S.C.J. Identifying novel genes and biological processes relevant to the development of cancer therapy-induced mucositis: An informative gene network analysis. PLoS ONE 2017, 12, e0180396. [Google Scholar] [CrossRef]
  24. Borchiellini, D.; Etienne-Grimaldi, M.C.; Bensadoun, R.J.; Benezery, K.; Dassonville, O.; Poissonnet, G.; Llorca, L.; Ebran, N.; Formento, P.; Château, Y.; et al. Candidate apoptotic and DNA repair gene approach confirms involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer. Oral Oncol. 2017, 67, 70–76. [Google Scholar] [CrossRef]
  25. Nanda, S.S.; Gandhi, A.K.; Rastogi, M.; Khurana, R.; Hadi, R.; Sahni, K.; Mishra, S.P.; Srivastava, A.K.; Bhatt, M.L.B.; Parmar, D. Evaluation of XRCC1 Gene Polymorphism as a Biomarker in Head and Neck Cancer Patients Undergoing Chemoradiation Therapy. Int. J. Radiat. Oncol. Biol. Phys. 2018, 101, 593–601. [Google Scholar] [CrossRef]
  26. Brzozowska, A.; Homa-Mlak, I.; Mlak, R.; Gołębiowski, P.; Mazurek, M.; Ciesielka, M.; Małecka-Massalska, T. Polymorphism of regulatory region of GHRL gene (-2531C>T) as a promising predictive factor for radiotherapy-induced oral mucositis in patients with head neck cancer. Head Neck 2018, 40, 1799–1811. [Google Scholar] [CrossRef]
  27. Brzozowska, A.; Powrózek, T.; Homa-Mlak, I.; Mlak, R.; Ciesielka, M.; Gołębiowski, P.; Małecka-Massalska, T. Polymorphism of Promoter Region of TNFRSF1A Gene (−610 T > G) as a Novel Predictive Factor for Radiotherapy Induced Oral Mucositis in HNC Patients. Pathol. Oncol. Res. 2018, 24, 135–143. [Google Scholar] [CrossRef]
  28. Duran, G.; Aguín, S.; Cruz, R.; Barros, F.; Giráldez, J.; Bernárdez, B.; López-López, R.; Carracedo, Á.n.g.e.l.; Lamas, M. Association of GSTP1 and ERCC1 polymorphisms with toxicity in locally advanced head and neck cancer platinum-based chemoradiotherapy treatment. Head Neck 2019, 41, 2704–2715. [Google Scholar] [CrossRef] [PubMed]
  29. Yang, Z.; Liu, Z. Potentially functional variants of autophagy-related genes are associated with the efficacy and toxicity of radiotherapy in patients with nasopharyngeal carcinoma. Mol. Genet. Genom. Med. 2019, 7, e1030. [Google Scholar] [CrossRef] [PubMed]
  30. Gupta, A.; Mathew, D.; Ghoshal, S.; Pal, A. XRCC1 (rs25487) polymorphism is associated with severe oral mucositis and poor treatment response after radiotherapy for oropharyngeal carcinoma. Oral Cancer 2019, 3, 37–47. [Google Scholar] [CrossRef]
  31. Mlak, R.; Powrózek, T.; Brzozowska, A.; Homa-Mlak, I.; Mazurek, M.; Gołębiowski, P.; Korzeb, D.; Rahnama-Hezavah, M.; Małecka-Massalska, T. Polymorphism of TNFRSF1 A may act as a predictor of severe radiation-induced oral mucositis and a prognosis factor in patients with head and neck cancer. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2020, 130, 283–291.e2. [Google Scholar] [CrossRef]
  32. Mlak, R.; Powrózek, T.; Brzozowska, A.; Homa-Mlak, I.; Mazurek, M.; Gołębiowski, P.; Sobieszek, G.; Małecka-Massalska, T. The relationship between TNF-α gene promoter polymorphism (−1211 T>C), the plasma concentration of TNF-α, and risk of oral mucositis and shortening of overall survival in patients subjected to intensity-modulated radiation therapy due to head and neck cancer. Support. Care Cancer 2020, 28, 531–540. [Google Scholar] [PubMed]
  33. Yang, D.W.; Wang, T.M.; Zhang, J.B.; Li, X.Z.; He, Y.Q.; Xiao, R.; Xue, W.Q.; Zheng, X.H.; Zhang, P.F.; Zhang, S.D.; et al. Genome-wide association study identifies genetic susceptibility loci and pathways of radiation-induced acute oral mucositis. J. Transl. Med. 2020, 18, 224. [Google Scholar] [CrossRef] [PubMed]
  34. Raturi, V.; Hojo, H.; Bhatt, M.L.B.; Suhel, M.; Wu, C.T.; Bei, Y.; Nakamura, M.; Okumura, M.; Zhang, H.; Parmar, D.; et al. Prospective evaluation of XRCC-1 Arg194Trp polymorphism as bio-predictor for clinical outcome in locally advanced laryngeal cancer undergoing cisplatin-based chemoradiation. Head Neck 2020, 42, 1045–1056. [Google Scholar] [CrossRef] [PubMed]
  35. Li, Q.; Liang, Y.; Liu, Z.; Yu, C. Associations of GWAS-Indentified risk loci with progression, efficacy and toxicity of radiotherapy of head and neck squamous cell carcinoma treated with radiotherapy. Pharmacogenomics Pers. Med. 2021, 14, 1205–1210. [Google Scholar]
  36. Peterson, D.E.; Keefe, D.M.S. New frontiers in mucositis. Am. Soc. Clin. Oncol. Educ. Book 2012, 545–551. [Google Scholar] [CrossRef]
  37. Cinausero, M.; Aprile, G.; Ermacora, P.; Basile, D.; Vitale, M.; Fanotto, V.; Parisi, G.; Calvetti, L.; Sonis, S. New frontiers in the pathobiology and treatment of cancer regimen-related mucosal injury. Front. Pharmacol. 2017, 8, 354. [Google Scholar] [CrossRef] [PubMed]
  38. Bossi, P.; Bergamini, C.; Miceli, R.; Cova, A.; Orlandi, E.; Resteghini, C.; Locati, L.; Alfieri, S.; Imbimbo, M.; Granata, R.; et al. Salivary Cytokine Levels and Oral Mucositis in Head and Neck Cancer Patients Treated with Chemotherapy and Radiation Therapy. Int. J. Radiat. Oncol. Biol. Phys. 2016, 96, 959–966. [Google Scholar] [CrossRef] [PubMed]
  39. Kalliolias, G.D.; Ivashkiv, L.B. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 2016, 12, 49–62. [Google Scholar] [CrossRef]
  40. Huang, R.; Zhou, P. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct. Target. Ther. 2020, 5, 60. [Google Scholar] [CrossRef]
Cancers 16 00949 sch001
Scheme 1. Flow diagram of the study selection.
Scheme 1. Flow diagram of the study selection.
Cancers 16 00949 sch001
Cancers 16 00949 g001
Figure 1. Frequency of genes in the included articles separated by colors. Blue: DNA repair genes. Green: Wnt/β-catenin. Brown: cell cycle. Red: inflammatory.
Figure 1. Frequency of genes in the included articles separated by colors. Blue: DNA repair genes. Green: Wnt/β-catenin. Brown: cell cycle. Red: inflammatory.
Cancers 16 00949 g001
Cancers 16 00949 g002
Figure 2. Frequency of different pathways in the included articles.
Figure 2. Frequency of different pathways in the included articles.
Cancers 16 00949 g002
Cancers 16 00949 g003
Figure 3. Number of genes studied in each pathway.
Figure 3. Number of genes studied in each pathway.
Cancers 16 00949 g003
Table 1. Main characteristics and findings of the selected articles.
Table 1. Main characteristics and findings of the selected articles.
AuthorCountryYearPrimary SitesPossible Treatments Number of Patients (n)Dose (Gy)Genes Accessed by the StudiesSampleType of StudyMain ConclusionsMucositis as One of the Primary End Points
Werbrouk et al. [13] Belgium2009Head and NeckRT/RT + CT/Surgery + RT8866–70DNA DSB repair genes XRCC3, Rad51, Lig4, Ku70, Ku80 BloodCohort- Association was found between the presence of the XRCC3c.562-14 A>G (rs1415120657) polymorphism and the risk of severe acute mucositis (adjusted OR = 1.96; p = 0.178).
- One variant allele of Rad51c.-3392 was associated with a small increase in the risk for severe mucositis after RT (adjusted OR = 1.21; p = 0.728).
- A negative but not significant association was found for Ku70c.-1310 SNP.		Yes
Patresi et al. [14]Italy2011Head and NeckRT/RT + CT10154–70XRCC1 c.1196A>G, XRCC3 c.722C>T, RAD51 (c.-3429G>C, c.-3392G>T), and GSTP1 c.313A>G.BloodCohort- Risk of mucositis was increased in patients with XRCC1-399Gln allele genotypes both in the chemoradiotherapy (p = 0.035, HR = 1.72, CI = 1.03–2.86) and radiotherapy alone (p = 0.049, HR = 2.50, CI = 0.97–6.47) groups. Yes
Li H et al. [15]China2013NasopharynxRT/RT + CT11466–70XRCC1 (194Arg/Trp and 399Arg/Gln) BloodCohort- XRCC1 399Arg/Gln was associated with higher incidence of grade 3 oral mucosa toxicity, OR = 2.11 (95% CI: 0.951–4.66), p = 0.065.Yes
Venkatesh et al. [16]India2014Head and NeckRT + CT18360–70ATM, XRCC1, XRCC3, XRCC4, Ku70, Ku80, LIG4, OGG1, NBN, RAD51, TGFb1, SOD2, CAT, GST BloodCohort- There was no association of NBN (rs1805794) polymorphism in univariate and multivariate analysis with severe mucositis.Yes
Yu J et al. [17]China2016NasopharynxRT/RT + CT18866–707 SNPS Wnt/β-CateninBloodCohort- APC rs454886 polymorphism (minor A allele) was associated with acute grade 3–4 radiation-induced oral mucositis in additive (p = 0.045) and recessive models (p = 0.038) after adjustment for BMI. Yes
Guo Z et al. [18]China2017NasopharynxRT + CT50568–72lncRNA GAS5BloodCohort- Slight relationship was found in the discovery stage between severe oral mucositis and rs2067079, as well as rs6790 (p = 0.049).
- Patients of rs2067079 TT genotype receiving DP for IC regimen (TT vs. CC, OR = 3.031, p = 0.047) or CCRT regimen (TT vs. CC, OR = 21.882, p = 0.043) were subjected to high risk of oral mucositis. 		Yes
Chen H et al. [19]China2017NasopharynxRT/RT + CT11470–76Base repair XRCC1 Codon 399 SNPBloodCohort- The injury degree of acute radiation oral mucositis showed no significant difference (p = 0.449, 95% CI: 0.691–2.304). Yes
Guo C et al. [20]China2017NasopharynxRT/RT + CT15466–703 SNPS Cell cycle/5 SNPS NF-κBBloodCohort- CCND1 rs9344 was related to grade 3–4 acute radiation-induced oral mucositis in recessive model among patients <51 years old. Yes
Le Z et al. [21]China2017NasopharynxRT/RT + CT2466–70.4Genome-wide screening BloodCohort- The SNP rs11081899-A in ZN24 was significantly associated with an enhanced risk of severe mucositis (OR = 14.631, 95% CI = 2.61–105.46, p = 1.2 × 10−4).
Ma W et al. [22]China2017NasopharynxRT/RT + CT18066–77Angiogenesis-related genes 3 SNPS EDN1/3 SNPS EDNRA/2 SNPS VEGFBloodCohort- GT genotype in EDN1 rs1800541 was significantly associated with an elevated risk of developing grade 3+ oral mucositis (p = 0.038).Yes
Reyes-Gibbi C [23]USA2017Head and NeckRT/RT + CT/Surgery + RTNINIInformative gene network analysisxX- SNP in RB1 (rs2227311, p-value = 0.034, OR = 0.67) showed a protective effect for oral mucositis.Yes
Borchiellini et al. [24]France2017Head and NeckRT/RT + CT12260–70ERCC1/ERCC2/XRCC1/M2MDiagnostic biopsyCohort- G allele of MDM2 309 (genotypes TG or GG) or the Thr allele of ERCC1 251 (genotypes Lys/Thr and Thr/Thr) were associated with a higher risk of acute G3-4 DMEX. No
Nanda S et al. [25]India2018Oral cavity, pharynx, larynxRT + CT10166–70Base repair XRCC1 Arg194TrpBloodCohort- Polymorphic variant had higher grade > 2 oral mucositis, 35.8% vs. 16.0% (OR: 2.91; 95% CI 1.13–7.46; p = 0.023).Yes
Brzozowska et al. [26]Poland2018Head and NeckRT/RT + CT/Surgery + RT6560–70GHRLBloodCohort - AA genotype was associated with 7-fold decrease in the risk of occurrence of intensified oral mucositis (grades 2 and 3) in the sixth week of RT. Yes
Brzozowska et al. [27]Poland2018Head and NeckRT/RT + CT5866–70TNFRSF1ABloodCohort - TT or GT genotype demonstrated higher risk of manifestation of grade 3 mucositis toxicity in 5th week of RT (p = 0.041; OR = 9.240; 95% CI: 1.101–77.581) compared to GG carriers. Yes
Duran G et al. [28]Spain2019Oral cavity, pharynx, larynx, unknown primaryRT + CT11050–76ABCC1BloodCohort- For rs1045642, patients with the variant T/T genotype showed higher acute mucositis than C/C or C/T genotype patients (47.1% vs. 24.1%; OR: 3.42; 95% CI: 1.04–11.21; p = 0.042 in a recessive model). Yes
Yang Z et al. [29]China2019NasopharynxRT/RT + CT46866–70Autophagy genes (ATG)BloodCohort- ATG10 rs10514231 and ATG16L2 rs10898880 were significantly associated with the occurrence of grade 3–4 oral mucositis.Yes
Gupta A et al. [30]India2019OropharynxRT/RT + CT17966XRCC1/XRCC3/XRCC4/XRCC6/ERCC4/Lig4/ATM BloodCohort- Homozygous AA genotype of XRCC1 (rs25487) and certain clinical characteristics are likely to develop severe acute mucositis (p = 0.024).Yes
Mlak R et al. [31]Poland2020Head and NeckRT/RT + CT6054–70(_135 T>C, rs767455) of TNFRSF1 A BloodCohort- SNP (_135 T>C) of the TNFRSF1 A gene may act as a predictor of OM occurrence in patients with HNC treated with IMRT.Yes
Mlak R et al. [32]Poland2020Head and NeckRT/RT + CT6266–70TNF⍺ rs1799964 (-1211 T>C)BloodCohort- CC genotype was related to over 7-fold (OR = 7.33, 95% CI 1.120–44.96, p = 0.031) and 23-fold (OR = 23.15, 95% CI 1.24– 432.14, p = 0.035) higher risk of 3rd-degree OM development after the 5th and 7th week of RTH, respectively.Yes
Yang D et al. [33]China2020NasopharynxRT/RT + CT146768–76Genome-wide association studyBloodCohort - The SNP rs117157809 located in TNKS gene was associated with increased risk of oral mucositis (95% CI 2.10–6.57; p = 6.33 × 10−6). Yes
Raturi V et al. [34]Japan2020LarynxRT + CT13470XRCC1 Arg194Trp BloodCohort- XRCC-1 Arg194Trp polymorphism is significantly associated with oral mucositis (p = 0.01). Yes
Quinghua L et al. [35]China2021Head and NeckRT/RT + CT500NIGenome-wide association studyBloodCohort- SNP rs1265081 in CCHCR1 gene (allele A vs. C: OR = 1.41, 95% CIs = 1.08–1.86, p = 0.012) and rs3135001 (allele T vs. allele C: OR = 0.53, 95% CIs = 0.35–0.79, p = 0.002) were significantly associated with the occurrence of grade 3–4 oral mucositis.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Cavalieri, R.; de Oliveira, H.F.; Louvain de Souza, T.; Kanashiro, M.M. Single Nucleotide Polymorphisms as Biomarker Predictors of Oral Mucositis Severity in Head and Neck Cancer Patients Submitted to Combined Radiation Therapy and Chemotherapy: A Systematic Review. Cancers 2024, 16, 949. https://doi.org/10.3390/cancers16050949

AMA Style

Cavalieri R, de Oliveira HF, Louvain de Souza T, Kanashiro MM. Single Nucleotide Polymorphisms as Biomarker Predictors of Oral Mucositis Severity in Head and Neck Cancer Patients Submitted to Combined Radiation Therapy and Chemotherapy: A Systematic Review. Cancers. 2024; 16(5):949. https://doi.org/10.3390/cancers16050949

Chicago/Turabian Style

Cavalieri, Ronaldo, Harley Francisco de Oliveira, Thais Louvain de Souza, and Milton Masahiko Kanashiro. 2024. "Single Nucleotide Polymorphisms as Biomarker Predictors of Oral Mucositis Severity in Head and Neck Cancer Patients Submitted to Combined Radiation Therapy and Chemotherapy: A Systematic Review" Cancers 16, no. 5: 949. https://doi.org/10.3390/cancers16050949

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop