Genetic Association on Radiation Induced Mucosal and Skin Toxicity in Patients with Nasopharyngeal Carcinoma
Isabella Wai Yin Cheuk, Vincent Wing Cheung Wu
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hunghom, Hong Kong
Corresponding Author: Vincent WC Wu, PhD, Email: htvinwu@polyu.edu.hk

Citation: Cheuk IWY, Wu VWC. Genetic association on radiation induced mucosal and skin toxicity in patients
with nasopharyngeal carcinoma. J Nasopharyng Carcinoma, 2014, 1(7): e7. doi:10.15383/jnpc.7.
Funding: This work was supported by grant from the Hong Kong Polytechnic University (RPFG).
Competing interests: The authors have declared that no competing interests exist.
Conflict of interest: None.
Copyright: 2014 By the Editorial Department of Journal of Nasopharyngeal Carcinoma. This is an open-access
article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract: Radiation therapy (RT) is the primary treatment for many head and neck cancers including
nasopharyngeal carcinoma (NPC). While prognosis has been greatly improved with the advancement of RT
technique, radiation-induced complications especially normal tissue surrounding tumour volume is unavoidable.
Genetic factors are thought to be the most important factors contributing to individual variation in radiation
sensitivity. Over 120 studies have been published since year 2000 to investigate the association of genetic variants
to radiation-induced toxicities in various types of cancer. Candidate gene approach is the most commonly used
approach in published studies, including studies in patients with NPC. Skin and mucosal toxicities are two of the
most common radiation induced complications in the radiotherapy of NPC patients. However, studies focused on
radiation toxicity in NPC patients are limited. Published literatures focused on genetic variations and radiation
sensitivity in NPC patients are summarized in this review, and recommendations for future studies are also
Keywords: Nasopharyngeal carcinoma; Radiation; Genetic association; Skin toxicity

1. Introduction

techniques to increase dose conformity to target volume [2].

Nasopharyngeal carcinoma (NPC), an endemic disease in

Overall survival rate and local regional control rate for NPC,

Southern China including Hong Kong, is primarily treated by

especially for advanced T3-4 diseases, have been improved from

radiotherapy (RT) due to its deep-seated anatomical location and

50-75% to about 90% with advanced RT technique [3].

its relatively high sensitivity to radiation, particularly for

Chemotherapy is used concurrently with RT to increase local

thehighest incidence subtype, undifferentiated carcinoma [1]. RT

regional control rate for advance stage disease and to reduce rate

has evolved from two-dimensional conventional RT techniques to

of distant metastasis, although the use of adjuvant chemotherapy is

three-dimensional intensity-modulated radiation therapy (IMRT)

still under debate [3]. Since the median age of NPC patients is

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around 50s, quality of life in these patients is one of the major
concerns in providing better patient care. Acute and late effects of

2. Risk Factors Contributing To Variations In Normal Tissue
Radiation Sensitivity

radiation induced toxicities have been receiving growing interest

Patients receiving similar treatment modality have been found to

in the field of radiation oncology, since radiation induced

experience different levels of radiation induced toxicities. There

toxicities are unavoidable and it is difficult to identify which

are probably several risk factors contributing to the individual

patients are with higher risk of developing severe radiation

variations in normal tissue sensitivity to radiation. One of the risk

induced toxicities before the start of RT. Acute reactions such as

factors in increasing the risk of radiation induced complications is

dermatitis, dysphagia, and mucositis and late complications such

treatment-related. The correlation between total irradiated volume

as xerostomia and neck fibrosis are some of the most common

and complication risk has been reported in many cancers [11]. For

radiation induced toxicities regardless of any RT techniques in

breast cancer patients with larger breast volume, higher risk of

NPC patients. Dose escalation to target volume can be achieved by

suffering severe skin reactions has been found. Correlation of

IMRT without compromising critical organs at risk (OAR) [4].

irradiated volume in lung cancer and liver cancer patients and

While incidence of radiation induced toxicities such as xerostomia,

increased risk of radiation induced toxicities have also been

temporal lobe neuropathy and cranial nerve palsy have been

reported [11]. Use of RT techniques and chemotherapeutic agents,

greatly reduced thanks to the improvement of dose-sparing

in addition to total radiation dose and number of fractions, may

technique achieved by IMRT [5,6], skin and mucosal toxicities are

contribute to the increase of developing radiation induced

unavoidable and remain the major treatment-related complications

complications [9,11]. Patient’s clinical characteristic is another

that may interrupt treatment schedule. Around 48% and 16% of

important confounding factor that increased risk of developing

NPC patients treated by RT alone suffered from grade 3 or above


mucositis and skin reactions respectively [7]. With the use of

complications and lifestyles such as smoking and drinking habits

chemotherapeutic agents such as cisplatin, the incidence of

are patient-related risk factors [11]. However, up to 80% of the

ototoxicity is significantly higher in patients treated with

radiation induced toxicities cannot be explained by these known

concurrent chemotherapy and RT (CRT) [8]. Over 61% of NPC

factors [12]. Genetic factors seem to be a most important

patients treated with CRT suffered from grade 3 or above acute

underlying factors contributing to variation in radiosensitivity in

mucositis [8]. The overall incidence of acute toxicity in any aspect

normal tissue. Several genes have been identified throughout the

was 83.2% and 53% for patients treated with CRT and RT

past years that are related to increase radiosensitivity. Patients with

respectively [8]. In terms of late toxicity, about 5% of NPC

genetic disorders such as Ataxia-telangiectasia and Fanconi’s

patients suffered from neck fibrosis treated with RT alone or CRT

anemia are known to be hypersensitivity to radiation due to

[8]. Treatment of radiation induced toxicities is mainly palliative

truncated mutations in genes responsible for cell cycle regulation

since there is no effective way to prevent the occurrence of

and DNA repair pathways, such as ataxia-telangiectasia mutated

radiation induced toxicities. Palifermin, a recombinant truncated

(ATM), DNA ligase IV (LIG4), and genes belong to Fanconi

human keratinocyte growth factor (KGF) protein, has been

anaemia complementation group (FANC) family [12-15]. RT

showed to reduce the incidence of severe oral mucositis in two

induces cell death mainly through the generation of reactive free

clinical trials with head and neck cancer patients. Management of

radicals that interact with DNA, RNA, proteins, and plasma

acute skin reactions include symptom-relieving agents such as

membrane [16]. Many signal transduction pathways are activated

moisturizing cream and hydrocortisone creams while anti-

by DNA double-strand break (DSB) to repair DNA damages, since

inflammatory and antioxidant treatments are used for late fibrosis

DSB is the primary lethal cell damage during RT [17]. ATM


protein recognizes the complexes formed by DSBs and DNA

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repair proteins and the activity of ATM further activates other

group (unpublished data) is shown is Table 1. Positive findings

proteins such as transcription factors p53 [17]. Genes that

from included studies are summarized in Table 2. With the low

involved in cell cycle checkpoint, DNA repair, and removal of

incidence of NPC worldwide except endemic areas [1], it is not

reactive free radicals, such as nuclear factor kappa-B (NF-κB),

surprising that there is a lack of information on genetic association

superoxide dismutase (SOD), transforming growth factor beta

study on radiation induced toxicities in NPC patients Even with

(TGFβ), p53, tumour necrosis factor (TNF-α), and x-ray repair

the inclusion of studies focused on radiation induced toxicities in

cross-complementing protein 1 (XRCC1) are activated by the

head and neck cancers [25-28], the total number of studies is still

DNA damages [16,18]. As a result, many genes that are associated

limited (data not shown). All five studies are retrospective, case-

with cell cycle regulation and DNA repair and their association to

control studies with different classification of “normal” and

radiation induced complications have been investigated using

“severe” toxicity. Among genetic association studies included

candidate gene approach. Candidate gene approach and genome-

NPC patients, skin reactions and mucositis are the major toxicities

wide association study (GWAS) are the two approaches used in

of interest. While genetic association to acute skin reactions and

genetic association studies. Candidate gene approach is a

acute mucositis was evaluated in two studies, the other three

hypothesis-driven approach that is useful in studying single

studies published by the same research group focused on

nucleotide polymorphisms (SNPs) and other types of genetic

subcutaneous and deep tissue fibrosis only. The largest sample

variants in genes with known biological roles in disease or

size among the five studies is 155 with median 40 months of

phenotype of interest [19]. In contrast, GWAS is a hypothesis-free

follow-up period after RT [21]. Genes investigated in these studies

approach that prior knowledge of functional roles of SNPs in

are involved in cell cycle regulations (ATM, CDKN1A, HDM2,

phenotype of interest is not required [20]. A dense set of SNPs is

TP53), inflammatory response (TGFβ1), DNA repair (LIG4,

captured by GWAS comprehensively and unbiasedly. Several

XRCC1, XRCC3, XRCC4, XRCC5), and endogenous oxidative

susceptibility loci in complex diseases such as diabetes have been

stress defense (SOD2). It is interesting to note that genetic variant

identified in GWAS [20].

rs25487 (Arg399Gln) located in XRCC1 was associated with
increased risk of acute dermatitis and acute mucositis in study by

3. Genetic Association Studies of Radiation Induced Toxicities
in NPC

Li et al. while in study by Alsbeih et al., the minor allele was
associated with lower risk of developing subcutaneous and deep

A literature search was performed on PubMed using a

skin fibrosis (Odd ratio = 0.41, CI = 0.21-0.79) [21,22]. Study by

combination of keywords “radiotherapy or radiation therapy”,

Pratesi et al. included seven types of head and neck cancers also

“radiation induced or radiosensitivit or hypersensitivit or

showed increased risk of rs25487 to acute mucositis (OR = 3.01,

radiotoxicit or normal tissue toxicity or complication”, and

CI = 1.27-7.11) [27]. However, these significant associations were

“polymorphism or single nucleotide polymorphism or SNP or

unable to be replicated by our group with similar sample size

genetic variant” (as of December 14, 2013). Over 120 published

(unpublished data). Conflicting results may be due to variation in

original and review articles were identified through literature

control and case classification, treatment modality, population

search, manual search of citations from identified articles and

stratification for studies with Chinese NPC patients, allele

selected journals (Figure 1). Candidate gene approach is the most

frequency in different ethnic groups, and other confounding

commonly used in identified articles. Among these articles, only 4

factors such as patient-related clinical information. Effect size of

articles included NPC patients, and 3 out of 4 articles were

common genetic variants may be small to moderate that a larger

published by the same research group [21-24]. A summary

sample size is needed to validate these positive findings.

characteristic of studies included NPC patients and data from our

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Figure 1. Number of genetic association studies from 2001-2013 (as of December 14, 2013).

Table 1. Summary characteristics of genetic association studies included NPC patients only
Year of
Sample Mean/Median
Origin Study Design
author Publication
Li [22]









Grading system

49.6 (19-76)




CTCAE v3.0

47 (15-77)











Saudi Retrospective,
Arabic case-control



Saudi Retrospective,
Arabic case-control


50 (18-77)




Saudi Retrospective,
Arabic case-control


49 (18-71)


54 (20-75)



unpublished Hong Retrospective,
Kong case-control




RFLP and UPr

Control and case
Control: Grade 12
Acute dermatitis,
acute mucositis
Case: Grade 3

Control: Grade 0Subcutaneous and
deep tissue
Case: Grade 3-4


Control: Grade 0Subcutaneous and
deep tissue
Case: Grade 2-3
Control: Grade 0Subcutaneous and
deep tissue
Case: Grade 2-3
Control: Grade 01


Case: Grade 2-3

Acute skin
reactions, acute
mucotisits, and
chronic neck

Abbreviation: RT = Radiotherapy; 3DCRT = Three-dimensional conformal radiotherapy; CRT = Concurrent chemotherapy and radiotherapy; RFLP = Restriction
fragment length polymorphism; UPr = Unlabeled Probe Melting Analysis; CTCAE = Common Terminology Criteria for Adverse Events; RTOG = Radiation Therapy
Oncology Group.

Table 2. Positive findings from genetic association studies included NPC patients only
First author

Year of

Li [22]



Polymorphism (s)

Mode of inheritance

XRCC1 G/A (rs25487)


Acute dermatitis

2.65 (1.04-6.73)

Acute mucositis

Alsbeih [21]


Subcutaneous and deep tissue

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OR (95% CI)

2.11 (0.95-4.66)
ATM G/A (rs1801516)

2.86 (1.18-6.48)

HDM2 T/G (rs2279744)

0.49 (0.29-0.84)

HDM2 T/A (rs1196333)

0.13 (0.02-0.99)

TGFβ1 C/T (rs1800469)

0.57 (0.34-0.96)

XRCC1 G/A (rs25487)


XRCC5 T/C (rs10510677)

0.39 (0.17-0.91)

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Alsbeih [23]

Alsbeih [24]



Subcutaneous and deep tissue
Subcutaneous and deep tissue

TGFβ1 C/T (rs1800470)

0.41 (0.20-0.86)

XRCC1 G/A (rs25487)
XRCC1 G/A (rs25487)

0.30 (0.10-0.89)

0.31 (0.09-1.04)

Abbreviation: OR = odd ratio; CI = confidence interval.
*ORs of both genotype and allele were calculated; only the most significant results were shown.

4. Reports In Other Cancers

While significant results were reported in many genetic

While there is still lack of available information for NPC-related

association studies using candidate gene approach, these results

radiation induced toxicities, studies of genetic association in other

were unable to replicate in subsequent studies with larger sample

cancers have changed from candidate gene approach to GWAS to

size. In addition, results were often conflicting. Future studies

identify genetic variants that are associated with ethnic group and

should include large number of samples, prospectively and

disease-specific radiation induced toxicities. In addition, several

retrospectively, in order to perform well-designed study with

meta-analysis have been published and addressed on common

adequate statistical power. Two ways to overcome sample size

radiation induced toxicities arose in different cancers. A validation

limitation are to perform meta-analysis and to collaborate with

study included 1613 breast cancer and prostate cancer patients

other research groups. One limitation of meta-analysis is that

showed no association between radiation toxicity and 92 SNPs in

adequate information may not be able to obtain through literature

46 genes [29]. A replication study using breast cancer patients

search since positive findings are more likely to be published than

from three independent European cohorts showed that a SNP

negative findings. In order to enhance data pooling for genetic

located in TNF-α may be associated to radiation toxicity [30].

association studies, a 18-item checklist guideline Strengthening

Association of genetic variants located in heat shock protein beta-

the Reporting Of Genetic Association studies in Radiogenomics

1 (HSPβ1) to risk of radiation induced pneumonitis was validated

(STROGAR) was suggested by the Radiogenomic consortium

in two independent cohorts of non-small cell lung cancer patients

[36,37]. This guideline was modified based on the STrengthening

[31]. The first GWAS focusing on radiation induced toxicities in

the REporting of Genetic Association Studies (STREGA)

African prostate cancer identified a genetic variant located in

recommendation [38] to include information related to RT.

follicle-stimulating hormone receptor (FSHR) that involved in

Besides meta-analysis, establishing international collaboration

testis development and function is associated with erectile

may help to increase the sample size, reduced confounding factors

dysfunction [32]. A two-stage GWAS performed by the same

by standardizing protocols and experimental design, and to

research group included mainly European ancestry showed that

perform population-based analysis. Individual gene expression

this SNP may not be the universal biomarker for all ethnic groups

profiles and genetic profiles may be combined to investigate

but an ethnic group and prostate cancer specific biomarker [33].

individual variation in radiation induced toxicity more effectively.

Two research groups published meta-analysis of genetic

Genes associated with cell cycle regulation and apoptosis

variantrs1800469 in TGFβ1 and association to fibrosis in breast

pathways showed significant changes in expression levels 2 hours

cancer patients and mixed cancer patients [34,35]. Results from

after irradiation [39]. Gene expression profiles and genetic profiles

these studies suggested that individual SNP may be ethnic-group

in future GWAS can be mapped using quantitative levels of

and complication-specific that may not be used as universal

expression (eQTLs) mapping [40]. Several cis-acting regulators

biomarker to predict all types of toxicities induced in different

involved in complex diseases have been identified using eQTLs

types of cancers.

mapping [40]. By identifying patients with higher susceptibility to

Conclusions And Future Directions

radiation, better patient cancer and customization of treatment

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protocol could be achieved that will improve not only the quality

Clin Oncol 2005; 23: 6966-6975.

of life, but also the treatment efficacy in future.

8. Lee AW, Tung SY, Chua DT et al. Randomized trial of





5. Conflict of interest

radiotherapy alone for regionally advanced nasopharyngeal


carcinoma. J Natl Cancer Inst 2010; 102: 1188-1198.
9. Wells M, MacBride S. Radiation skin reactions. In: Faithfull S

6. Funding

and Wells M, eds. Supportive care in radiotherapy, 2003; 135-159.

This work was supported by grant from the Hong Kong

10. Westbury CB, Yarnold JR. Radiation fibrosis--current clinical

Polytechnic University (RPFG).

and therapeutic perspectives. Clinical oncology 2012; 24: 657-672.
11. Azria D, Betz M, Bourgier C, Jeanneret Sozzi W, Ozsahin M.

7. References

Identifying patients at risk for late radiation-induced toxicity.

1. Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005;

Critical reviews in oncology/hematology 2012;84 Suppl 1:e35-41.

365: 2041-2054.

12. Barnett GC, West CM, Dunning AM et al. Normal tissue

2. Ng WT, Lee MC, Hung WM et al. Clinical outcomes and

reactions to radiotherapy: towards tailoring treatment dose by

patterns of failure after intensity-modulated radiotherapy for

genotype. Nat Rev Cancer 2009; 9: 134-142.

nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011; 79:

13. Borgmann K, Roper B, El-Awady R et al. Indicators of late


normal tissue response after radiotherapy for head and neck cancer:

3. Wei WI, Kwong DL. Current management strategy of

fibroblasts, lymphocytes, genetics, DNA repair, and chromosome


aberrations. Radiother Oncol 2002;64:141-152.





otorhinolaryngology 2010; 3: 1-12.

14. Popanda O, Marquardt JU, Chang-Claude J, Schmezer P.

4. Kam MK, Chau RM, Suen J, Choi PH, Teo PM. Intensity-

Genetic variation in normal tissue toxicity induced by ionizing

modulated radiotherapy in nasopharyngeal carcinoma: dosimetric

radiation. Mutat Res 2009;667:58-69.

advantage over conventional plans and feasibility of dose

15. Gatti RA. The inherited basis of human radiosensitivity. Acta

escalation. Int J Radiat Oncol Biol Phys 2003; 56: 145-157.

Oncol 2001;40:702-711.

5. Peng G, Wang T, Yang KY et al. A prospective, randomized

16. Faulhaber O, Bristow R. Basis of cell kill following clinical

study comparing outcomes and toxicities of intensity-modulated

radiotherapy. Application of apoptosis to cancer treatment

radiotherapy vs. conventional two-dimensional radiotherapy for


the treatment of nasopharyngeal carcinoma. Radiother Oncol 2012;

17. Kiang JG, Garrison BR, Gorbunov NV. Radiation combined

104: 286-293.

injury: DNA damage, apoptosis, and autophagy 2010; 2: 1-10.

6. Pow EH, Kwong DL, McMillan AS et al. Xerostomia and

18. Bentzen SM. Preventing or reducing late side effects of

quality of life after intensity-modulated radiotherapy vs.

radiation therapy: radiobiology meets molecular pathology. Nat


Rev Cancer 2006; 6: 702-713.





carcinoma: initial report on a randomized controlled clinical trial.

19. Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches

Int J Radiat Oncol Biol Phys 2006; 66: 981-991.

for studying complex genetic traits: practical considerations.

7. Lee AW, Lau WH, Tung SY et al. Preliminary results of a

Nature reviews. Genetics 2002; 3: 391-397.

randomized study on therapeutic gain by concurrent chemotherapy

20. McCarthy MI, Abecasis GR, Cardon LR et al. Genome-wide

for regionally-advanced nasopharyngeal carcinoma: NPC-9901

association studies for complex traits: consensus, uncertainty and

Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J

challenges. Nature reviews. Genetics 2008; 9: 356-369.

JNPC ★ http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

Published:2014-04 -09 ★ DOI:10.15383/jnpc.7


21. Alsbeih G, El-Sebaie M, Al-Harbi N et al. SNPs in genes

association between polymorphisms near TNFalpha and risk for

implicated in radiation response are associated with radiotoxicity

adverse reactions to radiotherapy. Br J Cancer 2012; 107:748-753.

and evoke roles as predictive and prognostic biomarkers. Radiat

31. Pang Q, Wei Q, Xu T et al. Functional promoter variant

Oncol 2013; 8: 125.

rs2868371 of HSPB1 is associated with risk of radiation

22. Li HJ, You YJ, Lin CF et al. XRCC1 codon 399Gln

pneumonitis after chemoradiation for non-small cell lung cancer.

polymorphism is associated with radiotherapy-induced acute

Int J Radiat Oncol Biol Phys 2013; 85: 1332-1339.

dermatitis and mucositis in nasopharyngeal carcinoma patients.

32. Kerns SL, Ostrer H, Stock R et al. Genome-wide association

Radiat Oncol 2013; 8.

study to identify single nucleotide polymorphisms (SNPs)

23. Alsbeih G, Al-Harbi N, Al-Hadyan K, El-Sebaie M, Al-Rajhi N.

associated with the development of erectile dysfunction in


African-American men after radiotherapy for prostate cancer. Int J






radiotherapy and polymorphic variations in TGFB1 and XRCC1

Radiat Oncol Biol Phys 2010; 78: 1292-1300.

genes. Radiat Res 2010; 173: 505-511.

33. Kerns SL, Stock R, Stone N et al. A 2-stage genome-wide

24. Alsbeih GA, El-Sebaie MM, Al-Rajhi NM et al. Association

association study to identify single nucleotide polymorphisms

between XRCC1 G399A polymorphism and late complications to

associated with development of erectile dysfunction following

radiotherapy in Saudi head and neck cancer patients. J Egypt Natl

radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys

Canc Inst 2008; 20: 302-308.

2013; 85: e21-28.

25. Kornguth DG, Garden AS, Zheng Y et al. Gastrostomy in

34. Barnett GC, Elliott RM, Alsner J et al. Individual patient data

oropharyngeal cancer patients with ERCC4 (XPF) germline

meta-analysis shows no association between the SNP rs1800469

variants. Int J Radiat Oncol Biol Phys 2005; 62: 665-671.

in TGFB and late radiotherapy toxicity. Radiother Oncol 2012;

26. Lundberg M, Saarilahti K, Makitie AA, Mattila PS. TGFbeta1

105: 289-295.

genetic polymorphism is associated with survival in head and neck

35. Zhu M-L, Wang M, Shi T-Y et al. No Association between

squamous cell carcinoma independent of the severity of

TGFB1 Polymorphisms and Late Radiotherapy Toxicity: A Meta-

chemoradiotherapy induced mucositis. Oral Oncol 2010; 46: 369-

Analysis. PLoS One 2013; 8: e76964.


36. Kerns SL, Ruysscher DD, Andreassen CN et al. STROGAR -

27. Pratesi N, Mangoni M, Mancini I et al. Association between

STrengthening the Reporting Of Genetic Association studies in

single nucleotide polymorphisms in the XRCC1 and RAD51

Radiogenomics. Radiother Oncol 2013.

genes and clinical radiosensitivity in head and neck cancer.

37. West C, Rosenstein BS. Establishment of a radiogenomics

Radiother Oncol 2011; 99: 356-361.

consortium. Radiother Oncol 2010; 94: 117-118.

28. Werbrouck J, De Ruyck K, Duprez F et al. Acute normal tissue

38. Little J, Higgins JP, Ioannidis JP et al. STrengthening the

reactions in head-and-neck cancer patients treated with IMRT:

REporting of Genetic Association Studies (STREGA): an

influence of dose and association with genetic polymorphisms in

extension of the STROBE statement. PLoS Med 2009; 6: e22.

DNA DSB repair genes. Int J Radiat Oncol Biol Phys 2009; 73:

39. Mayer C, Popanda O, Greve B et al. A radiation-induced gene


expression signature as a tool to predict acute radiotherapy-

29. Barnett GC, Coles CE, Elliott RM et al. Independent

induced adverse side effects. Cancer Lett 2011; 302: 20-28.

validation of genes and polymorphisms reported to be associated

40. Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M.

with radiation toxicity: a prospective analysis study. Lancet Oncol

Mapping complex disease traits with global gene expression.

2012; 13: 65-77.

Nature reviews. Genetics 2009; 10: 184-194.

30. Talbot CJ, Tanteles GA, Barnett GC et al. A replicated
JNPC ★ http://www.journalofnasopharyngealcarcinoma.org/

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Published:2014-04 -09 ★ DOI:10.15383/jnpc.7