ReviewFamilial and large-scale case–control studies identify genes associated with nasopharyngeal carcinoma
Introduction
Nasopharyngeal carcinoma (NPC) is a human squamous-cell carcinoma that arises in the upper lining epithelium in the retro-nasal cavity [1]. Radiotherapy is the standard treatment for NPC, although it is accompanied by undesirable complications. The overall 5-year survival rate is around 60% [2] and is even higher with the intensity-modulated radiation therapy [3]. It has been shown that the stage-specific 5-year survival rates ranged from 88% at Stage I down to 28% at late Stage IVB according to the TNM staging system [4], suggesting that early diagnosis is a key for better prognosis. However, the patients are largely at late stage at the time of presentation due to the non-specific symptoms for NPC at early stage. Revealing the etiology of NPC is fundamental for developing approaches towards more effective prevention, diagnosis, prognosis, and therapy.
The epidemiology studies showed that NPC has remarkable racial and geographic distribution, which is prevalent in southern China, northern Africa, and Alaska [5]. The annual incidence rate is about 30 per 100,000 in a prevalent region such as southern China, where the incidence rate is 50-fold higher than that in the Western world [6]. Especially the ethnic Chinese living in Guangdong province and nearby regions, such as Guangxi and Hong Kong, are prone to the disease [7]. It stands true for Chinese in Malaysia and Singapore [6]. Migration study showed that the incidence rate of the second and third generation Chinese in American is still higher than the local Caucasian [8]. Moreover, the familial clustering of NPC has been observed widely in Chinese population [9], [10] with a frequency around 10%, as well as in non-Chinese population [11]. These strongly suggest the effect of inherited genetic predisposition on the oncogenesis of NPC. Recently, based on the worldwide concordance of NPC incidence rates and history of Chinese migrations, a hypothesis that NPC originated from the ancient Southern Chinese cohort (Bai-Yue) further implicates the involvement of genetic lesions in NPC [12]. On the other hand, elevated Epstein-Barr virus (EBV) DNA load and the EBV-related antibodies in peripheral blood, as well as clonal EBV strain in tumor cells, were consistently detected in NPC patients [1], [13]. Furthermore, early exposures to smoke, salted fish, and other preserved foods containing carcinogenic nitrosamines have been associated with the risk of NPC [14], [15]. Taken together, these studies revealed that the etiology of NPC is multi-factorial, involving both genetic and non-genetic components. Herein, we will review current advances of the genetic analyses in searching for the susceptibility genes of NPC by using familial studies and case–control studies with emphasis on those with large-scale sample size. Additional information regarding this topic can also be found in another review paper by Hildesheim and Wang in this NPC issue [16].
Section snippets
Familial studies
The familial clustering of NPC has been documented in the Chinese population among NPC endemic regions, such as Guangdong, Hong Kong, and Taiwan, and also in White population in America and Australia, where the NPC incidence is rare [9]. Segregation studies in Guangdong and Taiwan Chinese suggested that the inherited susceptibility is under a multi-factorial mode [17], [18]. Linkage study is an important approach of genetic dissection of complex trait, such as NPC. Affected sib-pair (ASP) and
Case-control studies
Case–control study is a more common association design approach to dissect genetic lesions that contribute to the risk of NPC, since NPC is mostly sporadic and access to familial samples, especially for the extended pedigrees, is difficult. Genetic association study with a case–control design is to test the variants for association with NPC susceptibility by determining whether a particular allele, genotype, or haplotype of a polymorphism or polymorphism(s) will be observed more often than
Conclusions
The spectrum of genetic lesions ranges from low to high frequencies for risk alleles, and from high to low genetic effects or penetrance, correspondingly [131]. As in other complex diseases, familial studies and case–control association studies have been conducted to dissect the genetic variant underlying NPC susceptibility. So far, many susceptibility loci or genes have been significantly associated with NPC, consistent with the involvement of multiple genetic factors for NPC development.
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgments
We thank Malcolm Simons for providing comments for the contents. This work was partly supported by the National Natural Science Foundation of China (Grant No. 81101544) and 973 program of China (Grant No. 2011CB504300).
References (134)
- et al.
Nasopharyngeal carcinoma
Lancet
(2005) - et al.
Is the 1997 AJCC staging system for nasopharyngeal carcinoma prognostically useful for Chinese patient populations
Int J Radiat Oncol Biol Phys
(2001) - et al.
Familial nasopharyngeal carcinoma
Semin Cancer Biol
(2002) - et al.
Epidemiology of nasopharyngeal carcinoma
Semin Cancer Biol
(2002) - et al.
Genetic structure of the Han Chinese population revealed by genome-wide SNP variation
Am J Hum Genet
(2009) - et al.
Genomic dissection of population substructure of Han Chinese and its implication in association studies
Am J Hum Genet
(2009) - et al.
Association of IL-1B gene polymorphisms with nasopharyngeal carcinoma in a Chinese population
Clin Oncol (R Coll Radiol)
(2008) - et al.
Single nucleotide polymorphism and haplotype association of the interleukin-8 gene with nasopharyngeal carcinoma
Clin Immunol
(2007) - et al.
Genetic polymorphism of interleukin-16 and risk of nasopharyngeal carcinoma
Clin Chim Acta
(2009) - et al.
Functional IL-18 promoter gene polymorphisms in Tunisian nasopharyngeal carcinoma patients
Cytokine
(2008)
Evaluation of the associations between the single nucleotide polymorphisms of the promoter region of the tumor necrosis factor-alpha gene and nasopharyngeal carcinoma
J Chin Med Assoc
Polymorphism of the stress protein HSP 70-2 gene is associated with the susceptibility to the nasopharyngeal carcinoma
Cancer Lett
A functional single nucleotide polymorphism site detected in nasopharyngeal carcinoma-associated transforming gene Tx
Cancer Genet Cytogenet
TAP1 gene polymorphisms and nasopharyngeal carcinoma risk in a Tunisian population
Cancer Genet Cytogenet
Cytochrome P450 2A6 polymorphism in nasopharyngeal carcinoma
Cancer Lett
Carcinogen-mediated oxidant formation and oxidative DNA damage
Pharmacol Ther
Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: long-term results of a phase 2 study
Cancer
Prognostic factors in 677 patients in Singapore with nondisseminated nasopharyngeal carcinoma
Cancer
The aetiology of nasopharyngeal carcinoma
Clin Otolaryngol Allied Sci
Some epidemiologic observations of nasopharyngeal carcinoma in Guangdong, People's Republic of China
Natl Cancer Inst Monogr
The effect of migration on the risk of nasopharyngeal cancer among Chinese
Cancer Res
Familial risk and clustering of nasopharyngeal carcinoma in Guangdong, China
Cancer
Familial nasopharyngeal carcinoma in patients who are not Chinese
Cancer
Is nasopharyngeal cancer really a “Cantonese cancer”?
Chin J Cancer
Direct sequencing and characterization of a clinical isolate of Epstein-Barr virus from nasopharyngeal carcinoma tissue by using next-generation sequencing technology
J Virol
Risk factors associated with nasopharyngeal carcinoma
N Engl J Med
Genetic predisposition factors and nasopharyngeal carcinoma risk: A review of epidemiological association studies, 2000-2011. Rosetta Stone for NPC: Genetics, viral infection, and other environmental factors
Semin Cancer Biol
Multiple risk factors of nasopharyngeal carcinoma: Epstein-Barr virus, malarial infection, cigarette smoking and familial tendency
Anticancer Res
Complex segregation analysis of nasopharyngeal carcinoma in Guangdong, China: evidence for a multifactorial mode of inheritance (complex segregation analysis of NPC in China)
Eur J Hum Genet
The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology
Nat Genet
Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results
Nat Genet
Linkage of a nasopharyngeal carcinoma susceptibility locus to the HLA region
Nature
Nasopharyngeal carcinoma V: immunogenetic studies of Southeast Asian ethnic groups with high and low risk for the tumor
Cancer Res
HLA and nasopharyngeal carcinoma in Chinese – a further study
Int J Cancer
Association between microsatellites within the human MHC and nasopharyngeal carcinoma
Int J Cancer
Genetic susceptibility to nasopharyngeal carcinoma within the HLA-A locus in Taiwanese
Int J Cancer
Nasopharyngeal carcinoma-susceptibility locus is localized to a 132 kb segment containing HLA-A using high-resolution microsatellite mapping
Int J Cancer
Genome-wide scan for familial nasopharyngeal carcinoma reveals evidence of linkage to chromosome 4
Nat Genet
The susceptibility gene for familial nasopharyngeal carcinoma is mapped on chromosome 4p11–p14 by haplotype analyses
Chin Sci Bull
A functional variant in the transcriptional regulatory region of gene LOC344967 cosegregates with disease phenotype in familial nasopharyngeal carcinoma
Cancer Res
A susceptibility locus at chromosome 3p21 linked to familial nasopharyngeal carcinoma
Cancer Res
The progress on genetic analysis of nasopharyngeal carcinoma
Comp Funct Genomics
A genome-wide scan suggests a susceptibility locus on 5p13 for nasopharyngeal carcinoma
Eur J Hum Genet
The allelic architecture of human disease genes: common disease-common variant… or not?
Hum Mol Genet
What can genome-wide association studies tell us about the genetics of common disease?
PLoS Genet
Human papillomavirus and WHO type I nasopharyngeal carcinoma
Laryngoscope
A genome-wide search identifies potential new susceptibility loci for Crohn's disease
Inflamm Bowel Dis
Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies
Nat Genet
Immunogenetic aspects of nasopharyngeal carcinoma: I. Differences in HL-A antigen profiles between patients and control groups
Int J Cancer
Cited by (56)
Single nucleotide polymorphisms within NFKBIA are associated with nasopharyngeal carcinoma susceptibility in Chinese Han population
2021, CytokineCitation Excerpt :However, only a small proportion of infected individuals develop NPC [6]. Inherited genetic susceptibility was considered as an important risk factor for NPC patients [2,7]. To date, SNPs located within the CLPTM1L/TERT, MECOM, TNFRSF19, and CDKN2A/B genes regions have been demonstrated to be associated with the risk of NPC by genome-wide association studies [8].
Genetics of nasopharyngeal carcinoma and molecular signaling pathways
2020, An Evidence-Based Approach to the Management of Nasopharyngeal Cancer: From Basic Science to Clinical Presentation and TreatmentVirus-associated human cancers in Moroccan population: From epidemiology to prospective research
2019, Infection, Genetics and EvolutionNasopharyngeal carcinoma: Genetics and genomics
2019, Nasopharyngeal Carcinoma: From Etiology to Clinical PracticeNatural Variations in BRLF1 Promoter Contribute to the Elevated Reactivation Level of Epstein-Barr Virus in Endemic Areas of Nasopharyngeal Carcinoma
2018, EBioMedicineCitation Excerpt :Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)- associated human epithelial malignancy of the nasopharynx with a distinct ethnic and geographical distribution, which occur commonly in southern China and Southeast Asia, but rarely in northern China and most other populations around the world [1–5]. Although the unusual geographic distributions of NPC have been linked to the host genetic (notably the variants of major histocompatibility complex (MHC) class I genes on chromosome 6p21.3) and environmental factors (mainly the consumption of dietary nitrosamines) [6–8], whether naturally occurring variations among EBV strains could affect infection or the development of NPC is still contentious. There have been substantial studies in characterizing the natural variations, at key viral genetic regions or whole genome, among EBV strains isolated from NPC or healthy individuals.