Search

To identify genetic susceptibility loci for nasopharyngeal carcinoma (NPC), a genome-wide association study was performed using 464,328 autosomal SNPs in 1,583 NPC affected individuals (cases) and 1,894 controls of southern Chinese descent. The top 49 SNPs from the genome-wide association study were genotyped in 3,507 cases and 3,063 controls of southern Chinese descent from Guangdong and Guangxi. The seven supportive SNPs were further confirmed by transmission disequilibrium test analysis in 279 trios from Guangdong. We identified three new susceptibility loci, TNFRSF19 on 13q12 (rs9510787, Pcombined=1.53x10(-9), odds ratio (OR)=1.20), MDS1-EVI1 on 3q26 (rs6774494, Pcombined=1.34x10(-8), OR=0.84) and the CDKN2A-CDKN2B gene cluster on 9p21 (rs1412829, Pcombined=4.84x10(-7), OR=0.78). Furthermore, we confirmed the role of HLA by revealing independent associations at rs2860580 (Pcombined=4.88x10(-67), OR=0.58), rs2894207 (Pcombined=3.42x10(-33), OR=0.61) and rs28421666 (Pcombined=2.49x10(-18), OR=0.67). Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of pathways related to TNFRSF19 and MDS1-EVI1 in addition to HLA molecules.

The striking geographical and ethnic distribution of nasopharyngeal carcinoma (NPC) suggests the involvement of genetic and environmental factors in NPC development. The purpose of this study is to investigate the fit of single gene, polygenic and multifactorial models to the observed pattern of transmission of NPC in a hospital-based family history study conducted by the Cancer Center of Sun Yat-Sen University (CCSYU) in Guangzhou, China. Complex segregation analysis of a total of 1903 Cantonese pedigrees ascertained at CCSYU was conducted using a unified mixed model after the pedigrees were partitioned into 3737 nuclear families. The mixed model assumes that a phenotype is influenced by the additive and independent effect of a major gene, together with multifactorial components (genetic and environmental) and a random environmental effect. The current results do not provide evidence for a major gene and the observed data are best explained by a multifactorial mode of inheritance for NPC.

Background: Previous studies have suggested that genetic susceptibility may play an important role in the etiology of nasopharyngeal cancer (NPC). However, to date, few large-scale studies have been conducted on familial risk and clustering of NPC in a high-risk area of China., Methods: In the current study, 2252 patients with NPC who were treated at the Cancer Center of Sun Yat-Sen University in Guangdong Province, China, were identified as probands. Family histories of NPC and other malignancies were observed in first-degree relatives (FDRs) and second-degree relatives, and other information was obtained through interviews. One thousand nine hundred and three Cantonese families were selected for further investigation. To assess familial aggregation, the authors used standardized incidence ratios (SIRs) to measure the risk of NPC for FDRs and compared the observed number of cases with the number predicted by population-based frequencies in the Cantonese population of Hong Kong., Results: The current analysis indicated that families with > or = 3 relatives who had NPC were distributed predominantly among a high-risk subgroup of the Cantonese population in Guangdong Province and that the frequency of these families was 0.68%. An SIR of 2.09 (95% confidence interval [CI], 1.80-2.40) was observed among 13,833 FDRs in the high-risk subgroup, and a significantly elevated risk for NPC was observed in FDRs of probands with early age of onset (age < 40 years; SIR, 9.01 [95% CI, 6.10-13.30]). Furthermore, decreased risks of hepatic, lung, esophageal, gastric, and breast carcinoma, as well as malignancy of all sites, were observed among FDRs of probands with NPC when Hong Kong and Shanghai populations were used as reference groups., Conclusions: NPC tends to aggregate in Cantonese families in Guangdong Province, and the malignancies in these families appear to be site specific, with no excess of any other malignancy., (Copyright 2004 American Cancer Society.)

Background & Objective: Familial clustering of NPC has been widely observed, however, related investigations were mainly involved in individual reports for high-risk families or case-control study with small sample size, so no quantitive evaluation for NPC risk in relatives of high-risk families documented in high-risk area until now. The purpose of the study was to estimate NPC risk among relatives of high-risk pedigrees in Guangong province, so as to provide information for genetic epidemiology and clinical genetic consultation., Methods: One hundred and thirteen high-risk pedigrees were collected in the Cancer Center of Sun Yat-sen University, and standardized incidence ratio (SIR) was used to estimate NPC risk of first degree relatives (FDR)., Results: NPC risk was significantly higher in first degree relatives that in general population, and SIR was 37.55; in addition, SIRs were 50.72, 79.64, 7.12, and 33.58 in their brothers, sisters, fathers, and mothers respectively., Conclusion: NPC risk of relatives in familial NPC pedigrees elevates 7.12 to 79.64 times in high-risk families.

Nasopharyngeal carcinoma (NPC) occurs with high frequency in Asian populations, especially among people of Cantonese ancestry. In areas with high incidence, NPC clusters in families, which suggests that both geography and genetics may influence disease risk. Although the HLA-Bw46 locus is associated with increased risk of NPC, no predisposing genes have been identified so far. Here we report the results of a genome-wide search carried out in families at high risk of NPC from Guangdong Province, China. Parametric analyses provide evidence of linkage to the D4S405 marker on chromosome 4 with a logarithm of odds for linkage (lod) score of 3.06 and a heterogeneity-adjusted lod (hlod) score of 3.21. Fine mapping with additional markers flanking D4S405 resulted in a lod score of 3.54 and hlod score of 3.67 for the region 4p15.1-q12. Multipoint nonparametric linkage analysis gives lod scores of 3.54 at D4S405 (P = 5.4 x 10(-5)) and 4.2 at D4S3002 (P = 1.1 x 10(-5)), which is positioned 4.5 cM away from D4S405. When Epstein Barr virus antibody titer was included as a covariate, the lod scores reached 4.70 (P = 2.0 x 10(-5)) and 5.36 (P = 4.36 x 10(-6)) for D4S405 and D4S3002, respectively. Our findings provide evidence of a major susceptibility locus for NPC on chromosome 4 in a subset of families.

Development of nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. However, NPC occurs with a marked geographic and racial distribution, whereas EBV infection is ubiquitous in the world. This leads to a question whether certain subtypes of EBV have a greater potential to induce cell transformation. Latent membrane protein 1 (LMP1) is an EBV-encoded oncogenic protein and its 30-bp deleted variant (del-LMP1) has been reported to be predominant in biopsies of NPC. We have assessed the polymorphism of LMP1 in 47 biopsies of NPC, 107 cases of throat washings (TWs) from NPC patients, and 106 cases of TWs from non-NPC patients in Guangzhou, an endemic area of NPC in southern China, as well as 103 cases of TWs from healthy donors in Haerbin, a non-endemic area of NPC in northern China. Our results found a similar extent of the LMP1 polymorphism between NPC patients and non-NPC patients in Guangzhou, with the del-LMP1 being predominant in both Guangzhou and Haerbin. Sequence analyses showed identical substitutions in other coding regions of the del-LMP1 isolated from Guangzhou and Haerbin. These results indicate that del-LMP1 represents a geographic or race-associated polymorphism rather than an NPC disease phenotype-associated polymorphism.

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Southern China, especially in the Guangdong area. To demonstrate a comprehensive profile of loss of heterozygosity (LOH) in NPC, we applied a large panel of 382 microsatellite polymorphism markers covering all the 22 autosomes in 98 cases of sporadic primary NPC. Of the 335 informative markers, 83 loci showed high level of LOH (presence in equal to or more than 30% cases) and most of the high frequent loci were clustered to chromosome 1p36 and 1p34, 3p14-p21, 3p24-p26, 3q25-q26 and 3q27, 4q31 and 4q35, 5q15-21 and 5q32-q33, 8p22-p23, 9p21-p23 and 9q33-q34, 11p12-p14, 13q14-q13 and 13q31-q32, 14q13-q11, 14q24-q23 and 14q32. High frequency of LOH was found in chromosomes 3, 5, 9 and 11 (>/=50%), while medium frequency of LOH was found in chromosomes 1, 4, 6, 14, 17 and 19 (40-49%). Several new regions showing high frequency of LOH were found in chromosome 1p36, 3q25-q26, 3q27, 5q15-q21, 8p22-p23 and 11p12-14. The relationship between LOH and TNM stage of NPC was evaluated. Regions 6p23 (D6S289), 8p23.1 (D8S549) and 9q34.2 (D9S1826) showed higher frequency of LOH in later stages (III and IV) than in earlier stages (I and II) (P<0.05). Thus, our study provides a global view on allelic loss in the development of NPC and should shed light on the way for localization of putative tumor suppressor genes associated with the pathogenesis of NPC.