Familial Nasopharyngeal Carcinoma 6

Familial Nasopharyngeal Carcinoma 67the underlying risk of NPC in the general populationin the endemic area.The reported standardized incidence ratio (SIR)was 2.09 in a high-risk cohort of 13,833 first-degreerelatives (Jia et al. 2004). The SIRs for brothers, sisters,father, and mother were 2.17, 2.91, 1.46, and 2.76,respectively. These data demonstrated a higher riskamongst siblings of an NPC patient compared withother direct relatives. A similar study reported by Yuet al. (2009) analyzed 358 high-risk families with twoor more NPC cases. Over a 10-year period, thereported SIR of NPC was 15 (95% CI 10, 23). Guoet al. (2009) reported that the attributable risk of havinga first-, second-, or third-degree relative withNPC is 6% (OR = 3.1 [95% C.I. 2.0, 4.9]). The lattertwo studies provide clear evidence for the risk ofNPC in first-degree relatives of NPC patients.6.3.2Genetic Associations in Familial NPCGenetic changes associated with familial NPC havebeen well documented. In 2002, Feng et al. (2002) hadreported that genome wide scans of 20 high-risk familieswith multiple members having NPC identifiedlinkage to chromosome 4. On average, there weremore than three family members with NPC in thesefamilies, although the number of the first- or seconddegreerelatives affected was not clearly reported.However, no further reports are available in the literatureto confirm similar findings of linkage to chromosome4 in familial NPC. A study reported in 2004 byXiong et al. (2004) indicated that familial NPC waslinked to a susceptibility locus on chromosome 3p21.This study involved 18 families with two or moremembers involved with NPC, and did not demonstratelinkage to any other chromosomes. Fine mappinglocated the locus to a region on 3p21.31–21.2where a cluster of tumor suppressor genes resided.In a study of 15 families with two or more membersdiagnosed with NPC, Hu et al. (2008) reportedlinkage of chromosome 5 to familial NPC. A possiblelinkage was suggested and mapped to chromosome5p13.1. However, the study did not confirm any linkageto chromosomes 3 or 4.The association of HLA haplotypes with NPC hadbeen established for more than 30 years (Simonset al. 1975, 1976). The HLA loci are located on chromosome6. It was because of this strong associationbetween HLA haplotypes and NPC that the HLAregion was thought of being a possible region wheretumor susceptibility genes were present (Lu et al.1990). Ooi et al. (1997) had reported that in an analysisof a large pool of sib-pairs, a susceptibility regionwas localized to the major histocompatibility complex(MHC) region of chromosome 6. Subsequentstudies have also corroborated this finding (Lu et al.2003) and it is clear that there is an association in theregion of HLA-A with NPC. Despite the reportedassociation between chromosome 6 and the developmentof NPC, no study has supported a significantlinkage to the familial type of NPC.6.3.3Non-Genetic Associations in Familial NPCSince a consistent association between a genetic factorwith familial NPC has not been identified, sharedenvironment factors may play a role in the developmentof NPC including its familial type. A number ofnongenetic factors including dietary and nondietaryfactors have been postulated. The dietary factorsassociated with NPC have mainly been the use ofsalted fish, especially during a young age (Yu et al.1986, 1989; Ning et al. 1990). Other preserved foodshave also been reported to be associated with NPC(Yu et al. 1988). Like in other types of squamous cellcarcinoma of the head and neck areas (SCCHN), cigarettesmoking is associated with the development ofNPC, although the magnitude of the risk is not assubstantial as in other SCCHN (Yu et al. 1990; Yuanet al. 2000). Lending further weight to the role thatenvironmental and lifestyle factors play in the carcinogenesisof NPC, Luo et al. (2007) had studied thetrends of NPC in Singapore, Hong Kong, and LosAngeles. There was a clear reduction in incidence ofNPC over the period from 1973 to 1997. In addition,cohorts born in the 1940s in Hong Kong and 1958 inSingapore showed significant reduction in NPC. Theauthors concluded that the reductions in the incidenceof NPC over time in the endemic regions suggesta strong role for environmental factors. However,all the above-mentioned risk factors of NPC werelargely associated with the sporadic form, and theirlink with familial NPC has not been reported.Nevertheless, it is reasonable to postulate that theoccurrences of familial NPC, at least in part, were dueto environmental exposures by the first-degree familymembers to both dietary and/or nondietary factors.Well-designed case control studies are needed todetermine the nongenetic risk factors in the developmentof familial NPC. However, sufficient power