Mutational inactivation of the p53 tumor suppressor gene is an infrequent event in human nasopharyngeal carcinoma (NPC), a malignancy showing a high incidence in southern China and southeast Asia. To examine the possible involvement of an activated p53 pathway in nasopharynx carcinogenesis, we have screened primary NPC biopsies for possible point mutations in WAF-1/CIP-1/p21, an effector gene transcriptionally regulated by and functioning as a mediator of the p53 tumor suppressor gene. Mutations in WAF-1/CIP-1/p21 might mimic p53 mutations in tumors having wild-type p53 such as most NPCs. The mutational analysis of WAF/CIP/p21 by PCR-single strand conformational polymorphism-direct sequencing revealed no point mutation in 41 primary NPC biopsies. A codon 31ser-->arg polymorphism was, however, detected. A striking difference in the distribution of the serine (WAF-ser) and arginine (WAF-arg) forms of WAF-1/CIP-1/p21 was observed when normal healthy Caucasians and Chinese were compared (P < 0.0001). The majority of Caucasians examined were found to be homozygous for WAF-ser (89%, n = 65), while Chinese living in areas of high NPC incidence show a greater than 86% homozygous or heterozygous WAF-arg (Taiwan, n = 66; Hunan, n = 32). The two forms of WAF-1/CIP-1/p21 were examined for potential functional differences in their ability to inhibit cyclin-dependent kinases and tumor cell growth. No significant differences were detected. Furthermore, no association between WAF-1/CIP-1/p21 genotype and NPC risk was observed in a case-control study of 76 NPC cases and 66 normal controls conducted in Taiwan.(ABSTRACT TRUNCATED AT 250 WORDS)