P53 MUTATIONS IN HEAD AND NECK SQUAMOUS-CELL CARCINOMAS FROM SUDANESESNUFF (TOOMBAK) USERS

Toombak is a type of snuff used extensively in the Northern Sudan by a virtually nonsmoking/nondrinking population. This Sudanese snuff cont ains inordinately high levels of the tobacco-specific nitrosamines (TS NAs) N'-nitrosonornicotine (NNN) and (4-methylnitrosamino)-1-(3-pyridy l)-1-butanone (NNK). These are considered to be major contributors to the induction of cancers of the aerodigestive tract in tobacco chewers , snuff dippers, and smokers. To determine if toombak use may be assoc iated with the induction of mutations in the p53 tumor suppressor gene , we screened four head and neck squamous cell carcinomas (SCCs) obtai ned from three toombak-using patients and one non-toombak-using patien t using polymerase chain reaction/single-stranded conformational polym orphism analysis and DNA sequencing. p53 mutations were found in tumor s resected from two of three toombak-using patients, one at codon 282 (CGG(arg) --> TGG(trp)) and the other in intron 6 (AT --> GC). No p53 mutations were observed in the tumor from the non-toombak-using patien t. The observed mutations were similar in spectrum to those induced by nitrosamines in mouse lung tumors. No K-ras (codons 12 and 13) or H-r as (codon 12) mutations were found in any of the tumors. These results suggest that toombak components such as TSNAs may induce p53 mutation s in head and neck SCCs and are likely contributors to the tobacco-ind uced carcinogenic load in humans.