Identification of homozygous deletions at chromosome 16q23 in Aflatoxin B1exposed hepatocellular carcinoma

Loss of heterozygosity (LOH) represents the most frequent genetic alteratio n observed in hepatocellular carcinoma (HCC). Chromosome 16q is of particul ar interest as it exhibits LOH in 29% of HCC tumors and is frequently lost in breast, prostate, ovarian and gastric carcinomas. We genotyped 157 HCC t umors for 17 microsatellite markers distributed on chromosome 16q and deter mined a common region of LOH localized between the markers D16S518 and D16S 504. By refining the boundaries of two interstitial LOH and two homozygous deletions, the critical region was delimited to 180 kb between D16S3096 and D16S3029. This region is located in intron 8 of the WWOX/FOR gene, but a s earch for mutations in all coding exons of this gene in 27 HCC tumors and c ell lines did not reveal any tumor somatic alterations. Furthermore, by RT- PCR, no abnormal transcripts of this WWOX/FOR gene was detected in nine HCC cell lines. Finally, analysis of the p53 gene mutations with the clinical parameters of all tumors revealed that the two homozygous deletions have oc curred in tumors presenting a R249S mutation. Our data revealed a relations hip between chromosome 16q homozygous deletions and R249S p53 mutations in tumors where the patient had been exposed to Aflatoxin B1 (P = 0.002). Thes e results are consistent with a role of Aflatoxin B1 in the instability of chromosome 16q at the fragile site FRA16D. However, the nature of the speci fic gene that is altered during hepato carcino genesis remains to be elucid ated.