Identification of homozygous deletions at chromosome 16q23 in Aflatoxin B1 exposed hepatocellular carcinoma

Abstract

Loss of heterozygosity (LOH) represents the most frequent genetic alteration observed in hepatocellular carcinoma (HCC). Chromosome 16q is of particular 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 tumors for 17 microsatellite markers distributed on chromosome 16q and determined a common region of LOH localized between the markers D16S518 and D16S504. By re®ning 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 search for mutations in all coding exons of this gene in 27 HCC tumors and cell 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 occurred in tumors presenting a R249S mutation. Our data revealed a relationship between chromosome 16q homozygous deletions and R249S p53 mutations in tumors where the patient had been exposed to A¯atoxin B1 (P=0.002). These results are consistent with a role of A¯atoxin B1 in the instability of chromosome 16q at the fragile site FRA16D. However, the nature of the speci®c gene that is altered during hepatocarcinogenesis remains to be elucidated. Oncogene (2001) 20, 5232 ± 5238.

FRA16D common chromosomal fragile site oxido-reductase (FOR/WWOX) protects against the effects of ionizing radiation in Drosophila

“…However, the lack of mutations in the second allele in cancer cells and the sometimes elevated rather than diminished level of expression of the gene in cancer cells have led some to conclude that the WWOX gene does not encode a 'classical' tumour suppressor (Watanabe et al, 2003). While the normal function of WWOX is currently unknown, its aberrant expression in a variety of cancer cell types has been extensively reported, also suggesting a likely association with cancer cell biology Paige et al, 2001;Yakicier et al, 2001;Driouch et al, 2002;Kuroki et al, 2002;Ishii et al, 2003;Yendamuri et al, 2003;Aqeilan et al, 2004a;Guler et al, 2004;Kuroki et al, 2004).…”

Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

“…Chromosomal instability and LOH on chromosome 1p, 4q, 16p, 16q have been correlated to axin-1 inactivation. At least in aflatoxin B1-induced HCC, LOH at 16q results from activation of FRA16D, but the target gene remains to be found (Yakicier et al, 2001). In a recent work (Bluteau et al, 2002), 36 primary liver tumors with partial deletions of 4q have been studied by high-density allelotyping, which identified three distinct regions of LOH.…”

Genetics of hepatocellular tumors

“…In HCC, tumor suppressor genes, targeted by LOH, have been identified on chromosome 17p, 13q, 16p, 9p and 6q corresponding to inactivation of TP53, RB1 (retinoblastoma 1), AXIN1 (axis inhibition protein 1), CDKN2A (cyclin-dependent kinase inhibitor 2A, also named p16) and IGF2R (insulin-like growth factor 2 receptor), respectively. In contrast, on chromosome 1p, 4q, 8p and 16q, no targeted tumor suppressor genes have yet been identified and high-resolution allelotyping have been performed to define boundaries and physical map of the deleted chromosome regions (Koyama et al, 1999;Piao et al, 1999;Pineau et al, 1999;Balsara et al, 2001;Yakicier et al, 2001;Bluteau et al, 2002a).…”