Molecular genetic evidence supporting a novel human hepatocellular carcinoma tumor suppressor locus at 13q12.11

A novel 1‐cM (1.8 Mb) homozygous deletion (HD) on 13q12.11 was identified in a human hepatocellular carcinoma (HCC) cell line, SK‐Hep‐1, after high‐density genetic marker scan and Southern blotting analysis. A loss of heterozygosity (LOH) analysis indicated that LOH frequency of the HD region in 48 pairs of HCC tissues was 52%. Interestingly, the occurrence of LOH in the 13q12.11 HD region is significantly associated with early‐onset HCC, inferred from Fisher's exact test ( P = 0.0047) and Mann‐Whitney test ( P = 0.023). Since the novel 1‐cM (1.8 Mb) HD region is gene‐rich with more than 37 predicted transcripts, we used a candidate gene approach by examining down‐regulation of known tumor suppressor genes (TSGs), including LATS2 , TG737 , CRYL1 , and GJB2 , in HCC tissues. We detected only 14% down‐regulation of the LAST2 gene that flanks the outside of the HD, in HCC tissues, by quantitative RT‐PCR assays. However, we observed significant down‐regulation of the TG737 , CRYL1 , and GJB2 genes located within the HD in 59, 64, and 71% of HCC tissues, respectively. Together, our results indicated that the identified 13q12.11 HD region contained at least three significant down‐regulated TSGs, and preferential LOH in early‐onset HCC patients is a putative tumor suppressor locus in HCC. © 2005 Wiley‐Liss, Inc.