We previously reported 33 genome-wide minimal deleted regions (MDRs) in hepatocellular carcinoma (HCC) genome (Jou et al., Cancer Research 64:3030-3036, 2004). To further exam the two-hit theory that the frequent loss of heterozygosity (LOH) region will tend to harvest homozygous deletion (HD), we scan HD in 48 HCC tissues and 12 HCC cell lines. Interestingly, a novel 1-cM (1.8Mb) HD on 13q12.11 was identified in a human HCC cell line, SK-Hep-1. The HD region is not only a common LOH region in HCC (25/48=52%) but also in many other human cancers and the syntenic chromosomal loss regions of rodent liver cancer models. In addition, loss of 13q12.11 HD region is significantly associated with early-onset patients by statistical analyses including Mann-Whitney U test and Fishers exact test. Since the HD region is gene-rich with more than 37 predicted transcripts, we conducted candidate gene approach by examining down regulation of candidate tumor suppressor genes including LATS2, TG737, CRYL1, and GJB2 in 45 pairs of HCC and adjacent normal tissues. Down regulation of TG737, CRYL1, and GJB2 mRNAs were observed in 59%, 64% and 71% of HCC samples by quantitative RT-PCR assays, respectively. Interestingly, the down regulation of CRYL1 is statistically associated with p53 mutation and wild typeβ-catenin that is potentially involved in genome unstable pathway and advanced-stage HCC. Together, our results suggest that the HD on 13q12.11 is a putative HCC tumor suppressor locus with biological implication of rapid progression in hepatocarcinogenesis.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]