Genomic losses at 5q13.2 and 8p23.1 in dysplastic hepatocytes are common events in hepatitis B virus-related hepatocellular carcinoma

Abstract

Abstract. Chromosomal loci with genomic imbalances are frequently identified in hepatocellular carcinoma (HCC). Greater than two-thirds of hepatitis B virus (HBV)-relatedHCCs originate from liver cirrhosis following a duration of up to two decades. However, it is unclear whether these genomic imbalances occur and accumulate in dysplastic hepatocytes of the cirrhotic liver during the progression from regenerated nodules to preneoplastic lesions, including dysplastic nodules (DN). In the present study, high-grade DNs (HGDNs) of HBV-related liver cirrhosis were screened to identify loci with genomic imbalances, and the frequency of the identified loci in a group of HCCs was analyzed in order to determine whether there may be a genetic link between liver cirrhosis and HCC. Genomic DNA was extracted from six HGDNs of two cases of HBV-related liver cirrhosis and subjected to array comparative genomic hybridization (CGH) analysis with a NimbleGen 720K microarray. Loci with the most frequently observed genomic imbalances in DNs were further analyzed in 83 cases of HCC by differential polymerase chain reaction (PCR) and quantitative PCR. The array CGH analysis revealed that the majority of genomic imbalances in the HGDNs were genomic losses of small segments, with loss of heterozygosity (LOH) at 5q13.2 and 8p23.1 identified most frequently. Of the 83 HCC cases, 30 (36.1%) cases were identified with LOH at 5q13.2, where known tumor-associated genes are located, including general transcription factor IIH subunit 2 (GTF2H2), baculoviral IAP repeat-containing protein 1 (BIRC1) and occludin (OCLN). LOH frequency at 8p23.1 in HCC was 61.29% (D8S1130) and 68.4% (D8S503) respectively, similar to the results obtained in previous studies. In conclusion, the results of the present study provided evidence that genomic losses at 5q13.2 and 8p23.1 identified in dysplastic hepatocytes of the cirrhotic liver are common events in HCC. HCC-associated chromosomal abnormalities may occur and accumulate in preneoplastic lesions of liver cirrhosis.

Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers

“…We did not find any significant difference when comparing recurrently mutated genes between 52 cirrhotic and 63 non-cirrhotic samples for which cirrhotic status was available using CAP1. The LOH events [10,49–52] and CNVs [9–11,52,53] observed within our cohort are similar to those previously observed in cirrhotic HCC using alternative, investigative approaches including SNP array analysis. Within these regions, several genes such as LAMA2, ATK3, EFF1A1 , and PFN1 [14,54–56] have been previously investigated in the context of HCC development and progression.…”

Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers

“…We did not find any significant difference when comparing recurrently mutated genes between 52 cirrhotic and 63 non-cirrhotic samples for which cirrhotic status was available using CAP1. The LOH events [10,[49][50][51][52] and CNVs [9][10][11]52,53] observed within our cohort are similar to those previously observed in cirrhotic HCC using alternative, investigative approaches including SNP array analysis. Within these regions, several genes such as LAMA2, ATK3, EFF1A1, and PFN1 [14,[54][55][56] have been previously investigated in the context of HCC development and progression.…”

Recent advances in the molecular mechanism of sex disparity in hepatocellular carcinoma (Review)

“…General transcription factor IIH subunit (GTF2H) is located on 5q13.2 and encodes the 44-kDa RNA polymerase II TFIIH protein subunit 2 that interacts with other TFIIH subunits in the nucleotide excision repair pathway. Zhao et al (48) identified 30 (36.1%) of 83 HCC cases with loss of heterogeneity at 5q13.2, in which the tumor-associated gene GTF2H2 was present. GTF2H2 is an estrogen signaling pathway gene in breast cancer and is downregulated by luteolin (51).…”