Lack of frameshift mutations at coding mononucleotide repeats in hepatocellular carcinoma in Japanese patients

Abstract

BACKGROUND Microsatellite instability occurs frequently in hereditary nonpolyposis colorectal carcinoma, in sporadic gastrointestinal carcinoma, and in other tumors. In these tumors, slippage‐related frameshift mutations have been detected at coding mononucleotide repeats in genes such as those for transforming growth factor‐β receptor type II (TGFβRII), mannose 6‐phosphate/insulinlike growth factor II receptor (M6P/IGFIIR), hMSH3, hMSH6, and Bcl‐2–associated X protein (BAX). Because these genes regulate cell growth or repair DNA mismatches, loss of their function is thought to promote tumor development. The authors screened for these frameshift mutations and investigated the incidence of microsatellite instability (MI) in hepatocellular carcinoma (HCC) in Japan. METHODS Fifty HCC samples were analyzed in this study. The authors used polymerase chain reactions to screen for frameshift mutation at the TGFβRII (A)10 tract, the M6P/IGFIIR (G)8 tract, the hMSH3 (A)8 tract, the hMSH6 (C)8 tract, and the BAX (G)8 tract. For MI analysis, matched tumor and nontumor liver DNA were investigated with respect to 10 microsatellite loci. RESULTS No frameshift mutation was detected in any case, and only 4% of these cancers exhibited MI in comparisons between tumor and nontumor liver specimens. CONCLUSIONS This study suggests that frameshift mutation at coding mononucleotide repeats within TGFβRII, M6P/IGFIIR, hMSH3, hMSH6, and BAX genes did not seem to be involved in hepatocarcinogenesis in the Japanese population studied. Cancer 2000;88:1025–9. © 2000 American Cancer Society.

Hepatocellular expression of a dominant-negative mutant TGF-β type II receptor accelerates chemically induced hepatocarcinogenesis

“…Further evidence comes from DEN-initiated HCC in mice in which a reduction of TbRII has also been reported (Lim et al, 1999). However, it seems that downregulation of the TbRII receptor rather than mutation or deletion of the TbRII occurs more frequently in human hepatocarcinogenesis (Kiss et al, 1997;Bedossa et al, 1995;Kiso et al, 1994;Saeki et al, 2000;Salvucci et al, 1999).…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Additionally, several missense mutations in the extracytoplasmic domain of IGF-2R efficiently disrupt receptor/ligand interaction, which is then followed by increased ligand bioavailability Devi et al, 1999). However, these results are still controversially discussed, as other studies failed to detect any genetic alterations at the igf-2r locus (Wada et al, 1999;Saeki et al, 2000;Enomoto et al, 2001), which might be owing to methodical or populationbased differences.…”

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

“…Here, the reduced expression of IGF-ⅡR, the loss of heterozygosity (LOH) at the igf-Ⅱr gene locus, homozygous deletions, and missense mutations with an impact on ligand binding have been described with respect to HCCs [43][44][45][46][47][48][49] . However, other studies did not detect any genetic alterations at the igf-Ⅱr locus, which may be due to methodological and population-based differences [50][51][52] . Moreover, few studies described elevated IGF-ⅡR levels in HCCs [53,54] .…”