Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis

Abstract

This report shows that loss of heterozygosity at the mannose 6-phosphate͞insulin-like growth factor II receptor (M6P͞IGF2R) locus occurred in 5͞8 (63%) dysplastic liver lesions and 11͞18 (61%) hepatocellular carcinomas (HCCs) associated with the high risk factors of hepatitis virus infection and liver cirrhosis. Mutations in the remaining allele were detected in 6͞11 (55%) HCCs, including deletions in a polydeoxyguanosine region known to be a target of microsatellite instability. M6P͞IGF2R allele loss was also found in cirrhotic tissue of clonal origin adjacent to these dysplastic lesions and HCCs, demonstrating that M6P͞IGF2R inactivation occurs early in liver carcinogenesis. In conclusion, HCCs frequently develop from clonal expansions of phenotypically normal, M6P͞IGF2R-mutated hepatocytes, providing further support for the idea that M6P͞IGF2R functions as a liver tumor-suppressor gene.

M6P/IGF2R is mutated in squamous cell carcinoma of the lung

“…Although this mutation is present in 13% of HCCs (De Souza et al, 1995b;Yamada et al, 1997), it was not detected in squamous cell carcinoma of the lung. This is particularly interesting since carcinogens found in smoke such as benzo[a]pyrene diol epoxide preferentially attack deoxyguanine, frequently resulting in a G:C?T:A transversion (Greenblatt et al, 1994).…”

“…LOH at the M6P/IGF2R locus occurs in 60% of human HCCs (De Souza et al, 1995a;De Souza et al, 1995b;Yamada et al, 1997) and 30% of breast cancers (Hankins et al, 1996), and missense mutations that reduce receptor function have been identi®ed in the remaining allele Yamada et al, 1997;Byrd et al, 1999;. The M6P/IGF2R also contains a poly-G region that is a common target for frame-shift mutations in colon, gastric, endometrial and liver tumors with mismatch repair de®ciencies and microsatellite instability (MI) (Ouyang et al, 1997;Yamada et al, 1997). Moreover, the M6P/ IGF2R is mutated in human gliomas that do not contain mutations in the TGFb type II receptor or Bax genes (Leung et al, 1998).…”

“…This is particularly interesting since carcinogens found in smoke such as benzo[a]pyrene diol epoxide preferentially attack deoxyguanine, frequently resulting in a G:C?T:A transversion (Greenblatt et al, 1994). Furthermore, none of the M6P/IGF2R missense mutations found in squamous cell carcinomas of the lung have been detected in either HCCs or breast cancer (De Souza et al, 1995b;Hankins et al, 1996;Yamada et al, 1997). Thus, the M6P/IGF2R mutational spectrum appears to be tumor speci®c and/or dependent upon the carcinogenic agent involved in the etiology of tumor formation.…”

Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer

“…[2][3][4] It is inactivated early in the development of a number of cancers, including those in the liver, breast and lung. [3][4][5][6][7][8] M6P/IGF2R mutation furthermore predicts for poor therapeutic outcome. 9 Thus, the M6P/IGF2R gene encodes for a receptor that functions normally to suppress tumor formation.…”

“…The M6P/IGF2R gene is located at 6q26, a chromosomal location commonly deleted in cancer. 3,[5][6][7][8] It encodes for a multifunctional receptor required for the intracellular trafficking of lysosomal enzymes to the lysosomes, and the extracellular activation of the growth inhibitor, transforming growth factor b1 (TGFb1), and the degradation of the mitogen, IGF2. 2,10 Evidence suggests, however, that the M6P/IGF2R is not involved in cell signaling by IGF2.…”