LOH of chromosome 12p correlates with Kras2 mutation in non-small cell lung cancer

Abstract

Previous observation has shown that the wild-type Kras2 allele is a suppressor of lung cancer in mice. Here we report that loss of heterozygosity (LOH) of chromosome 12p was detected in B50% of human lung adenocarcinomas and large cell carcinomas, and Kras2 mutations were detected at codon 12 in B40% of adenocarcinomas and large cell carcinomas. Interestingly, all of the lung adenocarcinomas and large cell carcinomas containing a Kras2 mutation exhibited allelic loss of the wild-type Kras2 allele when a correlation between LOH of the region on chromosome 12p and Kras2 mutation was made. These results from human lung cancer tissues provide a strong evidence in support of our previous observation in mouse models that the wild-type Kras2 is a tumor suppressor of lung cancer.

Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer

“…Overexpression of PTPRO in the lung cancer cell line A549 (in which PTPRO is inactivated because of promoter methylation) resulted in inhibition of anchorage-independent growth, alteration in cell-cycle progression, and increased susceptibility to apoptosis-inducing agents, all of which are hallmarks of a bona fide tumor suppressor. Additionally, the PTPRO gene is localized in the chromosomal region 12p12.3, which is characterized by loss of heterozygosity in different types of cancers (29)(30)(31)(32)(33)(34), another established characteristic of many tumor-suppressor genes.…”

Prevention of lung cancer progression by bexarotene in mouse models

“…While mutations in K-ras are commonly observed in lung tumors from A/J mice, loss of the wt allele appears to be uncommon (Zhang et al, 2001). This is in contrast to many human non-small-cell lung cancers or lung adenocarcinomas from B6C3F1 mice where loss of one copy of the K-ras allele, often associated with mutation of the other allele, is relatively common (Zhang et al, 2001;Li et al, 2003). Therefore, we have developed models that carry a p53 val135 dominantnegative mutation or a K-ras deletion on the A/J mouse background.…”

“…The rationale for this alteration is twofold. First, loss of heterozygosity at the K-ras locus is relatively common in human lung cancers (Li et al, 2003). Second, a decrease in dosage of the K-ras wild-type allele has been shown to promote urethane-induced mouse lung tumorigenesis (Zhang et al, 2001).…”

Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling

“…Alternatively, different Ras isoforms might compete for common regulators, effectors, or proper localization. Prior studies indicate that wild-type Ras can antagonize the transforming potential of its oncogenic counterpart in a dose-dependent manner in vitro and in vivo (23)(24)(25), and show a strong selective pressure to lose expression of the corresponding wild-type allele of the oncogenic Ras isoform (35)(36)(37). Whereas these data support a tumor-suppressive role for the wild-type counterpart of the same oncogenic Ras isoform, our studies uncover a novel role for the remaining 2 wild-type Ras isoforms in antagonizing oncogenic Ras signaling.…”