Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers

Abstract

Loss of heterozygosity (LOH) involving several chromosome 3p regions accompanied by chromosome 3p deletions are detected in almost 100% of small (SCLCs) and more than 90% of non-small (NSCLCs) cell lung cancers. In addition, these changes appear early in the pathogenesis of lung cancer and are found as clonal lesions in the smoking damaged respiratory epithelium including histologically normal epithelium as well as in epithelium showing histologic changes of preneoplasia. These 3p genetic alterations lead to the conclusion that the short arm of human chromosome 3 contains several tumor suppressor gene(s) (TSG(s)). Although the first data suggesting that 3p alterations were involved in lung carcinogenesis were published more than 10 years ago, only recently has significant progress been achieved in identifying the candidate TSGs and beginning to demonstrate their functional role in tumor pathogenesis. Some of the striking results of these findings has been the discovery of multiple 3p TSGs and the importance of tumor acquired promoter DNA methylation as an epigenetic mechanism for inactivating the expression of these genes in lung cancer. This progress, combined with the well known role of smoking as an environmental causative risk factor in lung cancer pathogenesis, is leading to the development of new diagnostic and therapeutic strategies which can be translated into the clinic to combat and prevent the lung cancer epidemic. It is clear now that genetic and epigenetic abnormalities of several genes residing in chromosome region 3p are important for the development of lung cancers but it is still obscure how many of them exist and which of the numerous candidate TSGs are the key players in lung cancer pathogenesis. We review herein our current knowledge and describe the most credible candidate genes.

hOGG1 Ser326Cys polymorphism and G:C‐to‐T:A mutations: No evidence for a role in tobacco‐related non small cell lung cancer

“…28,49 The codon 326 polymorphism may be in linkage disequilibrium with other functional polymorphisms in cancerrelated genes on chromosome 3p. 50 In summary, the hOGG1 codon 326 Ser/Ser genotype was associated with an increase in p53 mutations in tobacco-related NSCLC. However, no difference in the pattern of oxidative damage (G:C-to-T:A transversions) was evident among codon 326 genotypes.…”

Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1

“…A stearate-Fus1 peptide inhibits the tyrosine kinase activity of c-Abl Fus1 is a TSG associated with NSCLC (Kondo et al, 2001;Zabarovsky et al, 2002). A C-terminal deletion mutant of FUS1 was isolated from a lung cancer tumor cell line, which encodes the first 80 amino acids of the 110-amino-acid wild-type Fus1 protein (Kondo et al, 2001).…”

“…Recently, new approaches in the treatment of NSCLC have arisen from the discovery that the epithelial growth factor receptor (EGFR) is frequently overexpressed and activated in NSCLC (Dowell and Minna, 2005). In lung cancer, loss of sequences within chromosome 3p is frequently seen in both SCLC and NSCLC, providing evidence of tumor suppressor genes (TSGs) in this chromosomal region (Girard et al, 2000;Zabarovsky et al, 2002). The FUS1 gene has been identified in the 3p21.3 critical chromosomal region and is considered a novel TSG (Zabarovsky et al, 2002;Ji et al, 2002).…”

“…In lung cancer, loss of sequences within chromosome 3p is frequently seen in both SCLC and NSCLC, providing evidence of tumor suppressor genes (TSGs) in this chromosomal region (Girard et al, 2000;Zabarovsky et al, 2002). The FUS1 gene has been identified in the 3p21.3 critical chromosomal region and is considered a novel TSG (Zabarovsky et al, 2002;Ji et al, 2002). The mechanism of Fus1 tumor suppressor activity is unknown.…”

Enhancement of antitumor activity of cisplatin in human lung cancer cells by tumor suppressor FUS1

“…3,5,7,8 Tumor suppressor genes (TSGs) on chromosome 3p play a key role in the pathogenesis of human lung cancer and other cancers. [9][10][11][12][13] FUS1 is one of novel candidate TSGs clustered in a 120-kb homozygous-deletion region in the human chromosome 3p21.3 region. 14,15 We have previously demonstrated that the forced expression of wild-type (wt)-FUS1 significantly inhibited tumor cell growth by induction of apoptosis and alteration of cellcycle kinetics in 3p21.3-deficient NSCLC cells in vitro, and efficiently suppressed tumor growth and metastasis in mouse models of human lung cancer.…”