Search for unknown tumor‐antagonizing genes

Abstract

Following the ingenious prediction of Alfred Knudson in 1971, the first tumor suppressor gene, RB1, has been isolated. Its product, the RB1 protein, was found to play a major role in the control of the cell cycle. The loss of heterozygosity (LOH) technique, introduced by Cavenee and colleagues, was an important milestone toward the confirmation of Knudson's hypothesis and the identification of the gene. Subsequently, the LOH technique has provided important clues that have led to the discovery of other tumor suppressor genes. Most of them play important roles in the regulation of the cell cycle and/or of apoptosis. Circumstantial evidence suggests that still other and perhaps many unknown genes may participate in the protection of the organism against malignant growth. The numerous genome losses in tumors, detected by LOH, comparative genomic hybridization, and by cytogenetic techniques, support this possibility. The early work of one of us (G.K.), together with Henry Harris and Francis Wiener, had shown that the malignant phenotype can be suppressed by hybridizing malignant with low- or non-tumorigenic cells. However, analysis of this phenomenon failed to assign the inhibition of tumorigenicity to any particular gene. We have pursued the search for new tumor-antagonizing genes with two unconventional approaches, focusing on human chromosomal subband 3p21.3, a region frequently targeted by cytogenetically detectable deletions. We have detected four clusters of candidate tumor suppressor genes at 3p21.3 by a combination of deletion mapping and the "elimination test." These findings raise the question whether the number and variety of genes that may contribute to the defense against uncontrolled proliferation may have been underestimated.

DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers

“…Virtually all known TSGs with methylation-mediated silencing in HCT116 became demethylated and reactivated in HCT116DKO, making it a good epigenetic model to identify novel candidate TSGs silenced in tumours (Rhee et al, 2002;Paz et al, 2003;Ying et al, 2005). Among the methylated target genes we identified, one is DLEC1 (Deleted in lung and oesophageal cancer 1), located at 3p22.3 -a common tumour suppressor locus with frequent genetic abnormalities in multiple cancers (Imreh et al, 2003). The expression of DLEC1 and its regulation in digestive tumours have yet to be evaluated.…”

RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies

“…The short arm of chromosome 3 carries frequent and often extensive deletions in most carcinomas and some other tumor types. 3p deletions were detected in Ϸ100% of small cell lung (SCLC) and renal cell (RCC) carcinomas, and Ͼ80% of breast carcinomas (BC) (1)(2)(3).…”

“…For more accurate deletion mapping in MECs, we performed a combined analysis with microsatellite and NotI markers, comparative genome hybridization and quantitative realtime PCR (QPCR) (2,6,10).…”

Normal cellular senescence and cancer susceptibility in mice genetically deficient in Ras-induced senescence-1 (Ris1)

“…Moreover, Ris1 was not induced by other forms of senescence, such as replicative senescence, or by other forms of cellular stress or organismal aging, suggesting a specific association with Ras-induced senescence (Barradas et al, 2002). Importantly, the chromosomal location of Ris1 at 3p21.3 is highly provocative, because this region is frequently deleted in a variety of human solid cancers and, more specifically, Ris1 is contained in a short segment of 1.4 Mb mapped by other investigators for its tumor suppressive activity (Imreh et al, 2003;Petursdottir et al, 2004). Indeed, high frequency of loss of heterozygosity has been demonstrated for Ris1 in breast carcinomas (Silva et al, 2006).…”