Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers

Abstract

Only a small proportion of cancers result from familial cancer syndromes with Mendelian inheritance. Nonfamilial, 'sporadic' cancers, which represent most cancer cases, also have a significant hereditary component, but the genes involved have low penetrance and are extremely difficult to detect. Therefore, mapping and cloning of quantitative trait loci (QTLs) for cancer susceptibility in animals could help identify homologous genes in humans. Several cancer-susceptibility QTLs have been mapped in mice and rats, but none have been cloned so far. Here we report the positional cloning of the mouse gene Scc1 (Susceptibility to colon cancer 1) and the identification of Ptprj, encoding a receptor-type protein tyrosine phosphatase, as the underlying gene. In human colon, lung and breast cancers, we show frequent deletion of PTPRJ, allelic imbalance in loss of heterozygosity (LOH) and missense mutations. Our data suggest that PTPRJ is relevant to the development of several different human cancers.

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

“…A number of linkage mapping studies with cross-breeding experiments were carried out for chemically induced colon tumors in mice (11)(12)(13)(14)(15)(16). As a result, 16 quantitative trait loci (QTL) responsible for chemically induced colon tumors have been mapped on the mouse genome, implying a very complex picture of inherited susceptibility of colon tumorigenesis exists.…”

Germline Genetics in Colorectal Cancer Susceptibility and Prognosis

“…Variants and genes studied include common variants in high-risk genes, genes in pathways believed to be important in CRC and genes in pathways linked to environmental factors associated with CRC. One strategy which has been under-utilized is to map loci for cancer susceptibility in the mouse and then test these genes/loci for cancer risk in human www.intechopen.com populations (Ruivenkamp et al, 2002;Ewart-Toland et al, 2005;Toland et al, 2008). A large number of cancer susceptibility and resistance loci for cancers of the lung, colon, skin, liver, and the hematopoetic system have been identified using mouse models.…”

“…A large number of cancer susceptibility and resistance loci for cancers of the lung, colon, skin, liver, and the hematopoetic system have been identified using mouse models. Two putative CRC susceptibility genes, PTPRJ and AURKA, were first identified from mouse studies (Ruivenkamp et al, 2002;Ewart-Toland et al, 2003). Variants in these genes show evidence of modest CRC risk in some human studies (Ewart-Toland et al, 2005;Toland et al, 2008).…”

Epigenetic regulation of protein tyrosine phosphatases: potential molecular targets for cancer therapy

“…PTPRG, PTPRK, PTPRJ) have been localized to regions marked by loss of heterozygosity (LOH), a hallmark of many tumor suppressor genes. [27][28][29] Inactivating mutations in some PTPs (e.g. PTPRF, PTPN14, PTPRG, PTPN13, PTPN11, PTPRT, PTPN3) are also associated with development of cancers.…”

“…32 To this date, however, DEP1 is the only protein tyrosine phosphatase that is classified as an authentic tumor suppressor. 29,31 is progressively methylated in the preneoplastic liver and primary hepatomas produced in rats fed methyl-deficient diet. This gene was identified in a genome-wide scan for methylation changes during tumor progression.…”