Deletion mapping suggests that the 1p22 melanoma susceptibility gene is a tumor suppressor localized to a 9‐mb interval

Abstract

Loss of the short arm of chromosome 1 is frequently observed in many tumor types, including melanoma. We recently localized a third melanoma susceptibility locus to chromosome band 1p22. Critical recombinants in linked families localized the gene to a 15-Mb region between D1S430 and D1S2664. To map the locus more finely we have performed studies to assess allelic loss across the region in a panel of melanomas from 1p22-linked families, sporadic melanomas, and melanoma cell lines. Eighty percent of familial melanomas exhibited loss of heterozygosity (LOH) within the region, with a smallest region of overlapping deletions (SRO) of 9 Mb between D1S207 and D1S435. This high frequency of LOH makes it very likely that the susceptibility locus is a tumor suppressor. In sporadic tumors, four SROs were defined. SRO1 and SRO2 map within the critical recombinant and familial tumor region, indicating that one or the other is likely to harbor the susceptibility gene. However, SRO3 may also be significant because it overlaps with the markers with the highest 2-point LOD score (D1S2776), part of the linkage recombinant region, and the critical region defined in mesothelioma. The candidate genes PRKCL2 and GTF2B, within SRO2, and TGFBR3, CDC7, and EVI5, in a broad region encompassing SRO3, were screened in 1p22-linked melanoma kindreds, but no coding mutations were detected. Allelic loss in melanoma cell lines was significantly less frequent than in fresh tumors, indicating that this gene may not be involved late in progression, such as in overriding cellular senescence, necessary for the propagation of melanoma cells in culture.

Fine allelotyping of Erbb2‐induced mammary tumors in mice reveals multiple discontinuous candidate regions of tumor‐suppressor loci

“…If the LOH occurring in these regions of murine tumors is a model for what is happening in human tumors, it may be anticipated that, similarly, multiple and restricted LOH sites will be uncovered in human tumors within the homologous human chromosome 1p32-36 and 10q23-26 regions. Similar multiple discrete, independent LOH sites have, in fact, been described previously in human tumors (Jakobovitz et al, 1996;Kim et al, 1997;Waber et al, 1997;Wistuba et al, 2000;Walker et al, 2004), including in human breast carcinoma (Kerangueven et al, 1997;Wang et al, 2004) and have been suggested to be the mutational signature of oxidative damages (Turker et al, 1999).…”

Microarray‐based CGH of sporadic and syndrome‐related pheochromocytomas using a 0.1–0.2 Mb bacterial artificial chromosome array spanning chromosome arm 1p

“…Mutations in TGFB-binding proteins may contribute to disturbances in the regulation of cell differentiation and proliferation, and lead to oncogenic transformation. However, no coding mutations of TGFBR3 could be detected in 1p22-linked melanoma kindreds (Walker et al, 2004). Melanoma cell lines showed significantly less allelic 1p loss compared with fresh tumors, indicating that the TGFBR3 gene may not be involved in cellular alterations necessary for the in vitro propagation of melanoma cells.…”

“…Recently, transforming growth factor-b receptor type III (TGFBR3) has been identified as a candidate tumor suppressor in one of three melanoma susceptibility loci at chromosome band 1p22 (Walker et al, 2004). TGFBR3, a TGFB-binding glycoprotein that exists in both a membrane-bound and a soluble form, may serve as a receptor accessory molecule in TGFB signaling.…”

MicroRNA-137 Targets Microphthalmia-Associated Transcription Factor in Melanoma Cell Lines

“…The publicly accessible database miRBase 3 was consulted to identify miRNA located on chromosome 1 in the region predicted to harbor a gene involved in melanoma. The data bases TargetScan 3.1 5 (17, 18) and miRgen 4 (15) were used to identify potential targets for miR-137 regulation in melanoma.…”

“…In an attempt to discern regions of the genome that might harbor genes contributing to the development of melanoma, several studies have characterized regions of the genome that are lost or amplified in melanoma cell lines and in families with a high risk for melanoma (2). One such region located on chromosome 1p22 harbors a gene or genes that are responsible for increasing melanoma risk but are not yet identified (3). With the identification of microRNAs (miRNA) as important regulators of gene expression, we hypothesized that a miRNA at 1p22 might be regulating target genes associated with a risk of developing melanoma.…”