Functional localization of a melanoma tumor suppressor gene to a small (≤2 Mb) region on 11q23

Abstract

We have previously demonstrated the existence of a melanoma tumor suppressor gene(s) on the long arm of chromosome 11 through suppression of tumorigenicity assays. Although loss of heterozygosity studies also support this ®nding, only a large critical region (44 cM) has been identi®ed to date on 11q22-25. To further localize a tumor suppressor gene(s) within this region, we have now generated and characterized nine melanoma microcell hybrids, each retaining an introduced fragment of 11q. Of the nine hybrids, four were suppressed for tumor formation in nude mice, while ®ve formed tumors at the same rate as the parental melanoma cell line (UACC 903). Molecular analysis of the hybrids with 118 microsatellite markers narrowed the location of a putative suppressor gene to a small (42 Mb) candidate region on 11q23 between the markers D11S1786 and D11S2077 and within the larger region frequently deleted in melanoma tumors and cell lines. While multiple tumor suppressor genes are likely to reside on 11q22-25, the presence of this region in all four suppressed hybrids supports the simplest model that a single locus is responsible for the suppressed phenotype observed in UACC 903.

A functional investigation of tumor suppressor gene activities in a nasopharyngeal carcinoma cell line HONE1 using a monochromosome transfer approach

“…Our data demonstrate that 89% of the informative cases displayed losses at this region and indicate that a putative TSG mapping within or near the D11S2000 locus is critical for the development of NPC. A recent report by Robertson et al (1999) suggests that a more precise location for this locus is 11q22.3-23.1. The previous LOH studies suggested that the common deletion region in NPC is at 11q22-24.…”

“…The D11S1647 marker overlaps with D11S2000, but was not informative in these cell lines. Other than NPC, a deletion at 11q22-23 has been reported in a variety of carcinomas, including melanoma (Robertson et al, 1999), breast (Carter et al, 1994), ovarian (Foulkes et al, 1993), lung (Rasio et al, 1995), cervical (Bethwaite et al, 1995), bladder (Shaw et al, 1995), colorectal (Keldysh et al, 1993), and prostate cancers (Dahiya et al, 1997). Molecular analysis of the chromosome 11 tumor segregants clearly indicates the existence of at least two putative TSGs residing on the long arm of chromosome 11, which may be critical to the development of NPC.…”

Molecular Clonality of In-Transit Melanoma Metastasis

“…21,29 Our finding of substantial LOH in the 11q21-23 region for in-transit lesions is in agreement with others suggesting this loss is a later event in tumor progression and may more likely be involved in tumor metastasis rather than cancer initiation. 26,30 LOH on chromosome 1p in early stage tumors is a rare event. 25 However, we found significant LOH in this region in in-transit metastasis.…”

“…23,24 Furthermore, because advanced metastasis may contain additional LOH events (ie, distal arm of 1p and 11q23) not identified or infrequent in primary tumors, the role of these findings is unknown. 25,26 Particularly, of interest is at which point in the course of tumor progression do these events occur and are they clinicopathologically relevant. Identification of those genetic events associated with early stages of metastasis offers the advantage of establishing potential tumor markers to assess patient risk and monitor subclinical disease.…”

Graph Models of Oncogenesis with an Application to Melanoma

“…All but one of the non-random breakpoints we selected using Brodeur's method are on chromosomes 1, 6, 7, 9 and 11, in good agreement with the established consensus. Among the studies that support some of the speci"c regions we selected are two studies Robertson et al, 1999) suggesting that there is one or more tumor suppressor genes on 11q2, and a cell fusion study of Trent et al (1990). The cell fusion study showed that the introduction of a normal chromosome 6 into a human melanoma cell line with a deletion in the long arm of the chromosome resulted in altered cell morphology and decreased cloning e$ciency, suggesting the presence of a tumor suppressor gene on chromosome 6.…”