A genetic model of melanoma tumorigenesis based on allelic losses

Abstract

Previous karyotypic studies have indicated a possible series of non-random chromosomal events involved in progression of melanoma. We sought to verify and augment this model of melanocyte tumorigenesis by studying allelic deletions of markers mapping to these regions in 30 matched pairs of melanoma and constitutional DNA samples. Polymorphic loci on chromosomes 1, 7, 10, 11, 17, and 21 were analyzed and data combined with those previously obtained for chromosome arms 6q and 9p in the same series of tumours. The most frequent and earliest deletions were found on 9p (57%) and 10q (32%). With the exception of one case, no sample had loss of markers on another chromosome without concomitant loss of markers on 9p or 10q. Losses on 6q were also a frequent (31%) and early event whereas losses of loci on distal 1p (22%) or 11q (26%) occurred only in metastatic melanomas. A "background" rate (0-17%) of allele loss was seen on chromosomes 7, 17, and 21. These data strongly support the previous model based on karyotypic findings in melanocytic lesions. However, we have been able to further, augment that model by delimiting the regions of loss on 10q, to that distal to D10S254, and on 1p, to between D1S243 and D1S160.

Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines

“…However, a review of the 10q LOH data in melanoma suggests an additional locus may be more distal on 10q than PTEN/ MMAC1. Walker et al found that the frequency of allelic loss in chromosome 10q markers ranges from 26% at D10S254 to 32% at D10S212 (Walker et al, 1995). They delimited the smallest region of overlap (SRO) to a 36cM area distal to D10S254.…”

PTEN/MMAC1 expression in melanoma resection specimens

“…As this tumour suppressor gene is located at chromosome 10q23.3 and melanomas frequently harbour deletions at chromosome 10q22-qter (Isshiki et al, 1993;Herbst et al, 1994;Walker et al, 1995;Healy et al, 1996Healy et al, , 1998 like carcinomas of the prostate (Trybus et al, 1996) and the kidney (Speicher et al, 1994), inactivation of PTEN/MMAC1 has been supposed to occur in melanomas. Actually, deletions and mutations of PTEN/MMAC1 have been found in 29 -43% of investigated melanoma cell lines (Guldberg et al, 1997;Tsao et al, 1998;.…”

“…Moreover, LOHs at chromosome 10 occur in 30 -60% of both early-and advanced-stage tumours (Newton, 1994;Bastian et al, 1998) and are an indicator of a poor clinical prognosis (Healy et al, 1998). Segmental deletions were cytogenetically localized to 10q (Richmond et al, 1986;Parmiter et al, 1988;Isshiki et al, 1993;Indsto et al, 1998) and subsequently narrowed by studies of LOH to 10q22-qter (Isshiki et al, 1993;Herbst et al, 1994;Walker et al, 1995;Healy et al, 1996). This region is also a common target of LOH in a wide spectrum of sporadic cancers, including neoplasias of the prostate (Trybus et al, 1996), thyroid (Nelen et al, 1996), kidney (Speicher et al, 1994), endometrium (Nagase et al, 1996), and bone (Raskind et al, 1996).…”

cDNA array technology in melanoma: An overview

“…2). Loss of the chromosome regions 9p21 and 10q are usually considered the earliest changes in melanoma progression, while alterations or deletions involving regions 6q and 11q occur in correspondence of the RGP (Radial Growth Phase) to VGP (Vertical Growth Phase) conversion, and deletions on 1p, and amplification of 7q usually occur last (Fountain et al, 1990;Healy et al, 1995Healy et al, , 1996Walker et al, 1995;Robertson et al, 1996;Bastian et al, 1998). In particular, linkage analysis of familial melanoma has suggested the presence of a melanoma susceptibility gene on chromosome 9p21, which harbors the gene CDKN2A, encoding for a protein called p16 INK4A (Cannon-Albright et al, 1992;Rocco and Sidransky, 2001).…”