Malignant melanoma in patients with multiple endocrine neoplasia type 1 and involvement of the MEN1 gene in sporadic melanoma.
Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome associated primarily with endocrine tumors of the parathyroids, enteropancreas and anterior pituitary. However, tumors of mesenchymal origin such as angiofibroma and collagenoma of the skin have also been associated with the syndrome. This highlights the possibility of an association between MEN 1 and some other types of tumors. Here we report 7 cases of primary malignant melanoma occurring in 7 MEN 1 families, all patients exhibiting classic features of MEN 1. Based on these findings and the previous implication of multiple melanoma tumor suppressor(s) in 11q, including the MEN1 region, we have investigated the involvement of the MEN1 gene in melanoma tumorigenesis. Mutation analysis was performed on a panel of 39 sporadic metastatic melanomas, 13 melanoma cell lines and 20 melanoma families without CDKN2A or CDK4 germline mutations. In addition, 19 sporadic metastatic tumors were screened for loss of heterozygosity (LOH) in 11q13. LOH was detected in 6 tumors (32%), and in 4 of the tumors the pattern of LOH suggested that the deletion included the MEN1 gene locus. A novel somatic nonsense mutation in exon 7 (Q349X) was identified in 1 sporadic tumor which also showed loss of the wild-type allele. We conclude that the MEN1 gene plays a role in the tumorigenesis of a small subgroup of melanoma.
Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden. brita.nord@cmm.ki.se
B
B
Nord
A
A
Platz
K
K
Smoczynski
S
S
Kytölä
G
G
Robertson
A
A
Calender
A
A
Murat
D
D
Weintraub
J
J
Burgess
M
M
Edwards
B
B
Skogseid
D
D
Owen
N
N
Lassam
D
D
Hogg
C
C
Larsson
B T
BT
Teh
D000328:Adult; D000368:Aged; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007621:Karyotyping; D019656:Loss of Heterozygosity; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D009154:Mutation; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured