The chromosome 10 monosomy common in human melanomas results from loss of two separate tumor suppressor loci.
Alteration of chromosome 10 is common in human melanomas and usually entails the loss of an entire chromosome homologue. Although the reasons for monosomy in cancer has remained obscure, one possibility is that multiple tumor suppressor genes residing on this chromosome must be lost in unison during tumor progression, and this is easier to accomplish by chromosome segregation rather than by multiple mutational and/or deletion events. The localization and identification of these genes has been hampered by the monosomy itself, which has resulted in a paucity of small defining deletions in tumors. Here, we have addressed the issue of monosomy in tumor development by using functional complementation mapping to localize and demonstrate the existence of different melanoma suppressor genes on chromosome 10 and assigned each locus a distinct tumorigenic phenotype. We report that a locus on 10q distal to 10q23.1, likely involving the PTEN tumor suppressor, causes a severe reduction in the kinetics of melanoma tumor formation in animals. In contrast, a previously unrecognized region at 10p15.3 has a distinct, but lesser, effect on in vivo melanoma growth. Thus, the loss of both of these regions, which is accomplished by tumor-associated monosomy, provides a significant growth advantage over the individual loss of either region, thereby explaining the monosomy observed in sporadic melanomas.
Robertson
G P
GP
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla 92093-0660, USA. gprobertson@ucsd.edu
Herbst
R A
RA
Nagane
M
M
Huang
H J
HJ
Cavenee
W K
WK
D000818:Animals; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics* / Q000648:ultrastructure; D018450:Disease Progression; D016147:Genes, Tumor Suppressor; D006801:Humans; D006822:Hybrid Cells; D019656:Loss of Heterozygosity; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009006:Monosomy; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human