Chromosome 22q alterations and expression of the NF2 gene product, merlin, in gastrointestinal stromal tumors.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. A characteristic genetic alteration in GISTs is constitutive activation of the c-kit proto-oncogene, but alterations in chromosomes 14 and 22 may also play a role in the molecular pathogenesis. In this study, 42 GISTs were analyzed for loss of heterozygosity (LOH) on the long arm of chromosome 22 (22q). Overall, 69% of the tumors studied showed LOH with at least 1 of the 22q markers. Allele losses were compared with tumor mitotic activity, the most commonly used prognostic marker for this tumor. Interestingly, allele deletion at 22q was significantly more frequent in tumors with high mitotic activity (>/= l2 mitoses/10 high-power fields [HPF]) than in tumors with low mitotic activity (< 2 mitoses/HPF)-88% versus 56% (P < 0.01). A total of 26% (11 of 42) of all tumors demonstrated loss of all 22q sites analyzed, consistent with the loss of 1 copy of the entire long arm. Such tumors carried a 4.6-fold (95% confidence interval, 0.5 to 49.8) risk for recurrence compared with tumors with no LOH. LOH was frequently detected at the neurofibromatosis 2 (NF2) tumor-suppressor gene locus at 22q12. Sequencing of the NF2 gene from 5 GISTs did not reveal mutations, however. Furthermore, 16 of 19 tumors (84%) analyzed by immunohistochemistry were positive for the NF2 gene product, merlin. The findings suggest that allelic losses at 22q are associated with high mitotic activity and recurring disease, and that alterations in the NF2 gene are unlikely to participate in the pathogenesis of GIST.
Pylkkänen
Lea
L
Department of Industrial Hygiene, Finnish Institute of Occuapational Health, Helsinki, Finland.
Sarlomo-Rikala
Maarit
M
Wessman
Maija
M
Hämäläinen
Eija
E
Sainio
Markku
M
Husgafvel-Pursiainen
Kirsti
K
Carpén
Olli
O
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002892:Chromosomes, Human, Pair 22; D018572:Disease-Free Survival; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D017154:Stromal Cells / Q000473:pathology*
C000715470:MAS1 protein, human; D025581:Neurofibromin 2; D000090063:Proto-Oncogene Mas