MOLECULAR-GENETIC STUDIES OF SPORADIC PITUITARY-TUMORS

Tumor formation may result from the activation of dominant oncogenes o r by inactivation of recessive, tumor suppressor genes. The role of su ch mutations in the development of pituitary tumors has been studied. Tumors from 88 patients, representing the 4 major classes of adenoma, were investigated. In DNA extracted from matched leukocyte and tumor s amples, allelic deletions were sought with 15 probes identifying restr iction fragment length polymorphisms on chromosomes 1, 5, 10, 11, 13, 17, 20, and 22. Evidence of amplification or rearrangement of 10 recog nized cellular oncogenes (N-ras, mycL1, mycN, myc, H-ros, bcl1, H-stf1 , sea, kraS2, and fos) was sought in tumor DNA. Activating dominant mu tations of G(s alpha) were detected using the polymerase chain reactio n to amplify exons 7-10 and hybridizing the product to normal and muta nt allele-specific oligonucleotides. Allelic deletions on chromosome 1 1 were identified in 16 tumors (18%) representing all 4 major subtypes . Deletions on other autosomes were observed in less than 6% of tumors . Three adenomas had deletions on multiple autosomes, 2 of these were aggressive and recurrent. Mutations of G(s alpha) were confirmed to be specific to somatotrophinomas, being identified in 36% of such tumors in this series. No evidence of amplification or rearrangement of othe r recognized cellular oncogenes was found. Inactivation of a recessive oncogene on chromosome 11 is an important and possibly early event in the development of the four major types of pituitary adenoma, whereas activating mutations of G(s alpha) are confirmed to be specific to so matotropinomas. Two aggressive tumors were found to have multiple auto somal losses, suggesting a multistep progression in the development of tumors of this phenotype.