MicroGIST Genomic Aberrations Highlight Early Mechanisms in GIST Pathogenesis
CW Liang, S Rossi, AP Dei Tos, WC Foo, JA Fletcher. Cathay General Hospl, Taipei, Taiwan; Brigham and Women's Hospl, Boston, MA; General Hospl of Treviso, Treviso, Italy
Background: MicroGISTs (0.1-1 cm in diameter) are on a biological continuum with larger clinically-significant GISTs, and hence provide compelling models in which to study early oncogenic aberrations. However, in contrast to clinical GISTs (annual incidence ∼15 cases per million), most microGISTs (identified in 20-30% of the population) involute, becoming hyalinized and calcified, and rarely progress to symptomatic GIST. To determine biological relationships, between micro and macro GISTs, we characterized genomic alterations by sequencing and array CGH analyses.
Design: Analyses were performed on 32 microGISTs, ranging from 0.1 to 1 cm in diameter, with variable hyalinization, of which 28 were spindle-cell, and 2 each were epithelioid or mixed type. DNAs from microdissected microGISTs and adjacent normal tissues were sequenced for KIT and PDGFRA mutations and were analyzed in genome-wide screens by Agilent 400K array CGH, using four whole genome amplification pools from each sample.
Results: KIT mutations were identified in 26 microGISTs (81%) and PDGFRA exon 12 mutation was found in one microGIST. The KIT mutations were similar in type and exonic distribution to those reported in clinically-significant metastatic GISTs [e.g. exon 9 mutation in 4 cases; exon 13 mutation in 2 cases; exon 11 deletions involving amino acid 558 in 7 cases]. Novel mutations, never before reported in GIST, involving exons 9, 11, 13 and 18, were demonstrated in four microGISTs. Array CGH demonstrated monosomy 14 in three microGISTs, and the monosomy 14 in these cases (evaluated by interphase FISH) involved both hyalinized and cellular regions. Other array CGH aberrations, found in one microGIST, each, were monosomies 10, 15 and 22, and trisomy 2.
Conclusions: Certain KIT mutations are known to correlate with unfavorable natural history in GIST [exon 9, exon 11 amino acid 557-558 deletions]. Our studies show that these same mutations are frequent in microGISTs that rarely progress to clinically problematic lesions. Therefore, such mutations are not, in and of themselves, biological mechanisms of aggressive behavior. Likewise, we show that known recurrent cytogenetic aberrations in GIST, particularly monosomy 14, are well-entrenched in microGISTs with very low-likelihood of clinical progression, and are therefore necessary, but not sufficient, events in genetic progression towards malignancy.
Category: Bone & Soft Tissue
Monday, March 22, 2010 1:00 PM
Poster Session II # 27, Monday Afternoon