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Loss of heterozygosity with acquisition of homozygous KIT-activating mutation promotes gastrointestinal stromal tumor progression.

9530 Background: Gastrointestinal stromal tumors (GISTs) originate from interstitial cells of Cajal and represent the most common mesenchymal tumor of GI tract. The activating mutations of KIT and platelet-derived growth factor receptor α (PDGFRA) have been demonstrated in 88% and 6% of GISTs respectively. Multiple genetic events are involved in tumor initiation and progression. Activation of an oncogene can result from a single hit of gain-of-function mutation, but two hits leading to loss of heterozygosity (LOH) are necessary for inactivation of a tumor suppressor gene for the initiation of neoplasia. Little is known about the significance and mechanism of LOH of oncogenes in tumor progression. The LOH of activating-oncogenes is not infrequent, i.e. in more than 8% of GIST. These GIST clones with LOH prevail and dominate, strongly suggestive of proliferative and metastatic advantages. However, the significance and mechanisms of LOH acquiring homozygous activating-oncogene mutation remain unknown.


METHODS
Genomic DNA and cDNA sequencing analysis of KIT, single-nucleotide polymorphisms (SNPs), immunohistochemistry of GISTs clones, and 3D structural analysis of the mutated KIT.


RESULTS
Real-time genetic studies in GIST show initial development of overexpression of KIT without mutation, to coexistence of various heterozygous-activating mutations; eventually, one clone dominates. Comparisons within the same patient show that clonal evolution from heterozygous to LOH acquiring homozygous (diploid) KIT-activating mutation results in dominance of the latter, with augmented KIT signaling and doubling of mitotic figures. Using SNPs for allelotyping, we found that mitotic nondisjunction, rather than mitotic recombination, represents an important mechanism of the second hit.


CONCLUSION
GIST clones with LOH acquiring homozygous KIT-activating mutation gain a selective advantage over the heterozygous counterpart. Mitotic nondisjunction, in addition to the commonly recognized mitotic recombination, is an important and perhaps the primary mechanism of LOH acquiring homozygous KIT-activating mutation during GIST progression. No significant financial relationships to disclose.