Novel tumor suppressor gene loci on chromosomes 1p, 11q and 22q in insulinomas

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Endocrine pancreatic tumors (EPTs) comprise a highly heterogeneous group of tumors with different clinical behavior and genetic constitution. Insulinomas represent the predominant syndromic subtype of EPTs. Our previous molecular studies have shown that gain of chromosome 9q is an important early event in tumor development, and that chromosomal instability is associated with metastatic disease (Endocrine-Related Cancer 2005, 12:435-447). In order to identify new gene loci and further narrow down previously detected regions of involvement, we investigated 27 insulinomas by array-based comparative genomic hybridization on 3.7 k genomic BAC arrays (resolution ≤ 1 Mb). Fluorescence in situ hybridization (FISH) was used to validate alterations in a subset of insulinomas. Along with previously identified alterations of large chromosomal regions, such as 9pq gain in 47% of the cases, several additional novel copy number changes encompassing relatively small genomic regions were identified. Loss of chromosome 1p36 (54%), 11q23.2-25 (43%) and 22q11-13.33 (44%) were most frequently detected. Amplification at chromosome 9q22 was found in one malignant insulinoma. In addition, genomic complexity was strongly increased with enhanced disease-state, as determined by the average number of chromosomal alterations present. Our study highlights novel locations of putative tumor suppressor gene loci that may contribute to the pathogenesis of insulinomas. Supported by the Netherlands Foundations Vanderes and Sacha Swarttouw-Hijmans, and the Association for International Cancer Research (AICR), St. Andrews, UK.