High‐resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss

Abstract

Carcinoid tumors of the small intestine are characterized by an indolent clinical course, secretion of neuropeptides, and resistance to standard cytotoxic chemotherapy. To evaluate the molecular events underlying carcinoid tumorigenesis, we used high-resolution arrays of single nucleotide polymorphisms to study chromosomal gains and losses in 24 primary and metastatic small bowel carcinoid tumors derived from 18 patients. Regions of gain or loss comprising whole chromosomes or large chromosomal regions constituted the most common class of anomalies. Loss of all or most of chromosome 18 was the commonest finding, evident in 11 of the 18 cases. Heterozygosity was also lost on chromosome arms 9p and 16q. The amplitude of observed gains was modest in comparison to those reported in some other tumor types. One focal region of recurrent gain on 14q mapped to the locus of the gene encoding the antiapoptotic protein DAD1, and immunohistochemical staining confirmed DAD1 protein expression in tumor samples. This detailed study of an uncommon neoplasm provides a basis to investigate putative oncogenes and tumor suppressor genes in intestinal carcinoid tumors.

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

“…Only one of our patients displayed segmental loss on chromosome 18 (18q22.2-qter). This is in line with previous studies demonstrating losses of 18q12-qter, 18q21-qter, 18q21.1 or 18q22-qter in ileal carcinoids using chromosome-based CGH or SNP analysis (Zhao et al 2000, Kytölä et al 2001, Kulke et al 2008.…”

“…Candidate genes at 18q21.1 include SMAD2 and SMAD4, but to date sequencing of these genes has not revealed any mutations (Löllgen et al 2001, Kulke et al 2008.…”

“…Our knowledge about the genetic and epigenetic alterations that lead to ileal carcinoid formation is limited and pathogenetic mechanisms have not yet been identified. Several genes have been studied, but no mutations have been identified in TP53, KRAS, CTNNB1, CDKN2A, SMAD2, SMAD4 and BRAF (Weckström et al 1996, Younes et al 1997, Löllgen et al 2001, Chan et al 2003, Wang et al 2005, Kulke et al 2008. However, epigenetic changes such as genome-wide hypomethylation of LINE-1 and Alu-repetitive sequences and promoter hypermethylation of specific genes, i.e.…”

“…Using microsatellite markers, chromosome-based comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) analysis, recurrent copy number alterations (CNAs) have been identified. The most common CNA is loss of chromosome 18 (Terris et al 1998, Zhao et al 2000, Kytölä et al 2001, Löllgen et al 2001, Tönnies et al 2001, Stancu et al 2003, Wang et al 2005, Kim do et al 2008, Kulke et al 2008. Other recurrent CNAs include losses involving chromosomes 9, 11q and/or 16q, and gains involving chromosomes 4, 5, 7, 14 and/or 20.…”

“…Other recurrent CNAs include losses involving chromosomes 9, 11q and/or 16q, and gains involving chromosomes 4, 5, 7, 14 and/or 20. No correlations have so far been identified between CNAs and clinicopathological data, most likely because ileal carcinoids are rare tumours and the fact that previous studies have been based on small numbers and used low-resolution techniques (Kim do et al 2008, Kulke et al 2008.…”