Genetics of neuroendocrine and carcinoid tumours.

Abstract

Neuroendocrine tumours (NETs) originate in tissues that contain cells derived from the embryonic neural crest, neuroectoderm and endoderm. Thus, NETs occur at many sites in the body, although the majority occur within the gastro-entero-pancreatic axis and can be subdivided into those of foregut, midgut and hindgut origin. Amongst these, only those of midgut origin are generally argentaffin positive and secrete serotonin, and hence only these should be referred to as carcinoid tumours. NETs may occur as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1), although the majority occur as non-familial (i.e. sporadic) isolated tumours. Molecular genetic studies have revealed that the development of NETs may involve different genes, each of which may be associated with several different abnormalities that include point mutations, gene deletions, DNA methylation, chromosomal losses and chromosomal gains. Indeed, the foregut, midgut and hindgut NETs develop via different molecular pathways. For example, foregut NETs have frequent deletions and mutations of the MEN1 gene, whereas midgut NETs have losses of chromosome 18, 11q and 16q and hindgut NETs express transforming growth factor-α and the epidermal growth factor receptor. Furthermore, in lung NETs, a loss of chromosome 3p is the most frequent change and p53 mutations and chromosomal loss of 5q21 are associated with more aggressive tumours and poor survival. In addition, methylation frequencies of retinoic acid receptor-β, E-cadherin and RAS-associated domain family genes increase with the severity of lung NETs. Thus the development and progression of NETs is associated with specific genetic abnormalities that indicate the likely involvement of different molecular pathways.

Array comparative genomic hybridization-based characterization of genetic alterations in pulmonary neuroendocrine tumors

“…Because carcinoids of GI origin may originate from midgut or hindgut embryologically (5), the chromosome 11q13 deletion was observed in only one of nine carcinoids of GI origin in our analysis. Our analysis was in agreement with the hypothesis of site-specific difference in the carcinogenesis of bronchial carcinoids and carcinoids of GI origin (14).…”

“…Zhao et al (42) reported on marked genomic imbalance differences between bronchial carcinoids and carcinoids of GI origin. The chromosome 11q13 deletion is a hallmark of multiple endocrine neoplasia type 1 (MEN-1)-related foregut carcinoids and was observed in 5 of 19 bronchial carcinoids in our analysis (13,14). Because carcinoids of GI origin may originate from midgut or hindgut embryologically (5), the chromosome 11q13 deletion was observed in only one of nine carcinoids of GI origin in our analysis.…”

Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers

“…First, the fact that arginine at AIP codon 16 is a highly conserved amino acid among species (Figure 2), second, from the possibility that an occult pituitary adenoma had been present in the MSS patient in which R16H was identified, one could speculate that such an occult PRL and GH-secreting adenoma may have promoted the breast enlargement, as well as the CRC. Third, the presence of carcinoid tumour in the brother of the MSI R16H-positive patient seems interesting; carcinoids are neuroendocrine tumours, which often occur as part of complex familial endocrine cancer syndromes, such as Multiple Endocrine Neoplasia Type 1 (Leotlela et al, 2003); however, no material was available for segregation studies of the R16H change in this family. Aryl hydrocarbon receptor interacting protein analyses in additional CRC cases and healthy controls would shed light on this possibility, and clarify whether or not R16H is associated with neoplasia.…”

Allelic alterations in well‐differentiated neuroendocrine tumors (carcinoid tumors) identified by genome‐wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors

“…The molecular mechanisms of WDNTs genesis are poorly understood but have been the focus of many recent reviews (Leotlela et al, 2003;Ö berg, 2005;Zikusoka et al, 2005) and reports of genetic and epigenetic alterations (Serrano et al, 2000;Lubomierski et al, 2001;Chan et al, 2003;Karnik et al, 2005;Wang et al, 2005;Yokoyama et al, 2005;Choi et al, 2007). There are site-specific differences among WDNTs from lung and various subsites of gastrointestinal tract, including clinicopathological features, behavior, and prognosis.…”