Section 4 -

Genetic and Epigenetic Alterations in Well-Differentiated Neuroendocrine Tumors Editor: Ricardo Lloyd, M.D. Asif Rashid, M.B.B.S., Ph.D. The University of Texas M. D. Anderson Cancer Center Houston, TX

Pancreatic endocrine tumors and carcinoid tumors are both uncommon, indolent well-differentiated neuroendocrine neoplasms with an age-adjusted annual incidence of less than 5 per 100,000. [1, 2] Neuroendocrine tumors are divided by their embryological site of origin into foregut carcinoid tumors, comprising tumors from the lung, stomach, duodenum and pancreas; midgut carcinoid tumors, comprising tumors from the jejunum, ileum, appendix and right colon; and hindgut carcinoid tumors, comprising tumors from the left colon and rectum. Tumors originating from the midgut are most common, with the majority located in the ileum. [1, 2] However, there is heterogeneity among the neuroendocrine tumors of various subsites, including clinicopathologic features, clinical behavior and genetic alterations. For example, the majority of appendiceal carcinoid tumors have a benign course, but the majority of ileal carcinoid tumors have metastasis at presentation. The molecular mechanisms of neuroendocrine tumorigenesis are poorly understood. Multiple endocrine neoplasia type-1 (MEN1) is an autosomal dominantly inherited disorder characterized by the development of multiple endocrine tumors including pancreatic endocrine tumors. [3, 4, 5] MEN1 results from germline mutations of MEN1, a 10-exon gene located on chromosome 11q13 that encodes for menin, a 610-amino-acid protein. [3, 6, 7, 8] Recent studies suggest menin regulates the transcription of multiple differentiation-regulating genes in association with a histone methyltransferase complex. [9] Mutations of the MEN1 gene and allelic loss of chromosome 11q13 are reported in sporadic carcinoid tumors and sporadic pancreatic endocrine tumors. [6, 10, 11] Patients with von Hippel Lindau disease have pancreatic endocrine tumors, but mutations of von Hippel Lindau gene are rarely present in sporadic neuroendocrine tumors. [12, 13] Comparative genomic hybridization analysis has shown that the chromosomal aberrations differ among the tumors of different subsites and pancreatic endocrine tumors have more chromosomal aberrations compared to pulmonary and gastrointestinal carcinoid tumors. [14, 15, 16] By comparative genomic hybridization pancreatic endocrine tumors have frequent loss of chromosomes 2, 3, 6, 10, 11, Xq and Y and gain of chromosomes 4, 5, 7, 9q, 12q, 14q, 17q, 18q, 20q and Xp. [15, 16, 17, 18, 19] These chromosomal aberrations were more frequent in the metastasis than primary tumors, malignant tumors than benign tumors, non-functioning tumors than the functioning tumors and in tumors more than 2 cm in size. [17, 18, 19] Gain of chromosomes 4, 7 and 21q was more frequent in the metastasis than in the corresponding primary tumor. [18] In contrast, gastrointestinal carcinoid tumors (predominately from ileum) had frequent loss of chromosome 18 and pulmonary carcinoid tumors had frequent loss of 11q. [20] Loss of chromosome 9p, 11q and 16q and gain of chromosomes 4, 5, 17q, 19 and 20q are other chromosomal aberrations frequently present in midgut carcinoid tumors. [14, 15, 16, 20] Allelic loss of chromosomes 2p, 6q, 10p, 11, 20q and 21 was frequent in pancreatic endocrine tumors by analysis using microsatellite markers [21]. Chromosomal regions on chromosomes 3p and 6q were deleted in pancreatic endocrine tumors and were more common in malignant tumors [22, 23]. In contrast, midgut carcinoid tumors (predominately from ileum) had frequent loss of chromosome 18 and infrequent loss of 11q and 16q [24, 25]. Allelic loss of chromosomes 11q and X has been reported in pulmonary carcinoid tumors [26, 27]. The localization of these chromosomal aberrations by comparative genomic hybridization and microsatellite analysis has not translated into identification of potential oncogenes and tumor suppressor genes in sporadic neuroendocrine tumors with the exception of MEN-1 gene alterations in sporadic foregut carcinoid tumors and pancreatic endocrine tumors. [6, 10, 11] Inactivation of p14 (ARF) and p16 (INK4a) tumor suppressor genes in pancreatic endocrine tumors and carcinoid tumors were not due to mutations but predominately due to methylation and uncommonly due to allelic loss. [28, 29] However, mutations of other oncogenes and tumor suppressor genes present at these loci of chromosomal aberrations were either not present, including smad4 gene [30] or different studies had conflicting results, including b -catenin [29, 31] and succinate-ubiqinone oxidoreductase subunit D [32, 33] genes. Methylation of p14 (ARF), p16 (INK4a), O [6]-methyl-guanine methyltransferase (MGMT) and ras association domain family 1A (RASSF1A) genes have been reported in pancreatic endocrine tumors and carcinoid tumors from lung and gastrointestinal tract. [29, 34, 35, 36, 37, 38] The methylation profile of neuroendocrine tumors from lung, gastrointestinal tract and pancreas differ from each other. [29, 34, 35, 36, 37, 38] Methylation of p16 and RASSF1A genes were associated with liver and lymph node metastasis in patients with pancreatic endocrine tumors and carcinoid tumors. [38] Methylation of p16 gene or methylation of three or more genes was associated with poor survival of patients with pancreatic endocrine tumors. [36] The low-grade neuroendocrine tumors of lung, pancreas, and subsites of gastrointestinal tract are indolent and share histological similarities, but these tumors have site-specific differences in the genetic and epigenetic alterations. References Modlin IM, Lye KD, Kidd M. 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