Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract

Silvia Pizzi, Cinzia Azzoni, Daniela Bassi, Lorena Bottarelli, Massimo Milione, Cesare Bordi

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

BACKGROUND. The molecular pathogenesis of poorly differentiated endocrine carcinomas of the gastrointestinal tract (GI PDECs) remains unclear. It has been suggested that these lesions either originate from multipotent stem cells that also can serve as the origin of nonendocrine adenocarcinomas or arise due to the dedifferentiation of well-differentiated endocrine carcinomas (WDECs). METHODS. Ten gastric and 9 colorectal PDECs, 9 gastric WDECs, and 12 colorectal carcinomas (CRCs) were analyzed for loss of heterozygosity (LOH) at 11q13 (MEN1), 17p13.1 (p53), 3p14.2 (FHIT), 3p21.3 (RASSF1A), and 18q23 (DCC/DPC4/ Smad2), and for immunohistochemical expression of p53, FHIT, Rb, and p16. RESULTS. PDECs exhibited high fractional allelic loss (FAL; 0.49), with frequent (> 40%) alterations in p53, Rb, MEN1, FHIT, and 18q. No significant differences were found between gastric and colorectal PDECs. Gastric WDECs also exhibited high FAL (0.44), with frequent alterations in Rb and/or p16, MEN1, and 3p21. CRCs exhibited a low level of FAL (0.23), with frequent (> 50%) p16 and p53 alterations. When gastric PDECs and WDECs were compared, substantial similarities were found with respect to FAL (0.42 vs. 0.44) and with respect to individual gene alterations, except in p53, which was consistently altered only in PDECs. CRCs, which were characterized by a lower FAL (0.56 vs. 0.23) and which lacked alterations in both 3p and Rb, were found to be significantly different from colorectal PDECs. CONCLUSIONS. GI PDECs demonstrated a high level of chromosomal instability; consistent inactivation of both the p53 and p16/Rb pathways; and frequent LOH at 3p (possibly involving FHIT), the MEN1 locus, and 18q. The profile of genetic alterations in PDECs was more consistent with the profile in WDECs than with the profile in CRCs.

Original languageEnglish
Pages (from-to)1273-1282
Number of pages10
JournalCancer
Volume98
Issue number6
DOIs
Publication statusPublished - Sep 15 2003

Fingerprint

Multiple Endocrine Neoplasia Type 1
Gastrointestinal Tract
Stomach
Carcinoma
Loss of Heterozygosity
Colorectal Neoplasms
Multipotent Stem Cells
Chromosomal Instability
Adenocarcinoma
Genes

Keywords

  • Colorectal carcinoma
  • Endocrine tumors
  • FHIT protein
  • Gastrointestinal tract
  • Immunohistochemistry
  • Loss of heterozygosity
  • MEN1
  • p16 protein
  • p53 gene and p53 protein
  • Rb protein

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract. / Pizzi, Silvia; Azzoni, Cinzia; Bassi, Daniela; Bottarelli, Lorena; Milione, Massimo; Bordi, Cesare.

In: Cancer, Vol. 98, No. 6, 15.09.2003, p. 1273-1282.

Research output: Contribution to journalArticle

Pizzi, S, Azzoni, C, Bassi, D, Bottarelli, L, Milione, M & Bordi, C 2003, 'Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract', Cancer, vol. 98, no. 6, pp. 1273-1282. https://doi.org/10.1002/cncr.11621
Pizzi, Silvia ; Azzoni, Cinzia ; Bassi, Daniela ; Bottarelli, Lorena ; Milione, Massimo ; Bordi, Cesare. / Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract. In: Cancer. 2003 ; Vol. 98, No. 6. pp. 1273-1282.
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abstract = "BACKGROUND. The molecular pathogenesis of poorly differentiated endocrine carcinomas of the gastrointestinal tract (GI PDECs) remains unclear. It has been suggested that these lesions either originate from multipotent stem cells that also can serve as the origin of nonendocrine adenocarcinomas or arise due to the dedifferentiation of well-differentiated endocrine carcinomas (WDECs). METHODS. Ten gastric and 9 colorectal PDECs, 9 gastric WDECs, and 12 colorectal carcinomas (CRCs) were analyzed for loss of heterozygosity (LOH) at 11q13 (MEN1), 17p13.1 (p53), 3p14.2 (FHIT), 3p21.3 (RASSF1A), and 18q23 (DCC/DPC4/ Smad2), and for immunohistochemical expression of p53, FHIT, Rb, and p16. RESULTS. PDECs exhibited high fractional allelic loss (FAL; 0.49), with frequent (> 40{\%}) alterations in p53, Rb, MEN1, FHIT, and 18q. No significant differences were found between gastric and colorectal PDECs. Gastric WDECs also exhibited high FAL (0.44), with frequent alterations in Rb and/or p16, MEN1, and 3p21. CRCs exhibited a low level of FAL (0.23), with frequent (> 50{\%}) p16 and p53 alterations. When gastric PDECs and WDECs were compared, substantial similarities were found with respect to FAL (0.42 vs. 0.44) and with respect to individual gene alterations, except in p53, which was consistently altered only in PDECs. CRCs, which were characterized by a lower FAL (0.56 vs. 0.23) and which lacked alterations in both 3p and Rb, were found to be significantly different from colorectal PDECs. CONCLUSIONS. GI PDECs demonstrated a high level of chromosomal instability; consistent inactivation of both the p53 and p16/Rb pathways; and frequent LOH at 3p (possibly involving FHIT), the MEN1 locus, and 18q. The profile of genetic alterations in PDECs was more consistent with the profile in WDECs than with the profile in CRCs.",
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T1 - Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract

AU - Pizzi, Silvia

AU - Azzoni, Cinzia

AU - Bassi, Daniela

AU - Bottarelli, Lorena

AU - Milione, Massimo

AU - Bordi, Cesare

PY - 2003/9/15

Y1 - 2003/9/15

N2 - BACKGROUND. The molecular pathogenesis of poorly differentiated endocrine carcinomas of the gastrointestinal tract (GI PDECs) remains unclear. It has been suggested that these lesions either originate from multipotent stem cells that also can serve as the origin of nonendocrine adenocarcinomas or arise due to the dedifferentiation of well-differentiated endocrine carcinomas (WDECs). METHODS. Ten gastric and 9 colorectal PDECs, 9 gastric WDECs, and 12 colorectal carcinomas (CRCs) were analyzed for loss of heterozygosity (LOH) at 11q13 (MEN1), 17p13.1 (p53), 3p14.2 (FHIT), 3p21.3 (RASSF1A), and 18q23 (DCC/DPC4/ Smad2), and for immunohistochemical expression of p53, FHIT, Rb, and p16. RESULTS. PDECs exhibited high fractional allelic loss (FAL; 0.49), with frequent (> 40%) alterations in p53, Rb, MEN1, FHIT, and 18q. No significant differences were found between gastric and colorectal PDECs. Gastric WDECs also exhibited high FAL (0.44), with frequent alterations in Rb and/or p16, MEN1, and 3p21. CRCs exhibited a low level of FAL (0.23), with frequent (> 50%) p16 and p53 alterations. When gastric PDECs and WDECs were compared, substantial similarities were found with respect to FAL (0.42 vs. 0.44) and with respect to individual gene alterations, except in p53, which was consistently altered only in PDECs. CRCs, which were characterized by a lower FAL (0.56 vs. 0.23) and which lacked alterations in both 3p and Rb, were found to be significantly different from colorectal PDECs. CONCLUSIONS. GI PDECs demonstrated a high level of chromosomal instability; consistent inactivation of both the p53 and p16/Rb pathways; and frequent LOH at 3p (possibly involving FHIT), the MEN1 locus, and 18q. The profile of genetic alterations in PDECs was more consistent with the profile in WDECs than with the profile in CRCs.

AB - BACKGROUND. The molecular pathogenesis of poorly differentiated endocrine carcinomas of the gastrointestinal tract (GI PDECs) remains unclear. It has been suggested that these lesions either originate from multipotent stem cells that also can serve as the origin of nonendocrine adenocarcinomas or arise due to the dedifferentiation of well-differentiated endocrine carcinomas (WDECs). METHODS. Ten gastric and 9 colorectal PDECs, 9 gastric WDECs, and 12 colorectal carcinomas (CRCs) were analyzed for loss of heterozygosity (LOH) at 11q13 (MEN1), 17p13.1 (p53), 3p14.2 (FHIT), 3p21.3 (RASSF1A), and 18q23 (DCC/DPC4/ Smad2), and for immunohistochemical expression of p53, FHIT, Rb, and p16. RESULTS. PDECs exhibited high fractional allelic loss (FAL; 0.49), with frequent (> 40%) alterations in p53, Rb, MEN1, FHIT, and 18q. No significant differences were found between gastric and colorectal PDECs. Gastric WDECs also exhibited high FAL (0.44), with frequent alterations in Rb and/or p16, MEN1, and 3p21. CRCs exhibited a low level of FAL (0.23), with frequent (> 50%) p16 and p53 alterations. When gastric PDECs and WDECs were compared, substantial similarities were found with respect to FAL (0.42 vs. 0.44) and with respect to individual gene alterations, except in p53, which was consistently altered only in PDECs. CRCs, which were characterized by a lower FAL (0.56 vs. 0.23) and which lacked alterations in both 3p and Rb, were found to be significantly different from colorectal PDECs. CONCLUSIONS. GI PDECs demonstrated a high level of chromosomal instability; consistent inactivation of both the p53 and p16/Rb pathways; and frequent LOH at 3p (possibly involving FHIT), the MEN1 locus, and 18q. The profile of genetic alterations in PDECs was more consistent with the profile in WDECs than with the profile in CRCs.

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KW - Endocrine tumors

KW - FHIT protein

KW - Gastrointestinal tract

KW - Immunohistochemistry

KW - Loss of heterozygosity

KW - MEN1

KW - p16 protein

KW - p53 gene and p53 protein

KW - Rb protein

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