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Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract
Author(s) -
Pizzi Silvia,
Azzoni Cinzia,
Bassi Daniela,
Bottarelli Lorena,
Milione Massimo,
Bordi Cesare
Publication year - 2003
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.11621
Subject(s) - loss of heterozygosity , fhit , men1 , cancer research , biology , adenocarcinoma , microsatellite instability , pathology , multiple endocrine neoplasia , gastrointestinal tract , cancer , endocrine system , colorectal cancer , medicine , allele , tumor suppressor gene , gene , carcinogenesis , genetics , hormone , microsatellite
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. Cancer 2003;98:1273–82. © 2003 American Cancer Society. DOI 10.1002/cncr.11621