Pizzi Silvia, Azzoni Cinzia, Bassi Daniela, Bottarelli Lorena, Milione Massimo, Bordi Cesare
Department of Pathology and Laboratory Medicine, University of Parma, Parma, Italy.
Cancer. 2003 Sep 15;98(6):1273-82. doi: 10.1002/cncr.11621.
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).
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.
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.
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.
胃肠道低分化内分泌癌（GI PDECs）的分子发病机制仍不清楚。有人提出，这些病变要么起源于多能干细胞，而多能干细胞也可作为非内分泌腺癌的起源，要么是由于高分化内分泌癌（WDECs）的去分化所致。
分析了10例胃和9例结直肠PDECs、9例胃WDECs以及12例结直肠癌（CRCs）在11q13（MEN1）、17p13.1（p53）、3p14.2（FHIT）、3p21.3（RASSF1A）和18q23（DCC/DPC4/Smad2）处的杂合性缺失（LOH），以及p53、FHIT、Rb和p16的免疫组化表达。
PDECs表现出较高的等位基因缺失分数（FAL；0.49），p53、Rb、MEN1、FHIT和18q频繁（>40%）改变。胃和结直肠PDECs之间未发现显著差异。胃WDECs也表现出较高的FAL（0.44），Rb和/或p16、MEN1和3p21频繁改变。CRCs表现出较低水平的FAL（0.23），p16和p53频繁（>50%）改变。当比较胃PDECs和WDECs时，发现FAL（0.42对0.44）以及单个基因改变方面存在实质性相似性，但p53除外，p53仅在PDECs中持续改变。CRCs的特征是FAL较低（0.56对0.23），且3p和Rb均无改变，发现其与结直肠PDECs有显著差异。
GI PDECs表现出高水平的染色体不稳定性；p53和p16/Rb途径均持续失活；3p（可能涉及FHIT）、MEN1位点和18q频繁出现LOH。PDECs的基因改变谱与WDECs的谱比与CRCs的谱更一致。
