Fogt Franz, Brown Charlotte A, Badizadegan Kamrari, Zimmerman Robert L, Odze Robert
Department of Pathology, University of Pennsylvania, Presbyterian Medical Center, 39th and Market Streets, Philadelphia, PA 19104, USA.
Am J Gastroenterol. 2004 Oct;99(10):2025-31. doi: 10.1111/j.1572-0241.2004.30502.x.
Juvenile polyps (JP) may develop sporadically or may be associated with the familial juvenile polyposis syndrome (FJPS). In FJPS, the epithelium is susceptible to dysplasia and, ultimately adenocarcinoma. However, the mechanisms involved in this transformation are unknown. Since the epithelium in colorectal carcinogenesis undergoes a stepwise genetic progression, the purpose of this study was to determine if loss of heterozygosity (LOH) abnormalities can aid in the differentiation between sporadic and FJPS-associated polyps.
Ninety-one routinely-processed JP from three groups of patients were evaluated for this study. Group 1 included 39 polyps from 39 patients with a single JP and no personal or family history of FJPS; group 2 consisted of 24 polyps from 15 patients with 2-5 JP and no history of FJPS; and group 3 included 29 polyps from 22 patients with > or =5 polyps either with (7) or without (15) a family history of FJPS. Epithelium from typical, atypical, and overtly dysplastic polyps, when present (2 cases in group 3 only), were evaluated separately by microdissection and PCR analysis for LOH of APC, p53, 3p, 9p, and mutations in exon 9 of the SMAD4 gene.
SMAD4 mutations were observed in 3 polyps from 2 patients in group 3 (10% of informative cases; p < 0.05 vs group 1), but not in any of the polyps from the other two groups. Overall, LOH of APC, p53, 3p, and 9p were detected in 1%, 15%, 10%, and 4% of JPs, but no differences were observed between the three clinical groups. Two polyps, both in group 3, with definite dysplasia did not show any genetic alterations. The morphologic appearance of the polyps was not a reliable feature in helping to differentiate sporadic from FJPS-associated polyps.
LOH of APC, p53, 3p, and 9p may not be involved in the carcinogenic pathway of FJPS-associated polyps. SMAD4 gene mutations show a low sensitivity but a high specificity for FJPS.
幼年性息肉（JP）可散发发生，也可能与家族性幼年性息肉病综合征（FJPS）相关。在FJPS中，上皮细胞易发生发育异常，并最终发展为腺癌。然而，这种转变所涉及的机制尚不清楚。由于结直肠癌发生过程中的上皮细胞经历了逐步的基因进展，本研究的目的是确定杂合性缺失（LOH）异常是否有助于鉴别散发性息肉和与FJPS相关的息肉。
本研究评估了来自三组患者的91个常规处理的JP。第1组包括来自39例仅有单个JP且无FJPS个人或家族史患者的39个息肉；第2组由来自15例有2 - 5个JP且无FJPS病史患者的24个息肉组成；第3组包括来自22例有≥5个息肉且有（7例）或无（15例）FJPS家族史患者的29个息肉。对典型、非典型和明显发育异常的息肉（仅第3组中有2例）的上皮细胞进行显微切割和PCR分析，以检测APC、p53、3p、9p的LOH以及SMAD4基因第9外显子的突变。
在第3组的2例患者的3个息肉中观察到SMAD4突变（占信息性病例的10%；与第1组相比，p < 0.05），但在其他两组的任何息肉中均未观察到。总体而言，在1%、15%、10%和4%的JP中检测到APC、p53、3p和9p的LOH，但三个临床组之间未观察到差异。第3组中两个有明确发育异常的息肉未显示任何基因改变。息肉的形态外观在帮助鉴别散发性息肉和与FJPS相关的息肉方面不是一个可靠的特征。
APC、p53、3p和9p的LOH可能不参与与FJPS相关息肉的致癌途径。SMAD4基因突变对FJPS显示出低敏感性但高特异性。
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