Jass J R, Young J, Leggett B A
Department of Pathology, The University of Queensland, and Conjoint Gastroenterology Laboratory, Royal Brisbane Hospital, Queensland, Australia.
Histopathology. 2000 Oct;37(4):295-301. doi: 10.1046/j.1365-2559.2000.01028.x.
Although the scientific and clinical rationale for classifying colorectal cancer according to mechanisms underlying genetic instability is well supported, little is known of the early morphogenesis of sporadic cancer showing high levels of DNA microsatellite instability (MSI-H). Evidence is accumulating that the traditional adenoma-carcinoma sequence may not apply to sporadic MSI-H colorectal cancer. The serrated pathway comprising hyperplastic polyps, mixed polyps and serrated adenomas may serve as the missing link. This review relates the recently described CpG island methylator phenotype (CIMP) to the serrated pathway. Two rate-limiting genetic steps may underlie the neoplastic pathway associated with CIMP. A transmembrane receptor expressed by pericryptal myofibroblasts (HPP1) may be implicated in the transition from normal to hyperplasia whereas inactivation of hMLH1 is responsible for the conversion of hyperplasia to dysplasia through loss of DNA mismatch repair. These mechanisms fit with clinical observations relating to sporadic MSI-H colorectal cancer, specifically proximal location, multiplicity, higher frequency among females and rapid evolution of early cancer.
尽管根据基因不稳定的潜在机制对结直肠癌进行分类的科学和临床依据得到了充分支持，但对于表现出高水平DNA微卫星不稳定（MSI-H）的散发性癌症的早期形态发生却知之甚少。越来越多的证据表明，传统的腺瘤-癌序列可能不适用于散发性MSI-H结直肠癌。由增生性息肉、混合性息肉和锯齿状腺瘤组成的锯齿状途径可能是缺失的环节。本综述将最近描述的CpG岛甲基化表型（CIMP）与锯齿状途径联系起来。两个限速遗传步骤可能是与CIMP相关的肿瘤发生途径的基础。隐窝周围肌成纤维细胞（HPP1）表达的一种跨膜受体可能与从正常到增生的转变有关，而hMLH1的失活则通过DNA错配修复的丧失导致增生向发育异常的转变。这些机制与散发性MSI-H结直肠癌的临床观察结果相符，特别是近端位置、多发性、女性中较高的发病率以及早期癌症的快速进展。
