Nakamura Y, Nishisho I, Kinzler K W, Vogelstein B, Miyoshi Y, Miki Y, Ando H, Horii A, Nagase H
Department of Biochemistry, Cancer Institute, Tokyo, Japan.
Princess Takamatsu Symp. 1991;22:285-92.
We have isolated several genes in the chromosome 5q21 region tightly linked to hereditary familial polyposis coli (FAP) and Gardner's syndrome (GS). Two of these genes (MCC and APC) were found to be somatically altered by point mutation, deletion or insertion in tumors of sporadic colorectal cancer patients. One of them (adenomatous polyposis coli; APC) was also found to mutate in the germ-line of both APC and GS patients. The identification of these genes has significant implications for understanding the pathogenesis of colorectal neoplasia and for the diagnosis and counseling of individuals with inherited predispositions to colorectal cancer. Furthermore, in one colon carcinoma, we identified an interesting mechanism causing dysfunction of the APC gene. This gene was disrupted by a somatic insertion of a long interspersed repetitive element (LINE-1 sequence: L1) into the last exon. As an insertional sequence contains a 3' portion of the L1 consensus sequence including the poly(A) tract and an 8 bp target-site duplication was observed, this insertion is suspected to be caused by a retrotranscriptional insertion of one of the L1 sequences. This is the first case of the disruption of a tumor suppressor gene by the insertion of a movable genetic element.
我们已经在5号染色体q21区域分离出了几个与遗传性家族性结肠息肉病（FAP）和加德纳综合征（GS）紧密连锁的基因。在散发性结直肠癌患者的肿瘤中，发现其中两个基因（MCC和APC）因点突变、缺失或插入而发生体细胞改变。其中一个基因（腺瘤性息肉病基因；APC）在APC和GS患者的生殖系中也发生了突变。这些基因的鉴定对于理解结直肠癌的发病机制以及对有遗传性结直肠癌易感性个体的诊断和咨询具有重要意义。此外，在一例结肠癌中，我们发现了一种导致APC基因功能障碍的有趣机制。该基因因一个长散在重复元件（LINE-1序列：L1）体细胞插入到最后一个外显子中而被破坏。由于插入序列包含L1共有序列的3'部分，包括聚腺苷酸尾，并且观察到一个8bp的靶位点重复，因此怀疑这种插入是由L1序列之一的逆转录插入引起的。这是可移动遗传元件插入导致肿瘤抑制基因破坏的首例。
