Rozenblum E, Schutte M, Goggins M, Hahn S A, Panzer S, Zahurak M, Goodman S N, Sohn T A, Hruban R H, Yeo C J, Kern S E
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.
Cancer Res. 1997 May 1;57(9):1731-4.
During tumorigenesis, positive selection is exerted upon those tumor cells that alter rate-limiting regulatory pathways. A corollary of this principle is that mutation of one gene abrogates the need for alteration of another gene in the same pathway and also that the coexistence in a single tumor of mutations in different genes implies their involvement in distinct tumor-suppressive pathways. We studied 42 pancreatic adenocarcinomas for genetic alterations in the K-ras oncogene and the p16, p53, and DPC4 tumor suppressor genes. All of them had the K-ras gene mutated. Thirty-eight % of the tumors had four altered genes, another 38% had three altered genes, 15% had two altered genes, and 8% of the tumors had one altered gene. Interestingly, we noted a high concordance of DPC4 and p16 inactivations (P = 0.007), suggesting that the genetic inactivation of p16 increases the selective advantage of subsequent mutation in DPC4. No statistically significant association was identified between the alteration of these cancer genes and pathological or clinical parameters. This type of multigenic analysis in human tumors may serve to substantiate experimental tumor models and thus increase our understanding of the truly physiologically relevant tumor-suppressive pathways that are abrogated during human tumorigenesis.
在肿瘤发生过程中，正向选择作用于那些改变限速调节途径的肿瘤细胞。这一原则的必然结果是，一个基因的突变消除了同一途径中另一个基因发生改变的必要性，而且单个肿瘤中不同基因的突变共存意味着它们参与了不同的肿瘤抑制途径。我们研究了42例胰腺腺癌中K-ras癌基因以及p16、p53和DPC4肿瘤抑制基因的基因改变情况。所有病例均有K-ras基因突变。38%的肿瘤有4个基因改变，另外38%有3个基因改变，15%有2个基因改变，8%的肿瘤有1个基因改变。有趣的是，我们注意到DPC4和p16失活存在高度一致性（P = 0.007），这表明p16的基因失活增加了DPC4后续突变的选择优势。这些癌基因的改变与病理或临床参数之间未发现统计学上的显著关联。这种在人类肿瘤中的多基因分析可能有助于证实实验性肿瘤模型，从而增进我们对人类肿瘤发生过程中被废除的真正生理相关肿瘤抑制途径的理解。
