Integrated mutation analysis in colorectal cancer

近年来的研究表明，apc、ras、p53、微卫星不稳定性等多种基因变化与结直肠癌的发生有关。我们在我院切除的许多临床样本中分析了这些基因突变，并研究了结直肠癌的发病机制、细胞凋亡机制和放化疗敏感性。在“所谓的”非息肉样癌中；对63例腺瘤（息肉样31例，浅表升高17例，浅表低下15例）、66例sm癌（息肉样47例，非息肉样19例）和34例晚期癌进行K-ras密码子12点突变和突变簇区的APC突变检测。K-ras突变：浅表凹陷性腺瘤的频率低于息肉样性腺瘤（0%比31%:p=0.018）。非息肉样癌的发生率低于息肉样癌（11% vs. 56%: p=0.0008），而息肉样腺瘤的发生率相对较低（11% vs. 31%）。浅表凹陷性腺瘤发生率低于息肉样腺瘤（7% vs. 43%: p=0.016），息肉样癌发生率与非息肉样癌相似。在这个非息肉样通路中，APC突变似乎是必需的，而K-ras突变则不是。可能在浅表抑郁性腺瘤发生后获得新的APC突变。转染反义Bcl-XL，而不转染Bcl-2，可显著提高结直肠癌细胞对5-Fu的敏感性。这表明通过Bcl-XL抑制细胞凋亡与5- fu的作用密切相关。用免疫组化方法检测直肠癌手术标本中的P53和p21。p21的表达与术前放疗敏感性相关，而p53的表达与术前放疗敏感性无关。这支持放射治疗p21阳性晚期直肠癌的有效性。

Recent studies have shown that many genetic changes such as apc, ras, p53 and microsattelite instability, were involved in the development of colorectal cancers. We analyzed those genetic mutations in many clinical samples resected in our institute, and examined the mechanisms of colorectal cancer, and apotosis mechanisms and radiochemosensitivity.1. In "so called" non-polypoid cancer ; DNA from 63 adenomas (31 polypoid, 17 superficial elevated, 15 superficial depressed), 66 sm carcinomas (47 polypoid, 19non-polypoid) and 34 advance carcinomas were examined for K-ras codon 12 point mutations and APC mutations in the mutation cluster region. K-ras mutation : The frequency in superficial depressed adenomas was lower than that in polypoid adenomas (0% vs. 31% : p=0.018). The frequency in non-polypoid carcinomas was lower than that in polypoid carcinomas (11% vs. 56% : p=0.0008), and was relatively low compared with that in polypoid adenomas (11% vs. 31%). The frequency in superficial depressed adenomas was lower than that in polypoid adenomas (7% vs. 43% : p=0.016), and that in polypoid carcinomas was similar to that in non-polypoid carcinomas. In this non-polypoid pathway, APC mutation seems to be requisite, but K-ras mutation not. It is possible that new APC mutations are acquired after the development of superficial depressed adenomas.2. Transfection of antisense of Bcl-XL, but not of Bcl-2, significantly increased the sensitivity to 5-Fu in colorectal cancer cells. This indicates suppression of apotosis through Bcl-XL is critically involved in the effects of 5-Fu.3. P53 and p21 were examined in surgical specimens of rectal cancers immunohistocchemically. The expression of p21, but not of p53, was sell correlated with the sensitivity of preoperative irradiation. This supports the effectiveness of the radiation therapy with p21 positive advanced rectal cancers.