鉴定出携带 TP53 突变的结直肠癌患者，该突变位于密码子 72 脯氨酸等位基因上，这些患者从基于 5-氟尿嘧啶（5-FU）的术后化疗中获益最大。
Identification of colorectal cancer patients with tumors carrying the TP53 mutation on the codon 72 proline allele that benefited most from 5-fluorouracil (5-FU) based postoperative chemotherapy.
机构信息
Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, 1-1-2 Nakao, Asahi-ku, Yokohama, Japan.
出版信息
BMC Cancer. 2009 Dec 2;9:420. doi: 10.1186/1471-2407-9-420.
BACKGROUND
Although postoperative chemotherapy is widely accepted as the standard modality for Dukes' stage C or earlier stage colorectal cancer (CRC) patients, biomarkers to predict those who may benefit from the therapy have not been identified. Previous in vitro and clinical investigations reported that CRC patients with wild-type p53 gene (TP53)-tumors benefit from 5-fluorouracil (5-FU) based chemotherapy, while those with mutated TP53-tumors do not. However, these studies evaluated the mutation-status of TP53 by immunohistochemistry with or without single-strand conformation polymorphism, and the mutation frequency was different from study to study. In addition, the polymorphic status at p53 codon 72, which results in arginine or proline residues (R72P) and is thought to influence the function of the protein significantly, was not examined.
METHODS
To evaluate the significance of the TP53 mutation as a molecular marker to predict the prognosis of CRC patients, especially those who received postoperative chemotherapy, we examined the mutation by direct sequencing from fresh CRC tumors and evaluated the R72P polymorphism of the mutated TP53 by a combined mutant allele- and polymorphic allele-specific polymerase chain reaction (PCR).
RESULTS
The TP53 mutation occurred in 147 (70%) of 211 Japanese CRC tumors. The mutation was observed in 93 (63%) tumors on the R72 allele and in 54 (37%) tumors on the P72 allele. Although the alterations to TP53 have no prognostic significance for CRC patients overall, we found that Dukes' stage C CRC patients who did not receive postoperative chemotherapy and carried the mutated TP53-R72 showed significantly longer survival times than those with the mutated TP53-P72 when evaluated by overall survival (p = 0.012).
CONCLUSION
Using a combined mutant allele- and polymorphic allele-specific PCR, we defined the codon 72 polymorphic status of the TP53 mutated allele in Japanese CRC patients. We raised a possibility that Dukes' stage C colorectal cancer patients with tumors carrying TP53 mutation, especially the P72 allele, benefited from 5-FU based postoperative chemotherapy.
背景
尽管术后化疗被广泛认为是 Dukes' 期 C 或更早阶段结直肠癌（CRC）患者的标准治疗模式，但尚未确定预测哪些患者可能受益于该治疗的生物标志物。先前的体外和临床研究报告称，野生型 p53 基因（TP53）-肿瘤的 CRC 患者从基于 5-氟尿嘧啶（5-FU）的化疗中获益，而突变型 TP53-肿瘤的患者则不然。然而，这些研究通过免疫组织化学（IHC）或单链构象多态性（SSCP）评估了 TP53 的突变状态，且突变频率因研究而异。此外，p53 密码子 72 处的多态性（导致精氨酸或脯氨酸残基（R72P），并被认为会显著影响蛋白质的功能）未被检测到。
方法
为了评估 TP53 突变作为预测 CRC 患者（尤其是接受术后化疗的患者）预后的分子标志物的意义，我们直接从新鲜 CRC 肿瘤中测序以检查 TP53 突变，并通过突变等位基因和多态性等位基因特异性聚合酶链反应（PCR）评估突变 TP53 的 R72P 多态性。
结果
在 211 例日本 CRC 肿瘤中，TP53 突变发生在 147 例（70%）中。在 R72 等位基因上观察到 93 例（63%）肿瘤中的突变，在 P72 等位基因上观察到 54 例（37%）肿瘤中的突变。尽管 TP53 的改变对 CRC 患者的整体预后没有意义，但我们发现 Dukes' 期 C CRC 患者未接受术后化疗且携带突变型 TP53-R72 时，总生存期（OS）评估的生存时间明显长于携带突变型 TP53-P72（p=0.012）。
结论
我们使用突变等位基因和多态性等位基因特异性 PCR 联合定义了日本 CRC 患者 TP53 突变等位基因的密码子 72 多态性。我们提出了一种可能性，即携带 TP53 突变的 Dukes' 期 C 结直肠癌患者，特别是 P72 等位基因，可能从基于 5-FU 的术后化疗中获益。
Zotero 插件