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结肠癌第二期復发患者可见独特的基因档案
密苏里州圣路易市召开的美国结肠暨直肠外科医师学会年会中所发表的资料指出，结肠癌第二期的復发似乎与特定的基因及生物路径有关，运用这些基因档案来预测哪些患者是復发的高风险群，而哪些能从额外的治疗中获得改善，是大有可為的。
　　
　　美国每年诊断出的结肠直肠癌的病例中，第二期疾患佔了近三分之一；资深作家David Shibata医师於访谈中向Medscape表示，约有80%的病例可经由手术而治癒，而剩下的患者在预后上则不尽理想；对於结肠癌第二期患者的最佳疗法仍有许多不确定性，致使医疗照护上的差异性颇大。
　　
　　Shibata医师表示，医界已确知化疗有益於结肠直肠癌第三期的患者，因此，医界对於辨别哪些第二期的患者将能从主动的预防性化疗（adjuvant therapy）中获益，而抱持高度的研究兴趣；Shibata医师為美国佛罗里达州坦帕市H. Lee Moffitt治癌中心暨研究机构外科及肿瘤科副教授。
　　
　　Shibata医师指出，来自随机型对照试验的大多证据并不支持这类患者例行地接受主动的预防性化疗，但接受手术切除的患者中，约有20%仍持续承受疾病復发及死亡率的苦痛；以组织病理辅助诊断為基础来预测结肠癌第二期的復发率，并非100%準确。
　　
　　这项研究的目标，是试图在临床和基因表现档案与结肠直肠癌第二期患者的治疗结果之间找出关联性，并辨别出与復发相关的个别基因及特定生物路径；研究人员分析取自於1993至2003年间的结肠直肠癌患者之肿瘤组织检体。美国Affymetrix公司的Affymetrix 133 Plus 2.0型基因晶片，可从各种不同的细胞类型和组织中检测出独特的基因表现，进而在肿瘤检体中找出超过30,000个可供研究的基因。
　　
　　Shibata医师及研究同仁诊察出54名结肠癌第二期的病患，其中有9人曾在切除手术后有疾病復发的状况；他解释道，此组患者的状况并不寻常，9名患者中有8人无转移性疾患，但却有局部疾患的復发。
　　
　　有疾患復发和无疾患復发的患者之间，在癌细胞分化、黏液性组织学及淋巴血管系统的侵袭上，没有显著差异；研究人员发现，相较於无疾患復发的患者，后续復发肿瘤的患者，显示出共有40个往上调节型（upregulated）的基因，其中并无往下调节型（downregulated）的基因；最受影响的基因倾向於与细胞骨架完整性（cytoskeletal integrity）、微血管增渗酶蛋白质分解（kallikrein proteolysis）、及葡萄糖传输（glucose transport）中的改变有关；与肿瘤生成（tumorigenesis）有关的数个已识别出基因，亦与乳癌及卵巢癌的往上调节型基因有关。
　　
　　Shibata医师表示，其基因档案是以在卵巢癌中呈现出的数个基因為主；CA125是最常用的卵巢癌诊断抗原之一，我们发现它是明显的往上调节型。
　　
　　另一个例子则是在微血管增渗酶蛋白质分解中所看到的改变；Shibata医师解释，人类微血管增渗酶基因家族中的许多基因，会在卵巢癌中產生差异性调节并表现出来。
　　
　　Shibata医师表示，局部復发的癌症可能与卵巢癌细胞档案有著相同的组成，这些资料相当具有前瞻性。
　　
　　研究人员总结指出，其研究是针对临床及遗传面向确诊之结肠癌第二期患者的全面性资料评估，识别出与第二期疾患復发有关之一组独特基因和特定生物路径，同时在预测哪些患者是手术切除后再做主动预防性化疗的最佳人选，可能是有用的。
　　
　　美国结肠暨直肠外科医师学会年会：会议摘要S12，2007年6月4日发表。

Distinct Genetic Profiles Seen in Patients with Recurrences of Stage II Colon Cancer


Certain genes and specific biologic pathways appear to be associated with disease recurrence in stage II colorectal cancer, according to data presented at the annual meeting of the American Society of Colon and Rectal Surgeons, in St. Louis, Missouri. It may be possible to use these genetic profiles to predict which patients are at risk for recurrence and may benefit from additional therapy.

Stage II disease accounts for approximately one-third of the cases of colorectal cancer diagnosed annually in the United States. \"While surgery is curative in about 80% of cases, the prognosis is less optimal in the remainder of patients,\" senior author David Shibata, MD, FACS, told Medscape in an interview. There is also a great deal of uncertainty regarding the optimal management strategy for patients with stage II colon cancer, and this has led to variations in care.

\"We have established that chemotherapy can benefit patients with stage III colorectal cancer,\" said Dr. Shibata, who is an associate professor of surgery and oncology at the H. Lee Moffitt Cancer Center and Research Institute, in Tampa, Florida. \"Because of that, there has been a great deal of interest to trying to figure out which patients with stage II disease will benefit from adjuvant therapy.\"

Most evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients in this category, he pointed out, but approximately 20% of patients who undergo surgical resection still go on to suffer recurrent disease and subsequent mortality. Disease recurrence is also not always predictable based on the histopathologic parameters associated with stage II colon cancer.

The goal of this study was to try to correlate clinical and gene-expression profiles with outcome in patients with stage II colorectal cancer and identify the individual genes and specific biologic pathways that are associated with recurrence. The researchers analyzed tumor tissue specimens taken from patients with colorectal cancer from 1993 to 2003. The Affymetrix 133 Plus 2.0 Genechip, which is able to examine differential gene expression in a wide variety of cell types and tissues, was able to characterize more than 30,000 genes in the tumor samples.

Dr. Shibata and colleagues identified 54 patients with stage II disease, and of this group, 9 had experienced a recurrence following a curative resection. \"This group was unusual,\" he explained, \"In that 8 of the 9 patients did not have metastatic disease but instead had local disease recurrence.\"

No significant differences were observed between the patients with disease recurrence and those without it, as far as differentiation, mucinous histology, and invasion of the lymphovascular system. The investigators did find that tumors with subsequent recurrence showed a total of 40 upregulated genes (0 downregulated), when compared with those in patients who did not relapse. The genes that were most affected tended to be associated with alterations in cytoskeletal integrity, kallikrein proteolysis, and glucose transport. A number of the identified genes are associated with tumorigenesis as well as being associated with upregulation in breast and ovarian cancers.

\"Our profile was characterized by a number of genes that are expressed in ovarian cancer,\" said Dr. Shibata. \"CA125 is 1 of the most commonly used diagnostic antigens of ovarian cancer, and we found that it was significantly upregulated.\"

Another example was the alterations seen in kallikrein proteolysis. Dr. Shibata explained that many members of the human kallikrein gene family are differentially regulated and expressed in ovarian cancer.

\"Cancers that recur locally may have the same components as ovarian cancer cell profiles,\" said Dr. Shibata. \"These data are very promising.\"

The researchers concluded that their study represents an evaluation of a comprehensive data set of patients with stage II colon cancer that is fully characterized from a clinical and genetic perspective. A panel of individual genes and specific biologic pathways were identified as being associated with recurrence in stage II disease and might be useful in predicting which patients may be the best candidates for adjuvant therapy following surgical resection.

Annual meeting of the American Society of Colon and Rectal Surgeons: Abstract S12. Presented June 4, 2007.


发布时间：2007年07月11日
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