p53 mutation is associated with progression in follicular lymphomas.
p53 mutation is associated with progression in follicular lymphomas.
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p53 突变与滤泡性淋巴瘤的进展相关。
作者：
C. Sander;T. Yano;H. Clark;C. Harris;D. Longo;E. Jaffe;M. Raffeld
大多数低级别滤泡性淋巴瘤最终会转变为侵袭性中级或高级别淋巴瘤。导致这种转变的分子机制尚未确定。我们通过免疫组织化学、单链构象多态性分析（SSCP）和测序相结合的方法，研究了34例接受组织学转化的滤泡性淋巴瘤患者的p53肿瘤抑制基因异常。我们在34个转化的侵袭性淋巴瘤中发现了10个p53过表达，其中9个包含通过SSCP分析和随后的测序鉴定的突变。10例患者中有7例行转化前低级别滤泡性淋巴瘤活检。免疫组化法研究的6个细胞中没有p53过表达，SSCP/测序法研究的4个细胞中只有1个在转化前活检中显示存在突变。有趣的是，在患者完全缓解5年后，第8例p53阳性转化淋巴瘤复发并伴有克隆相关的p53阴性低级别淋巴瘤。免疫组织化学还显示，来自p53阳性转化病例的几个转化前活检显示罕见的p53阳性细胞，在一个病例中，我们可以记录到它们的数量随着时间的推移而增加。另外25例低级别滤泡性淋巴瘤活检也进行了检查。3例淋巴瘤p53突变阳性。其中一个随后在活检研究的一年内发生了转变；第二例患者在较早的（无法获得的）不同部位活检显示组织学改变。第三例患者接受proproce - mopp联合化疗，完全缓解。我们得出结论：(1)在大约25% - 30%的滤泡性淋巴瘤中，p53突变与组织学转化有关；(2)p53阳性细胞在组织学转化之前可以检测到，但直到疾病晚期，即在组织学进展之前或之后，p53阳性细胞才占肿瘤细胞群的很大比例（通过SSCP可识别）。最后，数据还表明p53阳性的低级别淋巴瘤有进展的风险，在这个亚群中，可能需要积极的治疗。
The majority of low-grade follicular lymphomas will eventually transform to an aggressive intermediate, or high-grade lymphoma. The molecular mechanisms responsible for this transformation have not been determined. We studied serial biopsies from 34 patients with follicular lymphomas that underwent histologic transformation, for abnormalities of the p53 tumor suppressor gene by a combination of immunohistochemistry, single strand conformation polymorphism analysis (SSCP), and sequencing. We found overexpression of p53 in 10 of the 34 transformed aggressive lymphomas, 9 of which contained mutations identified by SSCP analysis and subsequent sequencing. Matched pretransformation low-grade follicular lymphoma biopsies were available for 7 of the 10 cases. None of six studied by immunohistochemistry showed overexpression of p53 and only 1 of 4 studied by SSCP/sequencing showed the presence of mutation in the pretransformation biopsy. Interestingly, an eighth p53 positive transformed lymphoma recurred with a clonally related, p53 negative low-grade lymphoma 5 years after the patient had achieved a complete remission. Immunohistochemistry also showed that several pretransformation biopsies from p53 positive transformed cases showed rare p53 positive cells and in one case we could document an increase in their number over time. Twenty-five additional low-grade follicular lymphoma biopsies were also examined. Three patients had lymphomas positive for p53 mutation. One of the three subsequently transformed within a year of the biopsy studied; the second patient had an earlier (unavailable) biopsy at a different site that showed transformed histology. The third patient was treated with ProMACE-MOPP combination chemotherapy and attained a complete remission. We conclude that (1) mutations of p53 are associated with histologic transformation in approximately 25% to 30% of follicular lymphomas and (2) p53 positive cells can be detected before histologic transformation, but do not comprise a significant percentage of the neoplastic cell population (identifiable by SSCP) until late in the disease, just before or after histologic progression. Finally, the data also suggest that p53 positive low-grade lymphomas are at risk for progression and that in this subset, aggressive therapy may be warranted.
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