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Genome Med:科学家揭示开发乳腺癌新型疗法的靶向基因的特殊突变

新药编辑:新特药 更新时间:2015-04-14

2015年4月13日 讯 /tumor.net.cn/ --发表自国际杂志Genome Medicine上的一篇研究论文中,来自斯坦福大学的研究人员通过研究发现,被认为可以作为开发乳腺癌药物靶点的主要候选基因或许并不像最初认为的那样;基因PIK3CA的突变是乳腺癌中常见的第二大突变,而且其在20%的乳腺癌中都存在;这就使得人们去思考这些改变如何诱发导致乳腺癌的发生,然而这些突变往往在肿瘤状物的癌变前生长中出现,而且许多这种肿瘤状物都被认为是良性的。

文章中,研究者想通过研究更好地理解肿瘤状物生长及其和癌症发生之间的关系,他们对来自6名女性患者乳腺组织中的基因进行测序,患者均进行了乳房切除术,研究者共对66份样本进行了分析,其中包括18份癌变组织及34份肿瘤病变组织。

PIK3CA基因的特殊突变往往会在同一患者机体中多次发生,研究者就在6名患者中发现了4名,这4名患者中又有2名患者机体的突变发生于肿瘤病变组织中,这些组织并不认为是癌变组织,而且也没有在侵袭性的癌变组织中发生突变。Arend Sidow说道,当前有许多种药物可以靶向作用PIK3CA基因,而且目前很多制药公司和研究人员都认为该基因是一个非常具有潜力的靶点。

研究者目前构建了系统树来追踪源头细胞发生的突变,从而确定这些组织损伤如何彼此相关,在4个PIK3CA阳性的病人中每一个病人机体中的突变都会多次独立地发生,通过观察系统树来追踪PIK3CA基因的突变或可帮助研究者揭示驱动癌症发生的分子机制。

本文研究对于后期开发新型药物靶向作用PIK3CA具有一定的指示意义,而后期研究者还将通过研究来阐明是否PIK3CA基因的突变在阳性病人的源头肿瘤细胞中存在,如果证实其的确是一个潜在的靶点,那么对于后期开发治疗癌症的新型疗法将会是非常大的希望。(tumor.net.cn)

doi:10.1186/s13073-015-0146-2

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Cell-lineage heterogeneity and driver mutation recurrence in pre-invasive breast neoplasia

Ziming Weng12, Noah Spies12, Shirley X Zhu1, Daniel E Newburger3, Dorna Kashef-Haghighi4, Serafim Batzoglou4*, Arend Sidow12* and Robert B West1*

Background All cells in an individual are related to one another by a bifurcating lineage tree, in which each node is an ancestral cell that divided into two, each branch connects two nodes, and the root is the zygote. When a somatic mutation occurs in an ancestral cell, all its descendants carry the mutation, which can then serve as a lineage marker for the phylogenetic reconstruction of tumor progression. Using this concept, we investigate cell lineage relationships and genetic heterogeneity of pre-invasive neoplasias compared to invasive carcinomas. Methods We deeply sequenced over a thousand phylogenetically informative somatic variants in 66 morphologically independent samples from 6 patients that represent a spectrum of normal, early neoplasia, carcinoma in situ, and invasive carcinoma. For each patient, we obtained a highly resolved lineage tree that establishes the phylogenetic relationships among the pre-invasive lesions and with the invasive carcinoma. Results The trees reveal lineage heterogeneity of pre-invasive lesions, both within the same lesion, and between histologically similar ones. On the basis of the lineage trees, we identified a large number of independent recurrences of PIK3CA H1047 mutations in separate lesions in four of the six patients, often separate from the diagnostic carcinoma. Conclusions Our analyses demonstrate that multi-sample phylogenetic inference provides insights on the origin of driver mutations, lineage heterogeneity of neoplastic proliferations, and the relationship of genomically aberrant neoplasias with the primary tumors. PIK3CA driver mutations may be comparatively benign inducers of cellular proliferation.

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