Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas
Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas
复制标题
DOI：
10.1158/0008-5472.can-05-4578
复制
发表时间：
2006-07-15
期刊：
影响因子：
11.2
通讯作者：
Anderson, Michael J.
中科院分区：
文献类型：
--
作者：
Davicioni, Elai;Finckenstein, Friedrich Graf;Anderson, Michael J.
腺泡状横纹肌肉瘤（ARMS）是侵袭性软组织肉瘤，影响儿童和年轻人。大多数ARMS肿瘤表达PAX 3-FKHR或PAX 7-FKHR（PAX-FKHR）融合基因，分别由t（2;13）或t（1;13）染色体易位引起。然而，高达25%的ARMS肿瘤是融合阴性的，使得不清楚ARMS是否代表单一疾病或具有共同表型的多种临床和生物学实体。为了测试PAX-FKHR在多大程度上决定ARMS的分类和行为，我们在139个原发性横纹肌肉瘤肿瘤和体外模型上使用寡核苷酸微阵列表达谱。我们发现，ARMS肿瘤表达PAX-FKHR基因共享一个共同的表达谱，不同于融合阴性ARMS和其他横纹肌肉瘤变体。我们还观察到PAX-FKHR表达高于最低水平对于检测该表达谱是必要的。使用异位PAX 3-FKHR和PAX 7-FKHR表达模型，我们鉴定了由PAX-FKHR调节的表达特征，其对PAX-FKHR阳性ARMS肿瘤具有特异性。特征基因功能注释的数据挖掘表明PAX-FKHR在调节ARMS增殖和分化中的作用。考克斯回归模型确定了PAX-FKHR表达特征中的一个基因子集，将ARMS患者分为3个风险组，5年总生存率估计值为7%、48%和93%。这些预后类别独立于传统的临床风险因素。我们的研究结果表明，PAX-FKHR决定了一个特定的表达特征，有助于定义PAX-FKHR阳性ARMS肿瘤的分子表型，因为它与ARMS患者的疾病结局有关，决定了肿瘤的行为。
Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhahdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior.