Rigolin Gian Matteo, del Giudice Ilaria, Formigaro Luca, Saccenti Elena, Martinelli Sara, Cavallari Maurizio, Lista Enrico, Tammiso Elisa, Volta Eleonora, Lupini Laura, Bassi Cristian, Bardi Antonella, Sofritti Olga, Daghia Giulia, Cavazzini Francesco, Marinelli Marilisa, Tavolaro Simona, Guarini Anna, Negrini Massimo, Foà Robin, Cuneo Antonio
Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
Section of Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I 'Sapienza' University, Roma, Italy.
Genes Chromosomes Cancer. 2015 Dec;54(12):818-26. doi: 10.1002/gcc.22293. Epub 2015 Sep 10.
To clarify whether karyotype aberrations (KA) involving regions not covered by the standard fluorescence in situ hybridization (FISH) panel have independent prognostic relevance, we evaluated KA by conventional cytogenetics in a learning cohort (LC; n = 166) and a validation cohort (VC; n = 250) of untreated chronic lymphocytic leukemia (CLL) patients. In the VC, novel mitogens were used to improve metaphase generation and TP53, NOTCH1, and SF3B1 mutations were assessed. KA undetected by FISH were found in 35 and 35% of the cases in the LC and VC, respectively. In addition to FISH, KA allowed reclassification of 23 and 26% of cases in the LC and VC, respectively, into a higher cytogenetic risk group. By multivariate analysis, both in the LC and VC, KA other than isolated 13q deletion correlated with a shorter time to first treatment (TFT; P < 0.001 and 0.003, respectively), while a complex karyotype predicted a worse overall survival (OS, P = 0.015 and 0.010, respectively). In the VC, where a comprehensive biologic assessment was performed, a shorter TFT was also predicted by stage (P < 0.001), IGHV mutational status (P = 0.05), and del(17p)/TP53 mutations (P = 0.033) while stage (P = 0.023) and del(17p)/TP53 mutations (P = 0.024) independently predicted a shorter OS. FISH results did not independently impact on TFT and OS, in the LC and VC cohorts; this was also the case for NOTCH1 and SF3B1 mutations in the VC. We suggest that in CLL, conventional karyotyping with novel mitogens could be more effective than FISH for the detection of KA allowing for a more precise refinement of prognosis.
为了阐明涉及标准荧光原位杂交（FISH）检测组未覆盖区域的核型畸变（KA）是否具有独立的预后相关性，我们通过传统细胞遗传学方法对未经治疗的慢性淋巴细胞白血病（CLL）患者的一个学习队列（LC；n = 166）和一个验证队列（VC；n = 250）中的KA进行了评估。在VC中，使用了新型有丝分裂原以改善中期细胞的产生，并评估了TP53、NOTCH1和SF3B1突变。在LC和VC中，分别有35%和35%的病例中发现了FISH未检测到的KA。除FISH外，KA分别使LC和VC中23%和26%的病例重新分类为更高的细胞遗传学风险组。通过多变量分析，在LC和VC中，除孤立的13q缺失外的KA均与首次治疗时间（TFT）缩短相关（分别为P < 0.001和0.003），而复杂核型预测总体生存期（OS）更差（分别为P = 0.015和0.010）。在进行了全面生物学评估的VC中，分期（P < 0.001）、IGHV突变状态（P = 0.05）和del(17p)/TP53突变（P = 0.033）也预测了TFT缩短，而分期（P = 0.023）和del(17p)/TP53突变（P = 0.024）独立预测了OS缩短。在LC和VC队列中，FISH结果对TFT和OS没有独立影响；VC中的NOTCH1和SF3B1突变情况也是如此。我们认为，在CLL中，使用新型有丝分裂原的传统核型分析在检测KA方面可能比FISH更有效，从而能够更精确地细化预后。
