Detection of chromothripsis-like patterns with a custom array platform for chronic lymphocytic leukemia

作者：Salaverria Itziar; Martin Garcia David; Lopez Cristina; Clot Guillem; Garcia Aragones Manel; Navarro Alba; Delgado Julio; Baumann Tycho; Pinyol Magda; Martin Guerrero Idoia; Carrio Ana; Costa Dolors; Queiros Ana C; Jayne Sandrine; Aymerich Marta; Villamor Neus; Colomer Dolors; Gonzalez Marcos; Lopez Guillermo Armando; Campo Elias; Dyer Martin J S; Siebert Reiner; Armengol Lluis; Bea Silvia^*

来源：Genes, Chromosomes and Cancer, 2015, 54(11): 668-680.

DOI：10.1002/gcc.22277

Chronic lymphocytic leukemia (CLL) is a common disease with highly variable clinical course. Several recurrent chromosomal alterations are associated with prognosis and may guide risk-adapted therapy. We have developed a targeted genome-wide array to provide a robust tool for ascertaining abnormalities in CLL and to overcome limitations of the 4-marker fluorescence in situ hybridization (FISH). DNA from 180 CLL patients were hybridized to the qChip (R) Hemo array with a high density of probes covering commonly altered loci in CLL (11q22-q23, 13q14, and 17p13), nine focal regions (2p15-p16.1, 2p24.3, 2q13, 2q36.3-q37.1, 3p21.31, 8q24.21, 9p21.3, 10q24.32, and 18q21.32-q21.33) and two larger regions (6q14.1-q22.31 and 7q31.33-q33). Overall, 86% of the cases presented copy number alterations (CNA) by array. There was a high concordance of array findings with FISH (84% sensitivity, 100% specificity); all discrepancies corresponded to subclonal alterations detected only by FISH. A chromothripsis-like pattern was detected in eight cases. Three showed concomitant shattered 5p with gain of TERT along with isochromosome 17q. Presence of 11q loss was associated with shorter time to first treatment (P=0.003), whereas 17p loss, increased genomic complexity, and chromothripsis were associated with shorter overall survival (P<0.001, P=0.001, and P=0.02, respectively). In conclusion, we have validated a targeted array for the diagnosis of CLL that accurately detects, in a single experiment, all relevant CNAs, genomic complexity, chromothripsis, copy number neutral loss of heterozygosity, and CNAs not covered by the FISH panel. This test may be used as a practical tool to stratify CLL patients for routine diagnostics or clinical trials.

• 出版日期2015-11