Clinical cancer research : an official journal of the American Association for Cancer Research · 2012
Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC at 8q24 in chronic lymphocytic leukemia.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Brown Jennifer R, Hanna Megan, Tesar Bethany, Werner Lillian, Pochet Nathalie, Asara John M, Wang Yaoyu E, Dal Cin Paola, Fernandes Stacey M, Thompson Christina, Macconaill Laura, Wu Catherine J, Van de Peer Yves, Correll Mick, Regev Aviv, Neuberg Donna, Freedman Arnold S
Аннотация
PURPOSE: The disease course of chronic lymphocytic leukemia (CLL) varies significantly within cytogenetic groups. We hypothesized that high-resolution genomic analysis of CLL would identify additional recurrent abnormalities associated with short time-to-first therapy (TTFT).
EXPERIMENTAL DESIGN: We undertook high-resolution genomic analysis of 161 prospectively enrolled CLLs using Affymetrix 6.0 SNP arrays, and integrated analysis of this data set with gene expression profiles.
RESULTS: Copy number analysis (CNA) of nonprogressive CLL reveals a stable genotype, with a median of only 1 somatic CNA per sample. Progressive CLL with 13q deletion was associated with additional somatic CNAs, and a greater number of CNAs was predictive of TTFT. We identified other recurrent CNAs associated with short TTFT: 8q24 amplification focused on the cancer susceptibility locus near MYC in 3.7%; 3q26 amplifications focused on PIK3CA in 5.6%; and 8p deletions in 5% of patients. Sequencing of MYC further identified somatic mutations in two CLLs. We determined which catalytic subunits of phosphoinositide 3-kinase (PI3K) were in active complex with the p85 regulatory subunit and showed enrichment for the α subunit in three CLLs carrying PIK3CA amplification.
CONCLUSIONS: Our findings implicate amplifications of 3q26 focused on PIK3CA and 8q24 focused on MYC in CLL.
EXPERIMENTAL DESIGN: We undertook high-resolution genomic analysis of 161 prospectively enrolled CLLs using Affymetrix 6.0 SNP arrays, and integrated analysis of this data set with gene expression profiles.
RESULTS: Copy number analysis (CNA) of nonprogressive CLL reveals a stable genotype, with a median of only 1 somatic CNA per sample. Progressive CLL with 13q deletion was associated with additional somatic CNAs, and a greater number of CNAs was predictive of TTFT. We identified other recurrent CNAs associated with short TTFT: 8q24 amplification focused on the cancer susceptibility locus near MYC in 3.7%; 3q26 amplifications focused on PIK3CA in 5.6%; and 8p deletions in 5% of patients. Sequencing of MYC further identified somatic mutations in two CLLs. We determined which catalytic subunits of phosphoinositide 3-kinase (PI3K) were in active complex with the p85 regulatory subunit and showed enrichment for the α subunit in three CLLs carrying PIK3CA amplification.
CONCLUSIONS: Our findings implicate amplifications of 3q26 focused on PIK3CA and 8q24 focused on MYC in CLL.
Предметные рубрики MeSH
Aged, 80 and overChromosome DeletionChromosome DuplicationChromosomes, Human, Pair 3Chromosomes, Human, Pair 8Class I Phosphatidylinositol 3-KinasesDNA Copy Number VariationsDisease ProgressionFemaleGene Expression ProfilingGenes, mycGenetic Association StudiesGenome, HumanHumansLeukemia, Lymphocytic, Chronic, B-CellMaleMiddle AgedPhosphatidylinositol 3-KinasesPolymorphism, Single Nucleotide