Abstract
BackgroundCopy neutral loss of heterozygosity (CN-LOH) refers to a special case of LOH occurring without any resulting loss in copy number. These alterations is sometimes seen in tumors as a way to inactivate a tumor suppressor gene and have been found to be important in several types of cancer.ResultsWe have used high density single nucleotide polymorphism arrays in order to investigate the frequency and distribution of CN-LOH and other allelic imbalances in neuroblastoma (NB) tumors and cell lines. Our results show that the frequency of these near-CN-LOH events is significantly higher in the cell lines compared to the primary tumors and that the types of CN-LOH differ between the groups. We also show that the low-risk neuroblastomas that are generally considered to have a "triploid karyotype" often present with a complex numerical karyotype (no segmental changes) with 2-5 copies of each chromosome. Furthermore a comparison has been made between the three related cell lines SK-N-SH, SH-EP and SH-SY5Y with respect to overall genetic aberrations, and several aberrations unique to each of the cell lines has been found.ConclusionsWe have shown that the NB tumors analyzed contain several interesting allelic imbalances that would either go unnoticed or be misinterpreted using other genome-wide techniques. These findings indicate that the genetics underlying NB might be even more complex than previously known and that SNP arrays are important analysis tools. We have also showed that these near-CN-LOH events are more frequently seen in NB cell lines compared to NB tumors and that a set of highly related cell lines have continued to evolve secondary to the subcloning event. Taken together our analysis highlights that cell lines in many cases differ substantially from the primary tumors they are thought to represent, and that caution should be taken when drawing conclusions from cell line-based studies.
Highlights
Copy neutral loss of heterozygosity (CN-LOH) refers to a special case of LOH occurring without any resulting loss in copy number
We have found that tumors presenting with 17 q gain, but without MYCN amplification or 11 q deletion, form a group with intermediate prognosis, and that tumors presenting with other segmental aberrations (i.e without MYCN amplification, 11 q deletion or 17 q gain) have a favorable prognosis [4]
Copy number estimations in complex tumors The NB tumors and cell lines were analyzed with respect to copy number change and LOH using CNAG 3.0
Summary
Copy neutral loss of heterozygosity (CN-LOH) refers to a special case of LOH occurring without any resulting loss in copy number. The most common genetic abnormalities found in aggressive NB good prognosis, while tumors with MYCN amplification and tumors with 11 q deletion constitute two groups with unfavorable prognosis and poor survival. Both these latter groups typically present with 17 q gain [4,5]. When calculating the allele specific intensities, this algorithm takes advantage of the false heterozygous calls that might appear as a result of contaminating normal cells [16] This makes it a robust method for visualizing LOH and other allelic imbalances even in complex tumor materials
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