Distinct patterns of somatic alterations in a lymphoblastoid and a tumor genome derived from the same individual

Abstract

Although patterns of somatic alterations have been reported for tumor genomes, little is known on how they compare with alterations present in non-tumor genomes. A comparison of the two would be crucial to better characterize the genetic alterations driving tumorigenesis. We sequenced the genomes of a lymphoblastoid (HCC1954BL) and a breast tumor (HCC1954) cell line derived from the same patient and compared the somatic alterations present in both. The lymphoblastoid genome presents a comparable number and similar spectrum of nucleotide substitutions to that found in the tumor genome. However, a significant difference in the ratio of non-synonymous to synonymous substitutions was observed between both genomes (P = 0.031). Protein–protein interaction analysis revealed that mutations in the tumor genome preferentially affect hub-genes (P = 0.0017) and are co-selected to present synergistic functions (P < 0.0001). KEGG analysis showed that in the tumor genome most mutated genes were organized into signaling pathways related to tumorigenesis. No such organization or synergy was observed in the lymphoblastoid genome. Our results indicate that endogenous mutagens and replication errors can generate the overall number of mutations required to drive tumorigenesis and that it is the combination rather than the frequency of mutations that is crucial to complete tumorigenic transformation.

Gene Copy-Number Polymorphism Caused by Retrotransposition in Humans

“…We also found evidence of chimeric transcripts derived from SKA3-DDX10 in a breast cancer cell line and in a lymphoid cell line (HCC1954 and HCC1954-BL from ref. [46]), both derived from an individual genotyped for SKA3 . The SKA3 retroCNV is inserted in-between the tenth and eleventh exons of DDX10 , forming a sense-antisense pair.…”

“…Sequencing reactions were carried out using DYEnamic (ET Terminator Cycle Sequencing Kit, Amersham Pharmacia) and an ABI 3130XL sequencer (Applied Biosystems). This experiment was performed in four cell lines: two from a single individual previously genotyped for the SKA3 retrogene [46], and two negative controls.…”

nFuse: Discovery of complex genomic rearrangements in cancer using high-throughput sequencing

“…Galante et al (2011), and nFuse. Previously discovered breakpoints are rediscovered by nFuse with a recall of 0.858.…”

“…The WGSS data (accession no. ERA010917) are the same data used in the study by Galante et al (2011), and the RNA-seq data (accession no. ERA015355) were produced in a separate study on allelespecific expression (Zhao et al 2010).…”

“…ERA015355) were produced in a separate study on allelespecific expression (Zhao et al 2010). Next we compiled a list of 345 validated breakpoints from the studies by Bignell et al (2007), Stephens et al (2009), and Galante et al (2011). Small deletions were excluded from the analysis since they are not the focus of this study.…”