title: 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.
authors.affiliation: Ludwig Institute for Cancer Research, São Paulo Branch at Hospital Alemão Oswaldo Cruz, São Paulo 01323-903, Brazil.
authors.forename: Pedro A F
authors.initials: PA
authors.lastname: Galante
authors.forename: Raphael B
authors.initials: RB
authors.lastname: Parmigiani
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Otávia L
authors.initials: OL
authors.lastname: Caballero
authors.forename: Jorge E
authors.initials: JE
authors.lastname: de Souza
authors.forename: Fábio C P
authors.initials: FC
authors.lastname: Navarro
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Gerber
authors.forename: Marisa F
authors.initials: MF
authors.lastname: Nicolás
authors.forename: Anna Christina M
authors.initials: AC
authors.lastname: Salim
authors.forename: Ana Paula M
authors.initials: AP
authors.lastname: Silva
authors.forename: Lee
authors.initials: L
authors.lastname: Edsall
authors.forename: Sylvie
authors.initials: S
authors.lastname: Devalle
authors.forename: Luiz G
authors.initials: LG
authors.lastname: Almeida
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ye
authors.forename: Samantha
authors.initials: S
authors.lastname: Kuan
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Pinheiro
authors.forename: Israel
authors.initials: I
authors.lastname: Tojal
authors.forename: Renato G
authors.initials: RG
authors.lastname: Pedigoni
authors.forename: Rodrigo G M A
authors.initials: RG
authors.lastname: de Sousa
authors.forename: Thiago Y K
authors.initials: TY
authors.lastname: Oliveira
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: de Paula
authors.forename: Lucila
authors.initials: L
authors.lastname: Ohno-Machado
authors.forename: Ewen F
authors.initials: EF
authors.lastname: Kirkness
authors.forename: Samuel
authors.initials: S
authors.lastname: Levy
authors.forename: Wilson A
authors.initials: WA
authors.lastname: da Silva
authors.forename: Ana Tereza R
authors.initials: AT
authors.lastname: Vasconcelos
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.forename: Marco Antonio
authors.initials: MA
authors.lastname: Zago
authors.forename: Robert L
authors.initials: RL
authors.lastname: Strausberg
authors.forename: Andrew J G
authors.initials: AJ
authors.lastname: Simpson
authors.forename: Sandro J
authors.initials: SJ
authors.lastname: de Souza
authors.forename: Anamaria A
authors.initials: AA
authors.lastname: Camargo
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D008214:Lymphocytes; D008875:Middle Aged; D009154:Mutation; D017354:Point Mutation; D025941:Protein Interaction Mapping; D017422:Sequence Analysis, DNA