title: Whole-genome sequencing analysis identifies a distinctive mutational spectrum in an arsenic-related lung tumor.
abstract: BACKGROUND
  Arsenic exposure is a significant cause of lung cancer in North America and worldwide. Arsenic-related tumors are structurally indistinguishable from those induced by other carcinogens. Because carcinogens, like tobacco, induce distinctive mutational signatures, we sought to characterize the mutational signature of an arsenic-related lung tumor from a never smoker with the use of whole-genome sequencing.
  
  
  METHODS
  Tumor and lung tissues were obtained from a never smoker with lung squamous cell carcinoma (LUSC), without familiar history of lung cancer and chronically exposed to high levels of arsenic-contaminated drinking water. The Illumina HiSeq-2000 platform was used to sequence each genome at approximately 30-fold haploid coverage. The mutational signature was compared with those observed in previously characterized lung tumors.
  
  
  RESULTS
  The arsenic-related tumor exhibited alterations common in LUSC, such as the increased number of copies at 3q26 (SOX2 locus). However, the arsenic-related genome not only harbored a lower number of point mutations, but also had a remarkably high fraction of T>G/A>C mutations and low fraction of C>A/G>T transversions, which is uncharacteristic of LUSCs. Furthermore, at the gene level, we identified a rare G>C mutation in TP53, which is uncommon in lung tumors in general (<0.2%) but has been observed in other arsenic-related malignancies.
  
  
  CONCLUSIONS
  We generated the first whole-genome sequence of an LUSC from a never-smoker patient chronically exposed to arsenic, and identified a distinct mutational spectrum associated with arsenic exposure, providing novel evidence supporting the hypothesis that arsenic-induced lung tumors arise through molecular mechanisms that differ from those of the common lung cancer.
authors.affiliation: *Department of Integrative Oncology, BC Cancer Agency, Vancouver, Canada; and †Program of Cell and Molecular Biology, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Victor D
authors.initials: VD
authors.lastname: Martinez
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.forename: Emily A
authors.initials: EA
authors.lastname: Vucic
authors.forename: Roland
authors.initials: R
authors.lastname: Hubaux
authors.forename: Marta
authors.initials: M
authors.lastname: Adonis
authors.forename: Lionel
authors.initials: L
authors.lastname: Gil
authors.forename: Calum
authors.initials: C
authors.lastname: MacAulay
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
mesh_terms: D000368:Aged; D020261:Arsenic Poisoning; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D017354:Point Mutation / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53