title: Shifting patterns of genomic variation in the somatic evolution of papillary thyroid carcinoma.
abstract: Cancer is increasingly understood to arise in the context of dynamically evolving genomes with continuously generated variants subject to selective pressures. Diverse mutations have been identified in papillary thyroid carcinoma (PTC), but unifying theories underlying genomic change are lacking. Applying a framework of somatic evolution, we sought to broaden understanding of the PTC genome through identification of global trends that help explain risk of tumorigenesis.
  
  
  
  Exome sequencing was performed on 53 PTC and matched adjacent non-tumor thyroid tissues (ANT). Single nucleotide substitution (SNS) signatures from each sample pair were divided into three subsets based on their presence in tumor, non-tumor thyroid, or both. Nine matched blood samples were sequenced and SNS signatures intersected with these three subsets. The intersected genomic signatures were used to define branch-points in the evolution of the tumor genome, distinguishing variants present in the tissues' common ancestor cells from those unique to each tissue type and therefore acquired after genomic divergence of the tumor, non-tumor, and blood samples.
  
  
  
  Single nucleotide substitutions shared by the tumor and the non-tumor thyroid were dominated by C-to-T transitions, whereas those unique to either tissue type were enriched for C-to-A transversions encoding non-synonymous, predicted-deleterious variants. On average, SNSs of matched blood samples were 81 % identical to those shared by tumor and non-tumor thyroid, but only 12.5 % identical to those unique to either tissue. Older age and BRAF mutation were associated with increased SNS burden.
  
  
  
  The current study demonstrates novel patterns of genomic change in PTC, supporting a theory of somatic evolution in which the zygote's germline genome undergoes continuous remodeling to produce progressively differentiated, tissue-specific signatures. Late somatic events in thyroid tissue demonstrate shifted mutational spectra compared to earlier polymorphisms. These late events are enriched for predicted-deleterious variants, suggesting a mechanism of genomic instability in PTC tumorigenesis.
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.|Department of Surgery, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Rubinstein
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.|Department of Surgery, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Brown
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Christison-Lagay
authors.affiliation: Department of Environmental Health Sciences, School of Public Health, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.|Department of Surgery, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Kunstman
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.|Department of Surgery, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.|Present Address: Department of Oncology-Pathology (OnkPat), Karolinska Universitetssjukhuset, Solna, 171 76, Stockholm, Sweden.
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.|Present Address: UCL Cancer Institute, University College London, London, UK.
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Quinn
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.
authors.forename: Glenda G
authors.initials: GG
authors.lastname: Callender
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Udelsman
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.|Howard Hugh Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.|Department of Surgery, Yale University School of Medicine, New Haven, 06520, Connecticut, USA.
authors.forename: Reju
authors.initials: R
authors.lastname: Korah
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, 06520, Connecticut, USA. tobias.carling@yale.edu.|Department of Surgery, Yale University School of Medicine, New Haven, 06520, Connecticut, USA. tobias.carling@yale.edu.|Yale School of Medicine, 333 Cedar Street, FMB130A, P.O. Box 208062, New Haven, CT, 06520, USA. tobias.carling@yale.edu.
authors.forename: Tobias
authors.identifier: 0000-0002-1308-187X
authors.initials: T
authors.lastname: Carling
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics*; D002291:Carcinoma, Papillary; D060965:Clonal Evolution; D059472:Exome; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics*; D055815:Young Adult
keywords: Exome sequencing; Papillary thyroid cancer; Somatic evolution