TY - JOUR
T1 - Shifting patterns of genomic variation in the somatic evolution of papillary thyroid carcinoma
AU - Rubinstein, Jill C.
AU - Brown, Taylor C.
AU - Christison-Lagay, Emily R.
AU - Zhang, Yawei
AU - Kunstman, John W.
AU - Juhlin, C. Christofer
AU - Nelson-Williams, Carol
AU - Goh, Gerald
AU - Quinn, Courtney E.
AU - Callender, Glenda G.
AU - Udelsman, Robert
AU - Lifton, Richard P.
AU - Korah, Reju
AU - Carling, Tobias
N1 - Publisher Copyright:
© 2016 The Author(s).
PY - 2016/8/18
Y1 - 2016/8/18
N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
KW - Exome sequencing
KW - Papillary thyroid cancer
KW - Somatic evolution
UR - http://www.scopus.com/inward/record.url?scp=84982166262&partnerID=8YFLogxK
U2 - 10.1186/s12885-016-2665-7
DO - 10.1186/s12885-016-2665-7
M3 - Article
C2 - 27538953
AN - SCOPUS:84982166262
SN - 1471-2407
VL - 16
JO - BMC Cancer
JF - BMC Cancer
IS - 1
M1 - 646
ER -