. 2024 Mar 26;43(3):113826.

doi: 10.1016/j.celrep.2024.113826. Epub 2024 Feb 26.

The genomic and evolutionary landscapes of anaplastic thyroid carcinoma

Peter Y F Zeng¹, Stephenie D Prokopec², Stephen Y Lai³, Nicole Pinto⁴, Michelle A Chan-Seng-Yue⁵, Roderick Clifton-Bligh⁶, Michelle D Williams⁷, Christopher J Howlett⁸, Paul Plantinga⁸, Matthew J Cecchini⁹, Alfred K Lam⁹, Iram Siddiqui¹⁰, Jianxin Wang⁵, Ren X Sun⁵, John D Watson², Reju Korah¹¹, Tobias Carling¹¹, Nishant Agrawal¹², Nicole Cipriani¹³, Douglas Ball¹⁴, Barry Nelkin¹⁵, Lisa M Rooper¹⁶, Justin A Bishop¹⁷, Cathie Garnis¹⁸, Ken Berean¹⁸, Norman G Nicolson¹¹, Paul Weinberger¹⁹, Ying C Henderson³, Christopher M Lalansingh⁵, Mao Tian²⁰, Takafumi N Yamaguchi², Julie Livingstone², Adriana Salcedo²¹, Krupal Patel²², Frederick Vizeacoumar²³, Alessandro Datti²⁴, Liu Xi²⁵, Yuri E Nikiforov²⁶, Robert Smallridge²⁷, John A Copland²⁸, Laura A Marlow²⁸, Martin D Hyrcza²⁹, Leigh Delbridge³⁰, Stan Sidhu³⁰, Mark Sywak³⁰, Bruce Robinson³¹, Kevin Fung³², Farhad Ghasemi⁴, Keith Kwan⁸, S Danielle MacNeil³², Adrian Mendez³², David A Palma³³, Mohammed I Khan⁴, Mushfiq Shaikh⁴, Kara M Ruicci⁴, Bret Wehrli⁸, Eric Winquist³³, John Yoo³², Joe S Mymryk³⁴, James W Rocco³⁵, David Wheeler²⁵, Steve Scherer²⁵, Thomas J Giordano³⁶, John W Barrett⁴, William C Faquin³⁷, Anthony J Gill³⁸, Gary Clayman³⁹, Paul C Boutros⁴⁰, Anthony C Nichols⁴¹

Affiliations

¹ Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada; London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada.
² Ontario Institute for Cancer Research, Toronto, ON, Canada; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada.
⁵ Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁶ Division of Endocrinology, Royal North Shore Hospital, and University of Sydney, Sydney, NSW, Australia.
⁷ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Pathology, Western University, London, ON, Canada.
⁹ Department of Pathology, School of Medicine, Griffith University, Gold Coast, QLD, Australia.
¹⁰ Department of Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Surgery, Yale University, New Haven, CT, USA.
¹² Department of Otolaryngology - Head and Neck Surgery, University of Chicago, Chicago, IL, USA.
¹³ Department of Pathology, University of Chicago, Chicago, IL, USA.
¹⁴ Division of Endocrinology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁵ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
¹⁶ Division of Pathology, Johns Hopkins University, Baltimore, MD, USA.
¹⁷ Department of Pathology, University of Texas Southwestern, Dallas, TX, USA.
¹⁸ BC Cancer Agency, Vancouver, BC, Canada.
¹⁹ Department of Otolaryngology - Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA; Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
²⁰ Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
²¹ Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
²² Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada.
²³ Cancer Research Cluster, University of Saskatchewan, Saskatoon, SK, Canada.
²⁴ Network Biology Collaborative Centre, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Department of Agricultural, Food, and Environmental Sciences, University of Perugia, Perugia, Italy.
²⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
²⁶ Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
²⁷ Division of Endocrinology, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA.
²⁸ Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
²⁹ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
³⁰ Department of Surgery, Royal North Shore Hospital, Sydney, NSW, Australia; University of Sydney, Sydney, NWS, Australia.
³¹ University of Sydney, Sydney, NWS, Australia; Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia.
³² Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada.
³³ London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada.
³⁴ Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada; London Regional Cancer Program, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada; Department of Microbiology and Immunology, Western University, London, ON, Canada.
³⁵ Department of Otolaryngology - Head and Neck Surgery, Ohio State University, Columbus, OH, USA.
³⁶ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
³⁷ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³⁸ University of Sydney, Sydney, NWS, Australia; Cancer Diagnosis and Pathology Group, Kolling Institute of Medicine, Royal North Shore Hospital, Sydney, NSW, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia.
³⁹ The Clayman Thyroid Surgery and Thyroid Cancer Center, The Thyroid Institute, Tampa General Hospital, Tampa, FL, USA.
⁴⁰ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: pboutros@mednet.ucla.edu.
⁴¹ Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada; London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada. Electronic address: anthony.nichols@lhsc.on.ca.

PMID: 38412093
PMCID: PMC11077417
DOI: 10.1016/j.celrep.2024.113826

The genomic and evolutionary landscapes of anaplastic thyroid carcinoma

Peter Y F Zeng et al. Cell Rep. 2024.

. 2024 Mar 26;43(3):113826.

doi: 10.1016/j.celrep.2024.113826. Epub 2024 Feb 26.

Authors

Affiliations

¹ Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada; London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada.
² Ontario Institute for Cancer Research, Toronto, ON, Canada; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada.
⁵ Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁶ Division of Endocrinology, Royal North Shore Hospital, and University of Sydney, Sydney, NSW, Australia.
⁷ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Pathology, Western University, London, ON, Canada.
⁹ Department of Pathology, School of Medicine, Griffith University, Gold Coast, QLD, Australia.
¹⁰ Department of Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Surgery, Yale University, New Haven, CT, USA.
¹² Department of Otolaryngology - Head and Neck Surgery, University of Chicago, Chicago, IL, USA.
¹³ Department of Pathology, University of Chicago, Chicago, IL, USA.
¹⁴ Division of Endocrinology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁵ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
¹⁶ Division of Pathology, Johns Hopkins University, Baltimore, MD, USA.
¹⁷ Department of Pathology, University of Texas Southwestern, Dallas, TX, USA.
¹⁸ BC Cancer Agency, Vancouver, BC, Canada.
¹⁹ Department of Otolaryngology - Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA; Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
²⁰ Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
²¹ Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
²² Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada.
²³ Cancer Research Cluster, University of Saskatchewan, Saskatoon, SK, Canada.
²⁴ Network Biology Collaborative Centre, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Department of Agricultural, Food, and Environmental Sciences, University of Perugia, Perugia, Italy.
²⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
²⁶ Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
²⁷ Division of Endocrinology, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA.
²⁸ Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
²⁹ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
³⁰ Department of Surgery, Royal North Shore Hospital, Sydney, NSW, Australia; University of Sydney, Sydney, NWS, Australia.
³¹ University of Sydney, Sydney, NWS, Australia; Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia.
³² Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada.
³³ London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada.
³⁴ Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada; London Regional Cancer Program, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada; Department of Microbiology and Immunology, Western University, London, ON, Canada.
³⁵ Department of Otolaryngology - Head and Neck Surgery, Ohio State University, Columbus, OH, USA.
³⁶ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
³⁷ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³⁸ University of Sydney, Sydney, NWS, Australia; Cancer Diagnosis and Pathology Group, Kolling Institute of Medicine, Royal North Shore Hospital, Sydney, NSW, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia.
³⁹ The Clayman Thyroid Surgery and Thyroid Cancer Center, The Thyroid Institute, Tampa General Hospital, Tampa, FL, USA.
⁴⁰ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: pboutros@mednet.ucla.edu.
⁴¹ Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON, Canada; London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada. Electronic address: anthony.nichols@lhsc.on.ca.

PMID: 38412093
PMCID: PMC11077417
DOI: 10.1016/j.celrep.2024.113826

Abstract

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Keywords: CP: Cancer; CP: Genomics; anaplastic thyroid cancer; cancer progression; genomics; tumour evolution; tumour heterogeneity.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests All authors declare that they have no competing interests.

Figures

**Figure 1.. Somatic mutational landscape of anaplastic thyroid cancer**
(A) Anaplastic thyroid cancers (ATCs) vary significantly in mutation density (single-nucleotide variants [SNVs] per million base pairs of DNA covered). Genes were selected based on SeqSig analysis p values (FDR < 0.05). (B) Copy-number aberrations (CNAs) across ATC; consensus clustering was used to identify the optimal method and designation for sample groupings. Each row represents the CNA profile for a single undifferentiated tumor along the genome (chromosome 1 on the left to chromosome Y on the right), ordered by percentage genome altered (PGA) within each subtype. (C and D) Metrics of mutation density for ATC, co-occurring DTC, and papillary thyroid cancer (PTC) were compared with 32 additional tumor types available in the PCAWG (Pan-Cancer Analysis of Whole Genomes) dataset: (C) SNVs/Mb and (D) total PGA. Light purple indicates the PCAWG thyroid carcinoma cohort (primarily PTC) and similar GATCI PTC cohort; co-occurring DTC samples are shown in medium purple, while ATCs are in dark purple; for SNVs/Mb, x’s indicate samples without a matched normal; these typically have higher than average rates. PGA for the GATCI PTC samples is similar to that of the PCAWG thyroid carcinoma cohort. Blue points for SNVs/Mb indicate results from WGS cohort. Red line indicates the median value. ATC shows higher PGA than either co-occurring DTC or PTC and a lower rate of point mutations than co-occurring DTC.

**Figure 2.. Genomic features of ATC and their associations with clinical features**
(A) Non-negative matrix factorization (NMF) identified five trinucleotide signatures within ATC, four of which matched known COSMIC signatures and one that was a novel signature. Within each signature, the percentage of mutations within the cohort presenting each base change is shown (broken down by trinucleotide context). (B) For each patient, the proportion of SNVs that contribute to each signature. There were no associations between these signatures and the covariates shown (Spearman’s correlation p < 0.1). (C and D) Average CNA profiles (C) and distribution of PGA (D) for samples from each ATC subtype, co-occurring DTC, and PTC, showing a significant difference between groups (one-way ANOVA, p < 0.01). (E) GISTIC was used to identify recurrent CNAs within ATC. (F) Pearson’s χ², Spearman’s correlation, Mann-Whitney U, or Kruskal-Wallis test was used to assess overlap across genomic features in ATC (SeqSig driver genes by SNV or CNAs, SNVs/Mb, PGA, trinucleotide signatures, CNA metrics); shading indicates FDR-adjusted p value. (G–I) Comparison of thyroid differentiation score (G), BRAF-RAS scores (H), and estimated immune cell subsets (I) between the RNA-seq samples from ATC (n = 24) and cell lines (n = 13) from the current study and normal thyroid (n = 58), primary PTC (n = 502), and metastatic PTC (n = 8) from TCGA. Error bar represents 1 SD. The p values are from FDR-adjusted Mann-Whitney U test. All samples are biological replicates.

**Figure 3.. Genomic hallmarks of anaplastic thyroid cancer implicate diverse pathways**
Single-nucleotide variants and copy-number alterations of co-occurring differentiated thyroid cancer and anaplastic thyroid cancers reveal recurrent alterations in gene sets such as tumor suppressors, MAPK-RAS, thyroid, epigenetic, WNT, SWI/SNF, and finally other identified GATCI genes (SeqSig FDR < 0.05). Red dashed box indicates samples with no known SNV alteration in the gene sets above.

**Figure 4.. ATC and co-occurring DTC share clonal origins, but with distinct driver events**
(A) GISTIC was used to identify recurrent CNAs within PTC; this identified multiple amplifications of chromosome 17 as being significant and recurrent compared with ATC. (B) GISTIC was used to identify recurrent CNAs within co-occurring DTC. Copy-number losses of CDKN2A were more frequent in ATC than co-occurring well/poorly differentiated samples (DTC). (C) Twenty-one patients had CNA profiles generated through copy-number arrays for multiple tumor regions. Each plot shows the genomic CNA profiles for a single patient, with different tumor regions as rows. Covariates on the right indicate ATC subtype (where available), tumor type (ATC, co-occurring DTC, or metastasis), patient sex, patient age at diagnosis, and *BRAF* V600E status. (D) Thirty patients had WES or WGS in multiple regions. Each subplot shows the mutational profile of the SeqSig genes (FDR < 0.05) in the paired samples. (E) Gene-wise mutation frequencies were contrasted between datasets (GATCI-ATC, GATCI-DTC, GATCI-PTC, and TCGA-PTC) to identify candidate drivers of tumor progression. Genes with a statistically significant difference (proportion-test) between ATC and TCGA-PTC were selected and further filtered to show only known driver genes (defined using COSMIC or Candidate Cancer Gene Database). FDR-adjusted p values from proportion-tests across the three tumor types (PTC [combined], co-occurring DTC, ATC) are shown. Results for pairwise comparisons are available in Table S11. (F) Landscape of CNAs determined by WGS for patients with both ATC and paired co-occurring DTC, along with matched normal tissue. CNAs are color-coded as to their origin (trunk, branch, or unclear). All samples are biological replicates.

**Figure 5.. ATC and DTC evolve in a mutagenic field**
(A) Key for interpreting plots. (B–J) Subclonal reconstruction of the nine patients profiled using WGS. Left: changes in percentage genome altered (PGA) are shown by blue lines and correspond to the left axis, while accumulation of SNVs is shown by gold lines and corresponds to the right axis. Right: representation of the total cancer cell fraction (CCF) for each distinct subclone for either the ATC (top) or the co-occurring DTC (bottom) component. Interestingly, ATCWGS33 (D) showed outgrowth of two distinct co-mixed lineages from a mutagenic field. (K) Proposed model of thyroid cancer progression.

See this image and copyright information in PMC

References

1. Bruinsma SM, Roobol MJ, Carroll PR, Klotz L, Pickles T, Moore CM, Gnanapragasam VJ, Villers A, Rannikko A, Valdagni R, et al. (2017). Expert consensus document: Semantics in active surveillance for men with localized prostate cancer - results of a modified Delphi consensus procedure. Nat. Rev. Urol. 14, 312–322. 10.1038/nrurol.2017.26. - DOI - PubMed
1. Shaha AR, and Tuttle RM (2018). Editorial: Risk of disease progression during active surveillance of papillary thyroid cancer. Surgery 163, 53–54. 10.1016/j.surg.2017.08.020. - DOI - PubMed
1. Garrido-Laguna I, and Hidalgo M. (2015). Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat. Rev. Clin. Oncol. 12, 319–334. 10.1038/nrclinonc.2015.53. - DOI - PubMed
1. Gross AM, Orosco RK, Shen JP, Egloff AM, Carter H, Hofree M, Choueiri M, Coffey CS, Lippman SM, Hayes DN, et al. (2014). Multi-tiered genomic analysis of head and neck cancer ties TP53 mutation to 3p loss. Nat. Genet. 46, 939–943. 10.1038/ng.3051. - DOI - PMC - PubMed
1. Bayani J, Yao CQ, Quintayo MA, Yan F, Haider S, D’Costa A, Brookes CL, van de Velde CJH, Hasenburg A, Kieback DG, et al. (2017). Molecular stratification of early breast cancer identifies drug targets to drive stratified medicine. NPJ Breast Cancer 3, 3. 10.1038/s41523-016-0003-5. - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

The genomic and evolutionary landscapes of anaplastic thyroid carcinoma

Affiliations

The genomic and evolutionary landscapes of anaplastic thyroid carcinoma

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous