Related Experiment Video
Updated: Feb 6, 2026
Author Spotlight: High-Throughput Image-Based Quantification of Mitochondrial DNA Synthesis and Distribution
Published on: May 5, 2023
Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma
Raj K Gopal1, Kirsten Kübler2, Sarah E Calvo3
1Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Hürthle cell carcinoma of the thyroid (HCC) is a form of thyroid cancer recalcitrant to radioiodine therapy that exhibits an accumulation of mitochondria. We performed whole-exome sequencing on a cohort of primary, recurrent, and metastatic tumors, and identified recurrent mutations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter. Parallel analysis of mtDNA revealed recurrent homoplasmic mutations in subunits of complex I of the electron transport chain. Analysis of DNA copy-number alterations uncovered widespread loss of chromosomes culminating in near-haploid chromosomal content in a large fraction of HCC, which was maintained during metastatic spread. This work uncovers a distinct molecular origin of HCC compared with other thyroid malignancies.
Insights
Hürthle cell carcinoma (HCC) is a thyroid cancer resistant to radioiodine therapy. Genetic analysis reveals unique mutations and near-haploidization, distinguishing it from other thyroid cancers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Hürthle cell carcinoma (HCC) is a rare thyroid malignancy.
- HCC is notably resistant to standard radioiodine therapy.
- Mitochondrial accumulation is a characteristic feature of HCC.
Purpose of the Study:
- To investigate the distinct molecular underpinnings of Hürthle cell carcinoma.
- To identify recurrent genetic alterations in primary, recurrent, and metastatic HCC.
- To compare the molecular profile of HCC with other thyroid malignancies.
Main Methods:
- Whole-exome sequencing of tumor DNA.
- Mitochondrial DNA (mtDNA) analysis.
- DNA copy-number alteration analysis.
Main Results:
- Recurrent mutations were identified in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter.
- Homoplasmic mutations in mitochondrial complex I subunits were recurrent.
- Widespread chromosome loss leading to near-haploidization was observed and maintained in metastases.
Conclusions:
- Hürthle cell carcinoma possesses a unique molecular signature.
- Genetic alterations in nuclear and mitochondrial DNA contribute to HCC pathogenesis.
- The observed near-haploidization suggests a distinct evolutionary trajectory for HCC.
More Related Videos
09:15Measuring Single-Cell Mitochondrial DNA Copy Number and Heteroplasmy Using Digital Droplet Polymerase Chain Reaction
Published on: July 12, 2022
06:25Chromosomics: Detection of Numerical and Structural Alterations in All 24 Human Chromosomes Simultaneously Using a Novel OctoChrome FISH Assay
Published on: February 6, 2012
Related Concept Videos
02:59Animal Mitochondrial Genetics
02:05DNA as a Genetic Template
02:05DNA as a Genetic Template
02:40Chromosome Structure
The centromere is a DNA sequence that links sister chromatids. This is also where kinetochores, protein complexes to which spindle microtubules attach, are constructed after the chromosome is replicated. The kinetochores allow the spindle microtubules to move the chromosomes within the cell during cell division.
Telomeres consist of non-coding repetitive nucleotide...
02:31Chromosome Replication
02:04Polytene Chromosomes