Genomic Landscape of Papillary Thyroid Carcinoma

TCGA study improves understanding of genetic drivers of thyroid cancer

A comprehensive analysis of the genomes of nearly 500 papillary thyroid carcinomas – the most common form of thyroid cancer – has provided new insights into the roles of frequently mutated cancer genes and other genomic alterations that drive disease development. The findings also may help improve diagnosis and treatment.

Investigators from The Cancer Genome Atlas (TCGA) Research Network identified new molecular subtypes that will help clinicians determine which tumours are more aggressive and which are more likely to respond to certain treatments. Their findings confirmed that papillary thyroid carcinomas are driven primarily by mutations in one of two cancer-associated genes: BRAF (and a particular mutation, V600E) or RAS.

The work also detailed many differences between the two genetic types, particularly in signalling pathways that promote tumour development and growth. The researchers developed a scoring system to reflect gene expression in the two papillary thyroid carcinoma types, allowing them to characterise tumours and determine both the pathway a tumour uses to send signals and its relative aggressiveness.

Where a tumour lies in a thyroid differentiation score can have important treatment implications because different tumour signalling properties can mean the cancer responds differently to particular therapies. These scores are being tested in a clinical trial to assess if it can lead to more targeted treatment recommendations.

The study also showed that BRAF-driven tumours have a broader range of genetic complexity than previously thought, with distinct subtypes. The results suggest a need for a new classification system that more accurately reflects underlying genetic characteristics of the cancer. The researchers, led by Dr Thomas Giordano, University of Michigan, Ann Arbor, and Gad Getz, PhD, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, reported their results online October 23, 2014, in the journal Cell.

The finding suggests the potential to reclassify the disease based on genetic markers and moves thyroid cancer into a position to benefit more from precision medicine. An initial recommendation is for the pathology and scientific communities to consider reclassifying thyroid cancer based on molecular subtypes to better reflect their underlying molecular properties.

"This understanding of the genomic landscape of thyroid cancer will refine how it's classified and improve molecular diagnosis. This will help us separate those patients who need aggressive treatment from those whose tumor is never likely to grow or spread," says Thomas Giordano.

"This study integrated a wide variety of genomic data to not only identify cancer drivers, but to compare how these different drivers behave," said Getz, who is also director of the Bioinformatics Program at the Massachusetts General Hospital Cancer Center and an associate professor of pathology at Harvard Medical School. "Interestingly, we found that subsets of BRAF-mutated thyroid cancers are driving cancer through distinct mechanisms, and that some of these subsets are associated with higher risk and less differentiated cancers."

The TCGA is a federally funded project to understand the molecular characterisation of various cancer types. The project has already published numerous signature papers in cancer types such as breast, colon, ovarian and lung. The TCGA is a collaboration jointly supported and managed by the USA National Cancer Institute and the National Human Genome Research Institute, both parts of the National Institutes of Health.

Reference

The Cancer Genome Atlas Research Network. Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell 2014; 159(3):676-690. DOI: 10.1016/j.cell.2014.09.050.