NEW YORK (GenomeWeb) – A new paper in the American Journal of Human Genetics outlines the mutation patterns present in thyroid cancers from hundreds of Saudi Arabian individuals, uncovering alterations associated with aggressive cancer and metastasis.
Researchers from Saudi Arabia used exome sequencing to profile tumor and matched normal samples from 101 individuals with papillary thyroid carcinoma — a form of cancer that's particularly common in Saudi Arabia. Based on the mutations detected, they went on to develop sequencing panels for profiling mutation patterns in another 785 papillary thyroid cancer cases.
The search led to both new and known thyroid cancer genes, along with alterations affecting the thyroglobulin gene TG that were over-represented in tumor samples from individuals with aggressive papillary thyroid carcinoma cases and poor outcomes.
"Our results suggest a previously unknown role of TG mutations in the pathogenesis of [papillary thyroid carcinoma] and its malignant evolution," co-corresponding authors Fowzan Alkuraya and Khawla Al-Kuraya, both affiliated with the King Faisal Specialist Hospital and Research Centre, and their co-authors wrote.
Although papillary thyroid carcinoma is particularly common in places such Saudi Arabia. Japan, Denmark, and Italy, the team noted that populations from these countries have not participated in large-scale genomics efforts aimed at the disease. With that in mind, the researchers decided to search thyroid cancer mutations in the Saudi Arabian population using tumor and matched normal samples from 101 papillary thyroid carcinoma patients diagnosed between 1988 and 2015. Using Nextera and SureSelect exome capture kits, they targeted protein-coding sequences in these samples before sequencing the exomes with Illumina HiSeq 2500 instruments.
As it turned out, all but one of the tumor genomes showed relatively few somatic mutations. Across the entire set of tumor exomes, the researchers explained, they uncovered 20,118 apparent somatic mutations. And more than 16,800 of those turned up in a single, highly mutated tumor.
As in past studies of thyroid cancer, the team saw highly recurrent mutations affecting genes such as BRAF, and the RAS genes that are related to the MAP-kinase signaling pathway. Another 21 genes — including TP53, DNMT3A, and TG — were mutated in at least two of the thyroid tumors.
Using the Illumina HiSeq 2500, the researchers explored the prevalence of these mutations by sequencing a panel of two-dozen genes in tumors from 785 more individuals with papillary thyroid carcinoma.
More than 3 percent of papillary thyroid carcinoma tumors in the discovery and validation groups contained mutations affecting TG, a gene previously implicated in a condition called congenital hypothyroidism that may predispose individuals to thyroid cancer.
When the team took a closer look at the 27 tumors containing TG mutations, it found that these cases tended to be more clinically aggressive and prone to distant metastasis than those involving TG mutation-free tumors. For example, the researchers discovered that TG mutations were roughly four times more common in tumor samples from 71 individuals with metastatic papillary thyroid carcinoma than they were across the complete set of thyroid tumors. And in a set of 11 metastatic papillary thyroid carcinoma tumors, TG mutations turned up more than one third of the time.
"[A]lthough they do not appear to drive initial oncogenesis, [TG mutations] are likely to drive the aggressive evolution of [papillary thyroid carcinoma], including metastatic potential," the study's authors noted.