Genetic variants common, predictive in poorly differentiated, anaplastic thyroid cancers

LAKE BUENA VISTA, Fla. — Comprehensive genomic analysis identified differences in the genetic makeup of poorly differentiated and anaplastic thyroid cancers, according to study results presented at the International Thyroid Congress.

The Cancer Genome Atlas (TCGA) completed a genomic landscape study of papillary thyroid carcinomas, according to study background. However, the study did not include poorly differentiated or anaplastic thyroid cancers, which account for 5% to 10% of tumors, but more than one-third of deaths.

“There are not many studies addressing these thyroid cancers, largely because these tumors are very lethal,” Inigo Landa, PhD, research fellow at Memorial Sloan Kettering Cancer Center, said during a presentation. “We also believe that because these tumors — particularly anaplastic tumors — are infiltrated with macrophages, which form a network around the cancer cells that makes them hard to micro-dissect and sequence.”

Landa and colleagues conducted a comprehensive cancer genome assessment using data from 117 poorly differentiated thyroid cancers (n = 84) and anaplastic thyroid cancers (n = 33). They performed a targeted sequencing of 341 genes, from which they evaluated somatic mutations, fusions and copy number alterations, in addition to an mRNA expression analysis of a representative subset.

The researchers reported notable differences between the tumor types. Anaplastic thyroid cancers harbored more frequent alterations in TERT promotor genes (73% vs. 40%), TP53 (73% vs. 8%), PIK3CA (18% vs. 2%), PTEN (15% vs. 4%) and NF1 (9% vs. 0).

However, poorly differentiated thyroid cancers expressed greater enrichments of RET, PAX8-PPARG and ALK rearrangements (combined, 13% vs. 0%).

EIF1AX mutations appeared more prevalent in poorly differentiated and anaplastic thyroid cancers than papillary thyroid carcinomas (10% vs. 1%). Further, these mutations had a pattern of co-occurrence with RAS mutations (14/15; P < .0001) and predicted worsened survival outcomes (P = .048).

The researchers also identified genetic alterations not previously reported in thyroid cancer, largely affecting the PIK3/AKT/mTOR pathway, the SWI/SNF chromatin remodeling complex, histone methyltransferases and mismatch repair proteins. These alterations exhibited particularly high expressions in anaplastic thyroid cancers.

Recurrent chromosomal losses of 1p, 8p, 13q, 15q, 17p and 22q — as well as gains in 1q and 20q — were also seen.

Distinct global, M2 macrophage and thyroid differentiation transcriptomic signatures also occurred between poorly differentiated thyroid cancers and anaplastic thyroid cancers. By applying the TCGA-derived BRAF-RAS expression score to these advanced tumors, the researchers observed a preserved dependence on BRAF and RAS driver alterations, with the exception of anaplastic thyroid cancers with BRAF-like RAS mutations.

Landa noted that the study findings emphasize the importance and efficacy of ultra-deep sequencing for heavily infiltrated thyroid tumors.

“Poorly-differentiated and anaplastic thyroid tumors differ in copy number and gene expression features, some of which have clear diagnostic and prognostic implications,” Landa said. “We think that the discovery of subclonal mutations in poorly differentiated tumors should raise particular concerns.” – by Cameron Kelsall

Reference:

Landa I, et al. Oral Abstract 9. Presented at: International Thyroid Congress; Oct. 18-23, 2015; Lake Buena Vista, Fla.

Disclosure: Landa reports no relevant financial disclosures. HemOnc Today was unable to obtain a list of the other researchers’ relevant financial disclosures at the time of reporting.