Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization

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Abstract

The discovery of actionable kinase gene rearrangements has revolutionized the therapeutic landscape of thyroid carcinomas. Unsolved challenges include histopathologic recognition of targetable cases, correlation between genotypes and tumor behavior, and evolving resistance mechanisms against kinase inhibitors (KI). We present 62 kinase fusion-positive thyroid carcinomas (KFTC), including 57 papillary thyroid carcinomas (PTC), two poorly differentiated thyroid carcinomas (PDTC), two undifferentiated thyroid carcinomas (ATC), and one primary secretory carcinoma (SC), in 57 adults and 5 adolescents. Clinical records, post-operative histology, and molecular profiles were reviewed. Histologically, all KFTC showed multinodular growth with prominent intratumoral fibrosis. Lymphovascular invasion (95%), extrathyroidal extension, gross and microscopic (63%), and cervical lymph node metastasis (79%) were common. Several kinase fusions were identified: STRN-ALK, EML4-ALK, AGK-BRAF, CUL1-BRAF, MKRN1-BRAF, SND1-BRAF, TTYH3-BRAF, EML4-MET, TFG-MET, IRF2BP2-NTRK1, PPL-NTRK1, SQSTM1-NTRK1, TPR-NTRK1, TPM3-NTRK1, EML4-NTRK3, ETV6-NTRK3, RBPMS-NTRK3, SQSTM1-NTRK3, CCDC6-RET, ERC1-RET, NCOA4-RET, RASAL2-RET, TRIM24-RET, TRIM27-RET, and CCDC30-ROS1. Individual cases also showed copy number variants of EGFR and nucleotide variants and indels in pTERT, TP53, PIK3R1, AKT2, TSC2, FBXW7, JAK2, MEN1, VHL, IDH1, PTCH1, GNA11, GNAQ, SMARCA4 and CDH1. In addition to thyroidectomy and radioactive iodine, 10 patients received multi-kinase and/or selective kinase inhibitor therapy, with 6 durable, objective responses and 4 with progressive disease. Among 47 cases with >6 months of follow-up (median [range]: 41 [6 to 480] months), persistent/recurrent disease, distant metastasis and thyroid cancer-related death occurred in 57%, 38% and 6%, respectively. In summary, KFTC encompass a spectrum of molecularly diverse tumors with overlapping clinicopathologic features and a tendency for clinical aggressiveness. Characteristic histology with multinodular growth and prominent fibrosis, particularly when there is extensive lymphovascular spread, should trigger molecular testing for gene rearrangements, either in a step-wise manner by prevalence or using a combined panel. Our findings further provide information on molecularly therapy in radioiodine-refractory thyroid carcinoma.

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Fast and accurate short read alignment with Burrows–Wheeler transform

Heng Li, Richard Durbin (2009)

Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: http://maq.sourceforge.net Contact: rd@sanger.ac.uk

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2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer.

Bryan Haugen, Erik Alexander, Keith Bible … (2016)

Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer.

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(2014)

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.