Differentiated thyroid cancer (DTC) of papillary (PTC) and follicular (FTC) types with invasive loco-regional or metastatic disease, poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC), as well as the C-cell derived medullary thyroid cancers (MTC), represent the major cause of mortality amongst thyroid cancer patients. Because such patients are resistant to standard therapy, they may be excellent candidates for innovative adjuvant approaches such as molecular targeted therapies. Thus, a better understanding of the molecular mechanisms underlying these advanced forms of thyroid cancer is essential for the design of newer and more efficient forms of treatment. Our knowledge of the molecular pathogenesis of thyroid carcinomas has improved dramatically in the past few years. Recently, the whole-exome sequencing of ~500 PTCs confirmed the dominant role of MAPK and PI3K pathways in PTC and also revealed other new driver mutations.1 Mutational analysis of PDTC and ATC showed that most mutations were present in TP53, RAS, TERT, PIK3CA, PTEN and CDKIs2,3 and mutually exclusive RET and RAS mutations represent the major mutational events in MTC.4
Knowledge of key oncogenic mutations in differentiated thyroid cancer rose interest on tyrosine kinase inhibitors and several phase III studies with these drugs have been performed in both follicular-derived and C-cell derived carcinomas with promising results. Unfortunately, studies on target-therapy of specific oncogenic mutations and immune-modulating approaches are yet to be published.
Next-generation sequencing, which enables analysis of multiple genes in DNA extracted from tumour biopsies or in tumour circulating DNA, combined with specific inhibition of target gene(s), will represent a powerful tool to manage advanced thyroid cancer analogously to other tumour models, such as the lung, in which this approach has revolutionized the treatment of the disease.
1. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014 159 (3) 676690. (doi:10.1016/j.cell.2014.09.050).
2. Pita JM, Figueiredo IF, Moura MM, Leite V & Cavaco BM. Cell cycle deregulation and TP53 and RAS mutations are major events in poorly differentiated and undifferentiated thyroid carcinomas. J Clin Endocrinol Metab 2014 99 (3) E497E507. (doi:10.1210/jc.2013-1512)
3. Kunstman JW, Juhlin CC, Goh G, Brown TC, Stenman A, Healy JM, Rubinstein JC, Choi M, Kiss N, Nelson-Williams C et al. Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing. Hum Mol Genet 2015 24 (8) 2318-2329. (doi:10.1093/hmg/ddu749)
4. Moura MM, Cavaco BM, Pinto AE & Leite V. High prevalence of RAS mutations in RET negative sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab 2011 96 (5) E863E868. (doi:10.1210/jc.2010-1921)
17 - 19 Feb 2016
European Society of Endocrinology