RET GENE ANALYSIS IN FAMILIAL MEDULLARY THYROID CARCINOMA & ANALYSIS OF RET AND RAS GENES IN SPORADIC MEDULLARY THYROID CARCINOMA
Familial Medullary Thyroid Cancer (FMTC) is characterised by the presence of medullary thyroid cancer (MTC) in the absence of phaeochromocytoma or parathyroid adenoma/hyperplasia. Variants in exons 5, 8, 10, 11, 13, 14, 15 and 16 of the RET gene have been identified in >95% FMTC cases (Hansford and Mulligan 2000 J Med Genet 37:817-827).
Sporadic MTC is defined by the absence of a familial history of MTC and other MEN2A-related tumours. Approximately 7% patients with presumed sporadic medullary thyroid cancer actually have a germline variant (Romei et al 2011 Clin Endocrinol 74:241-247). For patients where no germline RET variant has been identified, analysis of the RET and RAS genes can be undertaken in tumour tissue. Somatic RET variants are identified in 35-50% of sporadic MTC tumours, with the p.M918T variant being the most common. Up to 45% sporadic tumours harbour HRAS, NRAS or KRAS variants. RET and RAS variants are mutually exclusive (Boichard et al 2012 J Clin Endocrinol Metab 97: E2031–E2035). The presence of a somatic RET variant is a strong negative prognostic marker for overall and disease-free survival (Elisei et al 2008 J Clin Endocrinol Metab 93:682-687), whereas patients with somatic RAS variants have been shown to have a less aggressive tumour phenotype (Ciampi et al 2013 Thyroid 23:50-57).
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