Genotype‐specific progression of hereditary medullary thyroid cancer. Issue 6 (3rd May 2018)

• Record Type: Journal Article
• Authors: Machens, Andreas; Lorenz, Kerstin; Weber, Frank; Dralle, Henning
• Is Part Of: Human mutation. Volume 39:Issue 6(2018)
• Page Start: 860
• Page End: 869
• Publication Date: 2018-05-03
• Subjects: age‐related progression -- germline mutation -- lymph node metastasis -- medullary thyroid carcinoma -- RET proto‐oncogene -- translational medicine; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23430
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Although already 25 years into the genomic era, age‐related progression of hereditary medullary thyroid cancer (MTC), the prevalence of which is estimated at one in 80, 000 inhabitants, remains to be delineated for most unique RET ( RE arranged during T ransfection) mutations. Included in this study were 567 RET carriers. The age‐related progression of MTC across histopathological groups (normal thyroid/C‐cell hyperplasia; node‐negative MTC; node‐positive MTC) was statistically significant for 13 unique RET mutations (p.Cys611Phe/c.1832G > T; p.Cys611Tyr; p.Cys618Ser/c.1852T > A; p.Cys620Arg; p.Cys634Arg; p.Cys634Phe; p.Cys634Ser; p.Cys634Tyr; p.Glu768Asp; p.Leu790Phe/c.2370G > T; p.Val804Met; p.Ser891Ala; p.Met918Thr), whereas two unique RET mutations (p.Cys618Phe; p.Cys634Gly) trended toward statistical significance. When grouped by mutational risk (highest; high; moderate– high; low– moderate; polymorphism), the age‐related progression of MTC was significant for all four categories of RET mutations, which differed significantly across and within the three histopathological groups. For high, for moderate–high, and for low–moderate risk RET mutations, the age‐related progression of MTC by mutated codon was broadly comparable across and within the three histopathological groups, and essentially unaffected by the amino acid substitutions examined. These data argue in favor of splitting the American Thyroid Association's moderate‐risk category into moderate–high and low–moderate risk categories, while emphasizing the need to contradistinguish the latter from rare nonpathogenic polymorphisms. Abstract : When 32 unique RET sequence variants (29 mutations, 3 polymorphisms), dispersed over 567 gene carriers, were grouped by mutational risk (highest; high; moderate–high; low–moderate; polymorphism), the age‐related progression of medullary thyroid cancer (MTC) was significant for all categories of RET mutations, which differed significantly across and within the histopathological groups (normal thyroid/C‐cell hyperplasia; node‐negative MTC; node‐positive MTC). This finding argues in favor of splitting the American Thyroid Association's moderate‐risk category into moderate–high and low–moderate risk categories.