The synergy of germline C634Y and V292M RET mutations in a northern Chinese family with multiple endocrine neoplasia type 2A.
Genetic analysis for germline mutations of RET proto-oncogene has provided a basis for individual management of medullary thyroid carcinoma (MTC) and pheochromocytoma. Most of compound mutations have more aggressive phenotypes than single point mutations, but the compound C634Y/V292M variant in MTC has never been reported. Thus, we retrospectively investigated synergistic effect of C634Y and V292M RET germline mutations in family members with multiple endocrine neoplasia type 2A. Nine of 14 family members in a northern Chinese family underwent RET mutation screening using next-generation sequencing and PCR followed by direct bidirectional DNA sequencing. Clinical features of nine individuals were retrospectively carefully reviewed. In vitro, the scratch-wound assay was used to investigate the difference between the cells carrying different mutations. We find no patients died of MTC. All 3 carriers of the V292M variant were asymptomatic and did not have biochemical or structural evidence of disease (age: 82, 62 and 58). Among 4 C634Y mutation carriers, 2 patients had elevated calcitonin with the highest (156 pg/mL) in an 87-year-old male. Two carriers of compound C634Y/V292M trans variant had bilateral MTC with pheochromocytoma or lymph node metastasis (age: 54 and 41 years, respectively). Further, the compound C634Y/V292M variant had a faster migration rate than either single point mutation in vitro (P < .05). In conclusion, the V292M RET variant could be classified as 'likely benign' according to ACMG (2015). The compound variant V292M/C634Y was associated with both more aggressive clinical phenotype and faster cell growth in vitro than was either single mutation.
['Yang|Zheng|Z|', 'Qi|Xinmeng|X|', 'Gross|Neil|N|', 'Kou|Xiujuan|X|', 'Bai|Yunlong|Y|', 'Feng|Yaru|Y|', 'Wang|Bochun|B|', 'Zafereo|Mark E|ME|', 'Li|Guojun|G|0000-0001-9505-1502', 'Sun|Chuanzheng|C|', 'Li|Huihui|H|', 'Chen|Xiaohong|X|', 'Huang|Zhigang|Z|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D000818:Animals D002648:Child D002681:China D005192:Family Health D005260:Female D018095:Germ-Line Mutation D057809:HEK293 Cells D006579:Heterozygote D006801:Humans D008207:Lymphatic Metastasis D008297:Male D051379:Mice D008875:Middle Aged D018813:Multiple Endocrine Neoplasia Type 2a D041681:NIH 3T3 Cells D010375:Pedigree D010641:Phenotype D017354:Point Mutation D000090063:Proto-Oncogene Mas D051096:Proto-Oncogene Proteins c-ret D012189:Retrospective Studies
RET proto-oncogene compound mutation MEN2 hereditary medullary thyroid carcinoma