The rare intracellular RET mutation p.S891A in a Chinese Han family with familial medullary thyroid carcinoma

Abstract

We report intracellular RET mutation in a Han Chinese pedigree with familial medullary thyroid carcinoma (FMTC). Direct sequencing of RET proto-oncogene identified a missense c.2671T greater than G (p.S891A) mutation in 6 of 14 family members. The single nucleotide polymorphisms c. 135A greater than G (p.A45A), IVS4 + 48A greater than G, c. 1296A greater than G (p.A432A), c. 2071G greater than A (p.G691S), c. 2307T greater than G (p.L769L) and a variant c. 833C greater than A (p.T278N) were also found in 6 carriers. Among 5 of the 6 carriers presented medullary thyroid carcinoma (MTC) as an isolated clinical phenotype, with elevated basal serum calcitonin (Ct). Two underwent non-normative thyroidectomy either two or four times without physician awareness or diagnosis of this disease at initial treatment, but with elevated Ct. One with elevated pre-Ct accepted total thyroidectomy (TT) with modified bilateral neck dissection (MBiND), and whose seventh posterior rib MTC metastases was confirmed 5 months after surgery. Moreover, results of two affected individuals with elevated Ct were reduced to normal after TT with MBiND or prophylactic VI compartmental dissection. However, only another carrier with the variant p.T278N had slightly elevated Ct rejected surgery and was strictly monitored. Given these case results, we suggest that screening of RET and pre-surgical Ct levels in the management of MTC patients is essential for earlier diagnosis and more normative initial treatment, that FMTC patients with cervical lymph nodes metastases may be cured by TT with MBiND, and that prophylactic VI compartmental dissection should be avoided when Ct levels are low.

RET mutation p.S891A in a Chinese family with familial medullary thyroid carcinoma and associated cutaneous amyloidosis binding OSMR variant p.G513D

“…For example, it appears that p.V778I, p.Y806C, and the p.Y791F polymorphisms have additive effects to p.V804M and p.C634Y, whereas p.R844L has an inhibitory modifying effect on p.V804M [ 14 ]. Although the oncogenic activity of p.S891A was slightly enhanced by p.R525W, two patients with trans p.S891A/p.R525W in our study only presented with MTC, which shows similar clinical features to p.S891A described previously [ 11 , 12 , 36 ]. Nonetheless, the follow-up study needs to be validated to avoid misinterpretation and irreversible clinical outcomes [ 38 ].…”

“…Most patients with the p.S891A mutation have manifested FMTC, whereas just a few have manifested as MEN 2A [ 11 ]. Recently, 93 carriers of the p.S891A mutation were summarized [ 11 , 12 , 36 ]: MTC was present in 74.2% (69/93), and pheochromocytoma, hyperparathyroidism, and CNT were present in 3.2% (3/93). The mean age at MTC diagnosis in those carriers was 42.1 years.…”

“…Age-related penetrance of MTC in 36 patients with the p.S891A mutation was 20.0%, 71.4%, 92.3%, and 100.0% in those aged 0–20, 21–40, 41–60, and > 60 years, respectively [ 11 ]. In our study, three of the six p.S891A mutation carriers presented with MTC as the sole clinical endocrine tumor, whereas the other 3 carriers (mean age, 24 y; range, 7–44 y) still had consistently undetectable elevations in bCt or sCt and chose a watchful waiting approach to treatment [ 12 , 36 , 37 ]. The clinical data in this family is consistent with that in previous patients with the RET p.S891A mutation and other FMTC patients with ATA-A level mutations carrying “moderate risk” (ATA-MOD) as reported worldwide recently [ 1 , 37 ].…”

“…Genomic DNA was isolated from peripheral blood leukocytes of available family members as previously described (8), followed by polymerase chain reaction (PCR) amplification and sequencing of the entire exons and the flanking splice junctions of RET, OSMR , and IL31RA. One hundred unrelated healthy matched controls and 6 affected individuals with the RET p.S891A mutation along with matched controls were included as previously reported [ 12 ].…”

5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine

“…RET mutation testing can also facilitate early diagnosis and treatment of MEN2-related diseases (e.g., CLA, HD) (15,16). families, most of which are located in hotspot mutation regions (52)(53)(54)(55)(56)(57)(58)(59). Recently, our group used T-NGS to identify a novel mutation outside the hotspot mutation regions (S409Y in exon 6 of RET) in four families (33).…”