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

Abstract

Multiple endocrine neoplasia type 2 (MEN2) is a neuroendocrine cancer syndrome characterized by medullary thyroid carcinoma, in combination or not with pheochromocytoma, hyperparathyroidism, and extra-endocrine features. MEN2 syndrome includes two clinically distinct forms subtyped as MEN2A and MEN2B. Nearly all MEN2 cases are caused by germline mutations of the RET proto-oncogene. In this review, we propose "5P" strategies for management of MEN2: prevention, prediction, personalization, psychological support, and participation, which could effectively improve clinical outcomes of patients. Based on RET mutations, MEN2 could be prevented through prenatal diagnosis or preimplantation genetic testing. Identification of pathogenic mutations in RET can enable early diagnosis of MEN2. Combining RET mutation testing with measurement of serum calcitonin, plasma or urinary metanephrine/normetanephrine, and serum parathyroid hormone levels could allow risk stratification and accurately prediction of MEN2 progression, thus facilitating implementation of personalized precision treatments to increase disease-free survival and overall survival. Furthermore, increased awareness of MEN2 is needed, which requires participation of physicians, patients, family members, and related organizations. Psychological support is also important for patients with MEN2 to promote comprehensive management of MEN2 symptoms. The "5P" strategies for management of MEN2 represent a typical clinical example of precision medicine. These strategies could effectively improve the health of MEN2 patient, and avoid adverse outcomes, including death and major morbidity, from MEN2.

Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China

“…Over the past 25 years, new insight into the natural course of disease and genotype-phenotype data caused a paradigm shift in management of MEN2. Identification of asymptomatic carriers of RET mutations in exons 8, 10, 11, and 13–16 by a routine procedure, followed by appropriate screening through pedigree investigation, early diagnosis, and timely prophylactic treatment is essential to improving the likelihood of good outcomes [ 1 , 9 , 21 – 24 ]. In present study, 88.8% of 276 patients presenting with MEN2 carried RET -defined mutations, of which 87.3% had single mutations, and 12.7% had compound mutations.…”

“…The identification of RET mutations as the cause of MEN2 has significantly changed MEN2 disease management, including disease prevention, risk prediction, early diagnosis, and personalized treatment of MEN2-specific tumors. Together, these approaches represent a paradigm of precision medicine [ 1 , 4 – 9 ].…”

“…The RET proto-oncogene contains 20 exons and encodes a tyrosine kinase transmembrane receptor ( https://www.ncbi.nlm.nih.gov/gene/5979 ). Sequencing of RET has resulted in the identification of 199 variants, of which approximately 45% are pathogenic mutants involved in MEN2 [ 10 ], and thus far, mutation hotspots are known to mainly occur in exons 8, 10, 11, and 13–16 [ 1 , 9 – 17 ]. Based on the specific RET mutation (genotype) associated with phenotypes, the Revised American Thyroid Association (ATA) Guidelines (hereafter referred to as ATA-2015), among others, have defined the management of MTC risk category (moderate risk, ATA-MOD; high risk, ATA-H; and highest risk, ATA-HST) of each specific RET mutation and recommended the optimal age of prophylactic total thyroidectomy, timing by which patients carrying germline RET mutations should be screened for PHEO and HPTH, penetrance estimations, and surgical windows of opportunity [ 1 , 18 , 19 ].…”

Spectrum of Germline RET Variants Identified by Targeted Sequencing and Associated Multiple Endocrine Neoplasia Type 2 Susceptibility in China

“…The identi cation of RET mutations as the cause of MEN2 has signi cantly changed MEN2 disease management, including disease prevention, risk prediction, early diagnosis, and personalized treatment of MEN2-speci c tumors. Together, these approaches represent a paradigm of precision medicine [1,[4][5][6][7][8][9].The RET proto-oncogene contains 20 exons and encodes a tyrosine kinase transmembrane receptor (https://www.ncbi.nlm.nih.gov/gene/5979). Sequencing of RET has resulted in the identi cation of 199 variants, of which approximately 45% are pathogenic mutants involved in MEN2 [10], and thus far, mutation hotspots are known to mainly occur in exons 8, 10, 11, and 13-16 [1,[9][10][11][12][13][14][15][16][17].…”

“…Together, these approaches represent a paradigm of precision medicine [1,[4][5][6][7][8][9].The RET proto-oncogene contains 20 exons and encodes a tyrosine kinase transmembrane receptor (https://www.ncbi.nlm.nih.gov/gene/5979). Sequencing of RET has resulted in the identi cation of 199 variants, of which approximately 45% are pathogenic mutants involved in MEN2 [10], and thus far, mutation hotspots are known to mainly occur in exons 8, 10, 11, and 13-16 [1,[9][10][11][12][13][14][15][16][17]. Based on the speci c RET mutation (genotype) associated with phenotypes, the Revised American Thyroid Association (ATA) Guidelines (hereafter referred to as ATA-2015), among others, have de ned the management of MTC risk category (moderate risk, ATA-MOD; high risk, ATA-H; and highest risk, ATA-HST) of each speci c RET mutation and recommended the optimal age of prophylactic total thyroidectomy, timing by which patients carrying germline RET mutations should be screened for PHEO and HPTH, penetrance estimations, and surgical windows of opportunity [1, 18,19].…”