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21-07-2016 | Endocrine cancers | Book chapter | Article

6. Genetic Evaluation of the Patient with Medullary Thyroid Cancer

Author: Jennifer L. Geurts

Publisher: Springer International Publishing

Abstract

The hereditary form of medullary thyroid cancer (MTC) is termed multiple endocrine neoplasia type 2 (MEN2). The RET gene is the only gene known to cause MEN2 syndrome, and up to 98 % of patients with MEN2 have an identifiable pathogenic mutation in this gene.
Literature
1.
DeLellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and genetics: tumours of the endocrine organs. Lyon, France: IARC Press; 2004.
2.
Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2(7):851–6.CrossRefPubMed
3.
Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363(6428):458–60.CrossRefPubMed
4.
Eng C, Smith DP, Mulligan LM, Healey CS, Zvelebil MJ, Stonehouse TJ, et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene. 1995;10(3):509–13.PubMed
5.
Bolino A, Schuffenecker I, Luo Y, Seri M, Silengo M, Tocco T, et al. RET mutations in exons 13 and 14 of FMTC patients. Oncogene. 1995;10(12):2415–9.PubMed
6.
Hofstra RM, Fattoruso O, Quadro L, Wu Y, Libroia A, Verga U, et al. A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab. 1997;82(12):4176–8.PubMed
7.
Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, et al. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab. 1998;83(3):770–4.PubMed
8.
Papi G, Corsello SM, Cioni K, Pizzini AM, Corrado S, Carapezzi C, et al. Value of routine measurement of serum calcitonin concentrations in patients with nodular thyroid disease: a multicenter study. J Endocrinol Invest. 2006;29(5):427–37.CrossRefPubMed
9.
Carney JA. Familial multiple endocrine neoplasia: the first 100 years. Am J Surg Pathol. 2005;29(2):254–74.CrossRefPubMed
10.
Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D’etude des Tumeurs a Calcitonine. J Clin Endocrinol Metab. 1998;83(2):487–91.PubMed
11.
Jackson MB, Guttenberg M, Hedrick H, Moshang T Jr. Multiple endocrine neoplasia type 2A in a kindred with C634Y mutation. Pediatrics. 2005;116(3):e468–71.CrossRefPubMed
12.
Kraimps JL, Denizot A, Carnaille B, Henry JF, Proye C, Bacourt F, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d’Etude des Tumeurs a Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World J Surg. 1996;20(7):808–12; (discussion 12-3).
13.
Raue F, Kraimps JL, Dralle H, Cougard P, Proye C, Frilling A, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Intern Med. 1995;238(4):369–73.CrossRefPubMed
14.
Herfarth KK, Bartsch D, Doherty GM, Wells SA, Jr., Lairmore TC. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery. 1996;120(6):966–73; (discussion 73-4).
15.
Imai T, Uchino S, Okamoto T, Suzuki S, Kosugi S, Kikumori T, et al. High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. Eur J Endocrinol/Eur Fed Endocr Soc. 2013;168(5):683–7.CrossRef
16.
Frank-Raue K, Rybicki LA, Erlic Z, Schweizer H, Winter A, Milos I, et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011;32(1):51–8.CrossRefPubMed
17.
Inabnet WB, Caragliano P, Pertsemlidis D. Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery. 2000;128(6):1007–11; (discussion 11-2).
18.
Rodriguez JM, Balsalobre M, Ponce JL, Rios A, Torregrosa NM, Tebar J, et al. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg. 2008;32(11):2520–6.CrossRefPubMed
19.
Modigliani E, Vasen HM, Raue K, Dralle H, Frilling A, Gheri RG, et al. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med. 1995;238(4):363–7.CrossRefPubMed
20.
Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med. 2005;257(1):60–8.CrossRefPubMed
21.
Pomares FJ, Canas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ. Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma. Clin Endocrinol. 1998;48(2):195–200.CrossRef
22.
Lairmore TC, Ball DW, Baylin SB, Wells SA, Jr. Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Annals of surgery. 1993;217(6):595–601; (discussion-3).
23.
Boedeker CC, Erlic Z, Richard S, Kontny U, Gimenez-Roqueplo AP, Cascon A, et al. Head and neck paragangliomas in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. J Clinical Endocrinol Metab. 2009;94(6):1938–44.CrossRef
24.
Lips CJ, Landsvater RM, Hoppener JW, Geerdink RA, Blijham G, van Veen JM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med. 1994;331(13):828–35.CrossRefPubMed
25.
Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T, Tschen JA. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med. 1989;111(10):802–6.CrossRefPubMed
26.
Verga U, Fugazzola L, Cambiaghi S, Pritelli C, Alessi E, Cortelazzi D, et al. Frequent association between MEN 2A and cutaneous lichen amyloidosis. Clin Endocrinol. 2003;59(2):156–61.CrossRef
27.
Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid: Official J Am Thyroid Assoc. 2015;25(6):567–610.CrossRef
28.
Morrison PJ, Nevin NC. Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome). J Med Genet. 1996;33(9):779–82.CrossRefPubMedPubMedCentral
29.
Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985;42(2):581–8.CrossRefPubMed
30.
Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. Int RET Mutat Consortium Anal Jama. 1996;276(19):1575–9.
31.
Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV, et al. Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg (Chicago, Ill: 1960). 2003;138(4):409–16; (discussion 16).
32.
Zbuk KM, Eng C. Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer. 2007;7(1):35–45.CrossRefPubMed
33.
Seri M, Celli I, Betsos N, Claudiani F, Camera G, Romeo G. A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis. Clin Genet. 1997;51(2):86–90.CrossRefPubMed
34.
Feldman GL, Edmonds MW, Ainsworth PJ, Schuffenecker I, Lenoir GM, Saxe AW, et al. Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG → ATG) mutation. Surgery. 2000;128(1):93–8.CrossRefPubMed
35.
Frohnauer MK, Decker RA. Update on the MEN 2A c804 RET mutation: is prophylactic thyroidectomy indicated? Surgery. 2000;128(6):1052–7; (discussion 7-8).
36.
Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA. 1994;91(4):1579–83.CrossRefPubMedPubMedCentral
37.
Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994;3(2):237–41.CrossRefPubMed
38.
Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mulligan LM, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997;82(11):3902–4.CrossRefPubMed
39.
Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene. 1997;15(10):1213–7.CrossRefPubMed
40.
Miyauchi A, Futami H, Hai N, Yokozawa T, Kuma K, Aoki N, et al. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Japan J Cancer Res: Gann. 1999;90(1):1–5.CrossRef
41.
Iwashita T, Murakami H, Kurokawa K, Kawai K, Miyauchi A, Futami H, et al. A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun. 2000;268(3):804–8.CrossRefPubMed
42.
Kameyama K, Okinaga H, Takami H. RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. Biomed pharmacother = Biomedecine & pharmacotherapie. 2004;58(6–7):345-7.
43.
Nakao KT, Usui T, Ikeda M, Mori Y, Yamamoto T, Kawashima ST, et al. Novel tandem germline RET proto-oncogene mutations in a patient with multiple endocrine neoplasia type 2B: report of a case and a literature review of tandem RET mutations with in silico analysis. Head Neck. 2013;35(12):E363–8.CrossRefPubMed
44.
Margraf RL, Crockett DK, Krautscheid PM, Seamons R, Calderon FR, Wittwer CT, et al. Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat. 2009;30(4):548–56.CrossRefPubMed
45.
Colombo C, Minna E, Rizzetti MG, Romeo P, Lecis D, Persani L, et al. The modifier role of RET-G691S polymorphism in hereditary medullary thyroid carcinoma: functional characterization and expression/penetrance studies. Orphanet J Rare Dis. 2015;10:25.CrossRefPubMedPubMedCentral
46.
Network NCC. Neuroendocrine tumors (version 1.2015) 2015 [1 Sept 2015]. Available from: www.​nccn.​org.
47.
Wiench M, Wygoda Z, Gubala E, Wloch J, Lisowska K, Krassowski J, et al. Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol: Official J Am Soc Clin Oncol. 2001;19(5):1374–80.
48.
Eng C, Mulligan LM, Smith DP, Healey CS, Frilling A, Raue F, et al. Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol. 1995;43(1):123–7.CrossRef
49.
Elisei R, Romei C, Cosci B, Agate L, Bottici V, Molinaro E, et al. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab. 2007;92(12):4725–9.CrossRefPubMed
50.
Wohllk N, Cote GJ, Bugalho MM, Ordonez N, Evans DB, Goepfert H, et al. Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 1996;81(10):3740–5.PubMed
51.
Raue F, Rondot S, Schulze E, Szpak-Ulczok S, Jarzab B, Frank-Raue K. Clinical utility gene card for: multiple endocrine neoplasia type 2. Eur J Hum Genet: EJHG. 2012;20(1).
52.
Marquard J, Eng C. Multiple endocrine neoplasia type 2. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al. (eds) GeneReviews(R). University of Washington, Seattle, Seattle (WA).
53.
University of Washington, Seattle. All rights reserved.; 1993.
54.
Carlson KM, Bracamontes J, Jackson CE, Clark R, Lacroix A, Wells SA Jr, et al. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet. 1994;55(6):1076–82.PubMedPubMedCentral
55.
Schuffenecker I, Ginet N, Goldgar D, Eng C, Chambe B, Boneu A, et al. Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d’Etude des Tumeurs a Calcitonine. Am J Hum Genet. 1997;60(1):233–7.PubMedPubMedCentral
56.
Komminoth P, Kunz EK, Matias-Guiu X, Hiort O, Christiansen G, Colomer A, et al. Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas. Cancer. 1995;76(3):479–89.CrossRefPubMed
57.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med: Official J Am Coll Med Genet. 2015;17(5):405–24.CrossRef
58.
ASCO. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol: Official J Am Soc Clin Oncol. 2003;21(12):2397–406.
59.
Macher HC, Martinez-Broca MA, Rubio-Calvo A, Leon-Garcia C, Conde-Sanchez M, Costa A, et al. Non-invasive prenatal diagnosis of multiple endocrine neoplasia type 2A using COLD-PCR combined with HRM genotyping analysis from maternal serum. PLoS One. 2012;7(12):e51024.CrossRefPubMedPubMedCentral
60.
Lam KW, Jiang P, Liao GJ, Chan KC, Leung TY, Chiu RW, et al. Noninvasive prenatal diagnosis of monogenic diseases by targeted massively parallel sequencing of maternal plasma: application to beta-thalassemia. Clin Chem. 2012;58(10):1467–75.CrossRefPubMed
61.
Lun FM, Tsui NB, Chan KC, Leung TY, Lau TK, Charoenkwan P, et al. Noninvasive prenatal diagnosis of monogenic diseases by digital size selection and relative mutation dosage on DNA in maternal plasma. Proc Natl Acad Sci USA. 2008;105(50):19920–5.CrossRefPubMedPubMedCentral
62.
Lietman SA. Preimplantation genetic diagnosis for hereditary endocrine disease. Endocrine Pract: Official J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2011;17(Suppl 3):28–32.CrossRef
63.
Altarescu G, Barenholz O, Renbaum P, Beeri R, Levy-Lahad E, Margalioth EJ, et al. Preimplantation genetic diagnosis (PGD)–prevention of the birth of children affected with endocrine diseases. J Pediatr Endocrinol Metab: JPEM. 2011;24(7–8):543–8.PubMed
64.
Health law—genetics—Congress restricts use of genetic information by insurers and employers.—Genetic Information Nondiscrimination Act of 2008, Pub. L. No. 110-233, 122 Stat. 881 (to be codified in scattered sections of 26, 29, and 42 U.S.C.). Harvard law review. 2009;122(3):1038-45.