Elsevier

Surgery

Volume 141, Issue 1, January 2007, Pages 90-95
Surgery

Original communication
Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre

https://doi.org/10.1016/j.surg.2006.03.025Get rights and content

Background

Evidence that germline mutations in the RET proto-oncogene are the underlying cause of the familial form of medullary thyroid carcinoma (MTC) made it possible to identify gene carriers with a very high degree of accuracy. Aiming to define the mutational profile observed in our patients and to assess gene carriers’ compliance with an early surgery, we reviewed results of molecular analysis of RET performed at our institution since 1994.

Methods

One hundred fifty-eight individuals were screened for germline mutations of the RET proto-oncogene. Seventy-seven patients had apparently sporadic MTC; 8 patients had both MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B despite a negative family history; 8 patients were known to belong to affected kindreds; and 65 individuals were at-risk individuals to develop MTC.

Results

A germline mutation in RET was identified in 4% of apparently sporadic MTC patients, in 100% of patients with MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B, and in 100% of probands of clinically established kindreds. The most affected codon was 634 (58%) followed by codon 804 (16%). Among at-risk individuals, 49% were identified as gene carriers. Seven individuals were submitted to prophylactic thyroidectomy (mean age, 17.7 ± 12.5 years; range: 3-42 years), and all but 1 had MTC.

Conclusions

RET mutational spectrum observed in the present population disclosed a higher frequency of codon 804 mutations than expected. Compliance with an early prophylactic surgery seemed to be influenced not only by medical advice and cultural factors but also by the aggressiveness of disease in gene carriers’ families.

Section snippets

Subjects and methods

DNA was obtained from the peripheral blood of 158 individuals who were divided into 4 groups. Group A (n = 77) included patients with apparently sporadic MTC. Group B (n = 8) included patients presenting MTC associated with pheochromocytoma despite a negative family history for multiple endocrine neoplasia type 2 (MEN 2) (7 individuals) or presenting clinical features of MEN 2B (1 individual). Group C (n = 8) included patients with MTC and known to belong to clinically established FMTC/MEN 2

Results

Germline mutations in the RET proto-oncogene were identified in 3 of 77 (3.9%) apparently sporadic MTC patients, thus indicating heritable disease. Mutations were TGC620CGC; TTG790TTT, and GTG804ATG. It was not possible to define whether they corresponded to de novo or occult mutations.

All individuals in group B (n = 8) had a germline mutation in the RET proto-oncogene. Four different mutations were identified: TGC611TAC (1 case), TGC634CGC (5 cases), GTG804ATG (1 case), and ATG918ACG (1 case).

Discussion

In 98% of MEN 2A patients and in 90% of FMTC patients20 the germline RET mutation occurs in 1 of 5 cysteine codons of the extracellular domain of the RET protein: 609, 611, 618, 620 (exon 10), or 634 (exon 11). In the remaining cases, the mutation may occur in codon 630,21 another cysteine codon in exon 11, or in noncysteine-related codons located in the intracellular domain of the RET protein such as mutations affecting codons 768, 790, and 791 (exon 13); codon 804 (exon 14); or codon 891 in

References (41)

  • D.D. Bowtell

    Rapid isolation of eukaryotic DNA

    Anal Biochem

    (1987)
  • M.F. Saad et al.

    Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients

    Medicine

    (1984)
  • F. Raue

    German medullary thyroid carcinoma/multiple endocrine neoplasia registry. German MTC/MEN Study Group. Medullary Thyroid Carcinoma/Multiple Endocrine Neoplasia Type 2

    Langenbecks Arch Surg

    (1998)
  • E. Kebebew et al.

    Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems

    Cancer

    (2000)
  • H. Donis-Keller et al.

    Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC

    Hum Mol Genet

    (1993)
  • L.M. Mulligan et al.

    Germline mutations of the RET protooncogene in multiple endocrine neoplasia Type 2A

    Nature

    (1993)
  • K.M. Carlson et al.

    Single missense mutation in the tyrosine kinase catalytic domain of the RET proto-oncogene is associated with multiple endocrine neoplasia Type 2B

    Proc Natl Acad Sci USA

    (1994)
  • C. Eng 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)
  • R.M. Hofstra et al.

    A mutation in the RET protooncogene associated with multiple endocrine neoplasia Type 2B and sporadic medullary thyroid carcinoma

    Nature

    (1994)
  • S.A. Wells et al.

    Early diagnosis and treatment of medullary thyroid carcinoma

    Arch Intern Med

    (1985)
  • D.B. Evans et al.

    The surgical treatment of medullary thyroid carcinoma

    Semin Surg Oncol

    (1999)
  • J.B. Fleming et al.

    Surgical strategy for the treatment of medullary thyroid carcinoma

    Ann Surg

    (1999)
  • O. Gimm et al.

    Diagnosis and therapy of sporadic and familial medullary thyroid carcinoma

    J Cancer Res Clin Oncol

    (2001)
  • P. Niccoli-Sire et al.

    Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC)

    Eur J Endocrinol

    (1999)
  • A. Machens et al.

    European Multiple Endocrine Neoplasia (EUROMEN) Study GroupEarly malignant progression of hereditary medullary thyroid cancer

    N Engl J Med

    (2003)
  • M.A. Skinner et al.

    Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A

    N Engl J Med

    (2005)
  • L.M. Mulligan et al.

    Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene

    Hum Mol Genet

    (1994)
  • I. Ceccherini et al.

    DNA polymorphisms and conditions for SSCP analysis of the 20 exons of the ret proto-oncogene

    Oncogene

    (1994)
  • P. Pigny et al.

    A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma

    J Clin Endocrinol Metab

    (1999)
  • C. Eng et al.

    The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2International RET mutation consortium analysis

    JAMA

    (1996)
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