The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy

Sakorafas, George H.; Friess, Helmut; Peros, George

doi:10.1677/erc-08-0098

Cited by 42 publications

(25 citation statements)

References 113 publications

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“…A strong genetic component is known for medullary carcinoma, so that up to 25% of the cases are estimated to be heritable, caused by a gain-of-function germline mutation in the RET proto-oncogene (multiple endocrine neoplasia (MEN) type 2A and MEN2B and familial MTC (FMTC)) with an autosomal dominant mode of inheritance (Negri et al 2002, DeLellis et al 2004, Nose 2011. Despite the rarity of these syndromes and MTC in general, early diagnosis is especially important, since MTC is a lethal disease if not promptly and appropriately treated (Sakorafas et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Risk of thyroid cancer in relatives of patients with medullary thyroid carcinoma by age at diagnosis

Fallah

Sundquist

Hemminki

2013

Endocrine-Related Cancer

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The familial risk of medullary thyroid carcinoma (MTC alone or as part of multiple endocrine neoplasms, MEN2A/MEN2B) is high, so we aimed to answer open questions about the lifetime cumulative risk of thyroid cancer (LCRTC at 0-79 years) among relatives of MTC patients by age and sex. For this nationwide study, a cohort of 3217 first-/second-degree relatives (FDRs/SDRs) of 389 MTC patients diagnosed in 1958-2010 in the Swedish Family-Cancer Database was followed for the incidence of thyroid cancer. The LCRTC in female relatives of patients with early-onset MEN2B (diagnosis age !25 years) was 44-57%, representing 140-520 times increase over the risk in their peers without a family history of endocrine tumors (men: LCRTCZ22-52%, 320-750 times) depending on the number of affected FDRs/SDRs. The LCRTC in female relatives of patients with late-onset MEN2B (diagnosis age R25 years) was about 15-43% (menZ24%). The LCRTC among relatives of early-onset MTC-alone patients was 3-20%. The LCRTC among relatives of late-onset MTC-alone patients was 5-26%. The LCRTC in female relatives of MEN2A patients was 16-63% (menZ52%). The relatives of patients with early-onset MTC exhibited a high tendency to develop early-onset thyroid cancer. Simply available data on the number of FDRs and even SDRs affected with MTC and their age at diagnosis were quite informative for the estimation of the risk of thyroid cancer in probands. In settings where genetic testing is not available or affordable for all, evidence-based cumulative risks reported in this nationwide study may help physicians to identify very high-risk individuals.

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Section: Introductionmentioning

confidence: 99%

Risk of thyroid cancer in relatives of patients with medullary thyroid carcinoma by age at diagnosis

Fallah

Sundquist

Hemminki

2013

Endocrine-Related Cancer

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“…Mutations in RET codons 630, 790, 791, 804 and 891 are capable of producing the MEN-2A phenotype [19]. Mutations at codon 634 (exon 11) occur in 85% of cases with C634R being the most frequent RET alteration in MEN-2A [20]. Mutations at exon 10 account for a further 10-15% of cases, whereas mutations at other exons are rare ( Fig.…”

Section: Men-2amentioning

confidence: 99%

Medullary Thyroid Cancer: A Promising Model for Targeted Therapy

Torino¹,

Paragliola

Barnabei³

et al. 2010

CMM

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Abstract:In recent years, the clinical validation of molecular targeted therapies inhibiting the action of pathogenic tyrosine kinase (TK) has been one of the most exciting developments in cancer research. In this context, medullary thyroid carcinoma (MTC) represents a promising model. It is well known that in MTC, the RET receptor TK and its signal transduction pathways, lead to subsequent neoplastic transformation. Several strategies aimed at blocking the activation and signaling of RET have been preclinically tested. The most advanced results have been obtained by competitive inhibition of RET-TK activity by tyrosine kinases inhibitors (TKI). However, although the inhibition of the RET pathway is actually one of the most studied for therapeutic purposes, other signal transduction pathways have been recognized to contribute to the growth and functional activity of MTC and are considered attractive therapeutic targets.To date, surgery represents the only curative treatment of MTC. Despite promising initial results, studies on targeted agents are in early stages and several issues regarding preclinical evaluations and clinical trials of new targeted agents in MTC are still unresolved. Now, available mouse models bearing mutations of RET or other genes, which spontaneously develop MTC, promise to improve preclinical evaluation of activity of targeted compounds. Furthermore, the rarity of the disease and the number of patients available for enrolment may lessen the relevance of clinical trials. A major effort needs to be made by endocrinologists and oncologists to refer their patients for multi-institutional trials in order to optimize them, perform translational studies and expedite the availability of novel beneficial selective therapies.

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“…When admitted, the majority patients have already progressed to MTC or exhibit lymph node metastasis. MTC is the predominant cause of death in patients with MEN2A (6), and it has previously been reported that 50% of patients are at risk of MTC recurrence (7). However, the appearance of MTC or MEN2A may differ among family members.…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of RET mutation screening in a pedigree of multiple endocrine neoplasia type 2A

Ying

Feng

2016

Molecular Medicine Reports

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Abstract. The clinical characteristics and RET proto-oncogene (RET-PO) mutation status of a patient with multiple endocrine neoplasia type 2A pedigree (MEN2A) was analyzed with the aim of preliminarily exploring the molecular mechanisms and clinical significance of the disease. Clinical characteristics of a single MEN2A patient were analyzed. Genomic DNA was extracted from the peripheral blood of the proband and 10 family members. The 21 exons of RET-PO were PCR amplified and the amplified products were sequenced. Of the family members, 5 exhibited a C634Y (TGC→TAC) missense mutation in exon 11 of RET-PO, among which 2 family members were screened as mutation carriers, while the others did not exhibit clinical symptoms of the mutation. The screening and analysis of RET-PO mutations for the MEN2A proband and the family members suggests potential clinical phenotypes and enables assessment of the risk of disease development, thus providing useful information for determining the surgical timing of preventive thyroid gland removal.

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The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy

Cited by 42 publications

References 113 publications

Risk of thyroid cancer in relatives of patients with medullary thyroid carcinoma by age at diagnosis

Risk of thyroid cancer in relatives of patients with medullary thyroid carcinoma by age at diagnosis

Medullary Thyroid Cancer: A Promising Model for Targeted Therapy

Clinical significance of RET mutation screening in a pedigree of multiple endocrine neoplasia type 2A

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