Thyroid cancer and co-occurring RET mutations in Hirschsprung disease

Virtanen, Valtter; Pukkala, Eero; Kivisaari, Reetta; Salo, Perttu; Koivusalo, Antti; Arola, Johanna; Miettinen, Päivi J.; Rintala, Risto; Perola, Markus; Pakarinen, Mikko P.

doi:10.1530/erc-13-0082

Cited by 17 publications

(5 citation statements)

References 36 publications

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“…exon 10), such as C620R, it has been classically reported that HSCR develops in up to 7% of carriers. Since the initial report, other Y791F-carrier HSCR cases with no evidence of MTC have been reported, raising the question as to whether this variant is actually involved in tumourigenesis ( Virtanen et al . 2013 ).…”

Section: Resultsmentioning

confidence: 99%

Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility

Toledo¹,

Hatakana²,

Lourenço³

et al. 2014

Endocrine-Related Cancer

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Accurate interpretation of germline mutations of the rearranged during transfection (RET) proto-oncogene is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2904 cancer-free elderly individuals (1261 via Sanger sequencing and 1643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the Catalogue of Somatic Mutations in Cancer (COSMIC) project. The mean allelic frequency observed in the controls was 0.0031, with higher occurrences in Central European populations (0.006/0.008). The prevalence of RET Y791F in the control databases was extremely high compared with the 40 known RET pathogenic mutations (P=0.00003), while no somatic occurrence has been reported in tumours. In this study, we report new, unrelated Brazilian individuals with germline RET Y791F-only: two tumour-free elderly controls; two individuals with sporadic MTC whose Y791F-carrying relatives did not show any evidence of tumours; and a 74-year-old phaeochromocytoma patient without MTC. Furthermore, we showed that the co-occurrence of Y791F with the strong RET C634Y mutation explains the aggressive MTC phenotypes observed in a large affected family that was initially reported as Y791F-only. Our literature review revealed that limited analyses have led to the misclassification of RET Y791F as a probable pathogenic variant and, consequently, to the occurrence of unnecessary thyroidectomies. The current study will have a substantial clinical influence, as it reveals, in a comprehensive manner, that RET Y791F only shows no association with MTC susceptibility.

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Section: Resultsmentioning

confidence: 99%

Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility

Toledo¹,

Hatakana²,

Lourenço³

et al. 2014

Endocrine-Related Cancer

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“…However, medullary thyroid carcinoma incidence among Hirschsprung disease patients varies between 2.5% and 5%, with all activating mutations located in exon 10. 79 As it was not possible to perform functional studies to assess the pathogenicity of this specific variant, it was classified as a VUS and the recommendation for this case would be to follow it as a potential MEN2 case.…”

Section: Genetic Screeningmentioning

confidence: 99%

PheoSeq

Currás-Freixes

Piñeiro-Yáñez

Montero‐Conde

et al. 2017

The Journal of Molecular Diagnostics

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Genetic diagnosis is recommended for all pheochromocytoma and paraganglioma (PPGL) cases, as driver mutations are identified in approximately 80% of the cases. As the list of related genes expands, genetic diagnosis becomes more time-consuming, and targeted next-generation sequencing (NGS) has emerged as a cost-effective tool. This study aimed to optimize targeted NGS in PPGL genetic diagnostics. A workflow based on two customized targeted NGS assays was validated to study the 18 main PPGL genes in germline and frozen tumor DNA, with one of them specifically directed toward formalin-fixed paraffin-embedded tissue. The series involved 453 unrelated PPGL patients, of whom 30 had known mutations and were used as controls. Partial screening using Sanger had been performed in 275 patients. NGS results were complemented with the study of gross deletions. NGS assay showed a sensitivity ≥99.4%, regardless of DNA source. We identified 45 variants of unknown significance and 89 pathogenic mutations, the latter being germline in 29 (7.2%) and somatic in 58 (31.7%) of the 183 tumors studied. In 37 patients previously studied by Sanger sequencing, the causal mutation could be identified. We demonstrated that both assays are an efficient and accurate alternative to conventional sequencing. Their application facilitates the study of minor PPGL genes, and enables genetic diagnoses in patients with incongruent or missing clinical data, who would otherwise be missed.

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“…However, no clinical data from the deceased sisters were available, as they had lived abroad, and it was not apparent whether the deceased sisters had been tested for RET Y791F carrier status . To the best of our knowledge, the remaining studies on the RET Y791F variant have been centered around index cases, with no more than one occurrence of MTC in a proven RET Y791F carrier per family, enabling noncausative occurrences of RET Y791F in patients with sporadic MTC to have been attributed an unwarranted pathogenic significance . Further compounding this, a recent retrospective German study found no age‐related progression of MTC in RET Y791F carriers, which would otherwise often be expected in hereditary disease …”

Section: Discussionmentioning

confidence: 99%

Long‐term follow‐up of RET Y791F carriers in Denmark 1994‐2017: A National Cohort Study

Michaelsen

Ørnstrup

Poulsen

et al. 2019

Journal of Surgical Oncology

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Background and Objectives Recently, a comprehensive study presented evidence that a long‐disputed REarranged during Transfection (RET) variant, RET Y791F, should be classified as nonpathogenic. In spite of this, several subsequently published papers, including the revised American Thyroid Association guidelines for medullary thyroid carcinoma, refer to the variant as pathogenic. This study presents data from a unique national Danish cohort of RET Y791F carriers who have been followed by watchful waiting instead of being subjected to early thyroidectomy, to determine if any carrier shows evidence of multiple endocrine neoplasia 2A (MEN2A) at long‐term follow‐up. Methods A national cohort of all patients tested for RET mutations in Denmark from September 1994 to October 2017 was searched for carriers of RET Y791F. Medical records and laboratory reports of carriers were reviewed for signs of MEN2A at latest follow‐up (medullary thyroid carcinoma, primary hyperparathyroidism, pheochromocytoma, cutaneous lichen amyloidosis, or Hirschsprung's disease). Results In total, twenty RET Y791F‐carriers were identified, none of whom showed any evidence of MEN2A, despite an age range from 7 to 87 years. Conclusions Our national cohort study of all Danish RET Y791F carriers substantiates the claim that the RET Y791F variant is nonpathogenic.

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Thyroid cancer and co-occurring RET mutations in Hirschsprung disease

Cited by 17 publications

References 36 publications

Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility

Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility

PheoSeq

Long‐term follow‐up of RET Y791F carriers in Denmark 1994‐2017: A National Cohort Study

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