Oncological implications of RET gene mutations in Hirschsprung’s disease

Sijmons, Rolf H.; Hofstra, Robert; Wijburg, Frits A.; Links, Thera P.; Zwierstra, R. P.; Vermey, A; Aronson, D. C.; Tan-Sindhunata, Gita; Brouwers-Smalbraak, G.J.; Maas, SM; Buys, Chcm

doi:10.1136/gut.43.4.542

Cited by 55 publications

(50 citation statements)

References 43 publications

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“…No case that shows two-nucleotide alteration in one codon of the RET gene was previously reported, although some cases that have two codons with onenucleotide alteration in the RET gene were reported. 27 In addition, the present case showed no nucleotide alterations at polymorphic codons in the RET gene that may affect the development of HSCR. 34 -38 Germline mutations in several genes including GDNF, neurturin, endothelin receptor B, endothelin-3, SOX10, endothelin-converting enzyme 1, and ZFHX1B were reported in HSCR patients.…”

Section: Discussionmentioning

confidence: 93%

Cys611Ser mutation in RET proto-oncogene in a kindred with medullary thyroid carcinoma and Hirschsprung's disease

et al. 2003

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Germline mutations in the RET proto-oncogene are responsible for the development of human hereditary diseases, including multiple endocrine neoplasia (MEN) type 2A and 2B, familial medullary thyroid carcinoma (FMTC), and Hirschsprung's disease (HSCR). It has been reported that some families developed both MEN 2A/FMTC and HSCR, in which a mutation in a cysteine residue at codon 609, 618, or 620 in the RET gene was present. Here we report a novel RET mutation detected in a Japanese family with medullary thyroid carcinoma and HSCR. A germline mutation in cysteine 611 of the RET gene was identified in this family, which introduced an amino-acid change from cysteine to serine. By biological and biochemical analyses of mutant RET proteins, we previously predicted the potentiality that amino-acid substitution for cysteine 611 as well as cysteines 609, 618, and 620 would promote the development of MEN 2A/FMTC and HSCR. This clinical case substantiates our suggestion for the mechanism of the development of both the diseases.

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Section: Discussionmentioning

confidence: 93%

Cys611Ser mutation in RET proto-oncogene in a kindred with medullary thyroid carcinoma and Hirschsprung's disease

et al. 2003

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“…Activating RET mutations have been found previously in HSCR but were mostly found in the context of MEN2/familial MTC (eg, p.Cys610/618/620). 9 For all activating RET mutations, found in HSCR patients, it was shown that the mutant protein besides being activated, also results in a disturbed glycosylation. Our analysis did not show any difference in the glycosylation status.…”

Section: Rare Ret Variantsmentioning

confidence: 99%

“…The majority of patients with gain-of-function mutations suffered, besides HSCR, also from multiple endocrine neoplasia type 2 A (MEN2A) or familial medullary thyroid carcinoma (MTC). 9 Not many studies, however, determined the functional consequences these mutations really have on the encoded RET protein. [10][11][12] Most reports stated their classification of pathogenicity only on in silico predictions.…”

Section: Introductionmentioning

confidence: 99%

RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling

et al. 2015

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Hirschsprung disease (HSCR) is a major cause of chronic constipation in children. HSCR can be caused by germline mutations in RET and EDNRB. Defining causality of the mutations identified is difficult and almost exclusively based on in silico predictions. Therefore, the reported frequency of pathogenic mutations might be overestimated. We combined mutation analysis with functional assays to determine the frequencies of proven pathogenic RET and EDNRB mutations in HSCR. We sequenced RET and EDNRB in 57 HSCR patients. The identified RET-coding variants were introduced into RET constructs and these were transfected into HEK293 cells to determine RET phosphorylation and activation via ERK. An exon trap experiment was performed to check a possible splice-site mutation. We identified eight rare RET-coding variants, one possible splice-site variant, but no rare EDNRB variants. Western blotting showed that three coding variants p. (Pr270Leu) (Tyr1062Cys)) resulted in reduced ERK activation. Splice-site assays on c.1880-11A4G could not confirm its pathogenicity. Our data suggest that indeed almost half of the identified rare variants are proven pathogenic and that, hence, functional studies are essential for proper genetic counseling.

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“…In contrast to these cancer syndromes, which are caused by a germline mutation and associate with MTC, somatic gene rearrangements of the RET gene are associated with papillary thyroid cancer (Grieco et al 1990). The incidence of MTC has been reported to vary between 2.5 and 5% among HD patients (Decker et al 1998, Sijmons et al 1998, Pakarinen et al 2005.…”

Section: Introductionmentioning

confidence: 99%

“…Only mutations in codons 609, 611, 618, and 620 of exon 10 are known to co-segregate with HD and MEN syndromes (Mulligan et al 1994a,b, Romeo et al 1998, Sijmons et al 1998, Nishikawa et al 2003. Mutations in codon 791 of the RET gene are suggested to be weak or nonpathogenic mutations for MEN2A and familial medullary thyroid carcinoma (FMTC) (Frank-Raue et al 2008, Erlic et al 2010.…”

Section: Introductionmentioning

confidence: 99%

Thyroid cancer and co-occurring RET mutations in Hirschsprung disease

Virtanen

Pukkala

Kivisaari

et al. 2013

Endocrine-Related Cancer

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The objective of this study was to assess the occurrence of thyroid cancer and co-occurring RET mutations in a population-based cohort of adult Hirschsprung disease (HD) patients. All 156 patients operated for HD in a tertiary center during 1950-1986 were followed for thyroid malignancies up to 2010 through the nationwide Finnish Cancer Registry. Ninety-one individuals participated in clinical and genetic screening, which included serum calcitonin and thyroid ultrasound (US) with cytology. Exons 10, 11, 13, and 16 were sequenced in all, and all exons of RET in 43 of the subjects, including those with thyroid cancer, RET mutations, suspicious clinical findings, and familial or long-segment disease. Through the cancer registry, two cases (aged 35 and 37 years) of medullary thyroid cancer (MTC) were observed; the incidence for MTC was 340-fold (95% CI 52-1600) compared with average population. These individuals had C611R and C620R mutations in exon 10. One papillary thyroid cancer without RET mutations was detected by clinical screening. Four subjects (aged 31-50 years) with co-occurring RET mutations in exons 10 (C609R; nZ1) and 13 (Y791F, nZ3) had sporadic short-segment HD with normal thyroid US and serum calcitonin. Three novel mutations and five single-nucleotide polymorphisms were found outside exons 10 and 13 without associated signs of thyroid cancer. MTC-associated RET mutations were restricted to exons 10 and 13 affecting w5% of unselected adults with HD. Clinical thyroid assessment did not improve accuracy of genetic screening, which should not be limited to patients with familial or long-segment disease.

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Oncological implications of RET gene mutations in Hirschsprung’s disease

Cited by 55 publications

References 43 publications

Cys611Ser mutation in RET proto-oncogene in a kindred with medullary thyroid carcinoma and Hirschsprung's disease

Cys611Ser mutation in RET proto-oncogene in a kindred with medullary thyroid carcinoma and Hirschsprung's disease

RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling

Thyroid cancer and co-occurring RET mutations in Hirschsprung disease

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