Skip to main content

Advertisement

SpringerLink
Log in

RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients

  • Published:
Journal of Biosciences Aims and scope Submit manuscript

Abstract

Germline mutations of RET gene are pathognomonic of multiple endocrine neoplasia (MEN; MEN 2A/MEN 2B) and familial medullary thyroid carcinoma (FMTC), constituting 25% of medullary thyroid carcinomas (MTCs). We investigated RET gene mutations and polymorphisms at exons 10, 11, 13, 14, 15 and 16 in 140 samples, comprising 51 clinically diagnosed MTC patients, 39 family members of patients and 50 normal individuals. The method of choice was PCR and direct nucleotide sequencing of the PCR products. RET gene mutations were detected in 15 (29.4%) patients, with MEN 2A/FMTC in 13 patients and MEN 2B in 2 patients. Further, 39 family members of seven index cases were analysed, wherein four of the seven index cases showed identical mutations, in 13 of 25 family members. We also examined single nucleotide polymorphisms (SNPs) in RET gene exons in 101 unrelated samples. Significant differences in the allelic frequencies of SNPs at codons 691, 769, 836 and 904 between patient and control groups were not observed. However, SNP frequencies were significantly different in the Indian group as compared with other European groups. We identified two novel, rare and unique SNPs separately in single patients. Our study demonstrated presence of MEN 2A/MEN 2B/FMTC-associated mutations in accordance with the reported literature. Thus, RET gene mutations in exons 10, 11, 13, 14, 15 and 16 constitute a rapid test to confirm diagnosis and assess risk of the disease in familial MEN 2A/MEN 2B/FMTC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Baumgartner-Parzer SM, Lang R, Wagner L, Heinze G, Niederle B, Kaserer K, Waldhausl W and Vierhapper H 2005 Polymorphisms in Exon 13 and Intron 14 of the RET protooncogene: Genetic modifiers of medullary thyroid carcinoma. J. Clin. Endocrinol. Metabol. 90 6232–6236

    Article  CAS  Google Scholar 

  • Bergant D, Hocevar M, Besic N, Glavac D, Korosec B and Caserman S 2006 Hereditary medullary thyroid cancer in Slovenia-genotype-phenotype correlations. Middle Eur. J. Med. 118 411–416

    Google Scholar 

  • Bounacer A, Villard JAD, Wicker R, Caillou B, Schlumberger M, Sarasin A and Suárez HG 2002 Association of RET codon 691 polymorphism in radiation-induced human thyroid tumours with C-cell hyperplasia in peritumoural tissue. Brit. J. Cancer 86 929–1936

    Article  Google Scholar 

  • Costa P, Domingues R, Sobrinho L and Bugalho MJ 2005 RET polymorphisms and sporadic medullary thyroid carcinoma in a Portuguese population. Endocrine 27 239–243

    Article  PubMed  CAS  Google Scholar 

  • de Groot JWB, Links TP, Plukker JTM, Lips CJM and Hofstra RMW 2006 RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocrinol. Rev. 27 535 –560

    Article  Google Scholar 

  • Desai S, Sarkar S and Borges A 2005 A study of histopathological features of medullary carcinoma of the of the thyroid: Cases from a single institute in India. Indian J. Cancer 42 21–25

    Article  Google Scholar 

  • Eng C 1996 The RET proto-oncogene in Multiple endocrine neoplasia type 2 and Hirschsprung’s disease. New Engl. J. Med. 335 943 –951

    Article  PubMed  CAS  Google Scholar 

  • Eng C 1999 RET proto-oncogene in the development of human cancer. J. Clin. Oncol. 17 380 –393

    PubMed  CAS  Google Scholar 

  • Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, Amstel HKP, Lips CJM, Nishisho I, et al. 1996 The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2 International RET mutation consortium analysis. J. Am. Med. Association 276 1575–1579

    Article  CAS  Google Scholar 

  • Fernandez RM, Navarro E, Antinolo G, Ruiz-Ferrer M and Borrego S 2006 Evaluation of the role of RET polymorphisms/haplotypes as modifier loci for MEN 2, and analysis of the correlation with the type of RET mutation in a series of Spanish patients. Int. J. Mol. Med. 17 575–581

    PubMed  CAS  Google Scholar 

  • Frilling A, Dralle H, Eng C, Raue F and Broelsch CE 1995 Presymptomatic DNA Screening in families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Surgery 118 1099–1104

    Article  PubMed  CAS  Google Scholar 

  • Griseri P, Sancandi M, Patrone G, Bocciardi R, Hofstra R, Ravazzolo R, Devoto M, Romeo G and Ceccherini I 2000 A single-nucleotide polymorphic variant of the RET proto-oncogene is underrepresented in sporadic Hirschsprung disease Eur. J. Human Genet. 8 721–724

    Article  CAS  Google Scholar 

  • Guerrero IM, Pessoa CHC, Olmedo DB, Pontes ERP, Matos LC, Tilli TM, Barcinski MA and Gimba ERP 2006 Analysis of inherited genetic variants in ret proto-oncogene of Brazilian patients with apparently sporadic medullary thyroid carcinoma. Thyroid 16 9 –12

    Article  PubMed  CAS  Google Scholar 

  • Gursoy A, Erdogan MF and Erdogan G 2006 Significance of the RET proto-oncogene polymorphisms in Turkish sporadic medullary thyroid carcinoma patients. J. Endocrinol. Invest. 29 858 –862

    PubMed  CAS  Google Scholar 

  • Jindrichová S, Vcelák J, Vlcek P, Neradilová M, Neˇmec J and Bendlová B 2004 Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J. Endocrinol. 183 257 –265

    Article  PubMed  Google Scholar 

  • Kameyama K, Okinaga H and Takami H 2004 RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. Biomed. Pharmacotherapy 58 345 –347

    Article  CAS  Google Scholar 

  • Klein I, Ésik O, Homolya V, F Szeri and Váradi A 2001 Molecular genetic diagnostic program of multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma syndromes in Hungary. J. Endocrinol. 170 661–666

    Article  PubMed  CAS  Google Scholar 

  • Magalhães KRP, Castro M, Elias LLK, Soares EG and Maciel LM Z 2004 Polymorphisms in the RET proto-oncogene and the phenotypic presentation of familial medullary thyroid carcinoma. Thyroid 14 848 –852

    PubMed  Google Scholar 

  • Menon M and Simha MR 2005 RET mutation status in medullary thyroid cancer (MTC) patients and the significance of genetic screening for mutations in their immediate relatives--a preliminary report. Indian J. Pathol. Microbiol. 48 161–165

    PubMed  Google Scholar 

  • Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Zedenius J, Lips CJ, Gagel RF, Takai SI, Noll WW, Fink M, et al. 1995 Genotype phenotype correlation in multiple endocrine neoplasia type 2: report of the international RET mutation consortium. J. Intern. Med. 238 343 –346

    Article  PubMed  CAS  Google Scholar 

  • Patocs A, Klein I, Szilvasi A, Gergics P, Toth M, Valkusz Z, Forizs E, Igaz P, Al-Farhat Y, Tordai A, Varadi A, Racz K and Esik O 2006 Genotype-phenotype correlations in Hungarian patients with hereditary medullary thyroid cancer. Wien Klin Wochenschr. 118 417–21

    Article  PubMed  Google Scholar 

  • Ponder BAJ 1999 The phenotypes associated with ret mutations in the multiple endocrine neoplasia type 2 syndrome. Cancer Res. 59 1736 –1742

    Google Scholar 

  • Rekhi B, Badhe RR, Desouza MA, Chaukar D, D’Cruz AK, Arya S and Kane SV 2007 A Unique RET exon 11 (G691S) polymorphism in an Indian patient with a collision tumor of the thyroid. Diagnostic Pathol. 2 doi:10.1186/1746-1596-2-39

  • Sakorafas G, Friess H and Peros G 2008 The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy. Endocrine-Related Cancer 15 871–884

    Article  PubMed  CAS  Google Scholar 

  • Sánchez B, Robledo M, Biarnes J, Sáez ME, Volpini V, Benítez J, Navarro E, Ruiz A, Antiñolo G and Borrego S 1999 High prevalence of the C634Y mutation in the RET proto-oncogene in MEN 2A families in Spain. J. Med. Genet. 36 68–70

    PubMed  Google Scholar 

  • Strahm B and Malkin D 2006 Hereditary cancer predisposition in children: Genetic basis and clinical implications. Int. J. Cancer 119 2001–2006

    Article  PubMed  CAS  Google Scholar 

  • Weinhaeusel A, Scheuba C, Lauss M, Kriegner A, Kaserer K, Vierlinger K, Haas O and Niederle B 2008 The influence of gender, age, and RET polymorphisms on C-cell hyperplasia and medullary thyroid carcinoma. Thyroid 18 1269–1276

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge Dr Vinay Deshmane, Consultant Oncosurgeon, Hinduja Hospital and Research Centre, Mumbai, the patients, relatives and volunteers who participated in the study, and the encouragement and support of Reliance Life Sciences Pvt Ltd, Navi Mumbai.

Author information

Authors and Affiliations

  1. Molecular Medicine, Reliance Life Sciences Pvt Ltd, Dhirubhai Ambani Life Sciences Center, Navi Mumbai, 400 701, India

    B P Sharma & D Saranath

Authors
  1. B P Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Saranath
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Saranath.

Additional information

Corresponding editor: Partha P Majumder

[Sharma BP and Saranath D 2011 RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients. J. Biosci. 36 603–611] DOI 10.1007/s12038-011-9095-0

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sharma, B.P., Saranath, D. RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients. J Biosci 36, 603–611 (2011). https://doi.org/10.1007/s12038-011-9095-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12038-011-9095-0

Keywords

Search

Navigation