{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:19:45Z","timestamp":1784557185280,"version":"3.55.0"},"reference-count":37,"publisher":"Bioscientifica","issue":"4","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,4]]},"abstract":"\n The clinical course of medullary thyroid carcinoma (MTC) associated with the MEN2A syndrome as well as of sporadic MTC shows considerable heterogeneity. The disease picture varies not only between the same\n RET<\/jats:italic>\n proto-oncogene mutation carriers but also among sporadic MTC patients with no\n RET<\/jats:italic>\n germinal mutations, which suggests the involvement of additional modulators of the disease. However, genetic factors responsible for this heterogeneity of the MTC clinical course still remain unknown. The aim of this study was to determine if polymorphic variants or specific haplotypes of the\n RET<\/jats:italic>\n gene may modify the MTC clinical course. We genotyped the following\n loci:<\/jats:italic>\n c.73+9277T>C, c.135G>A, c.1296A>G, c.2071G>A, c.2307T>C, c.2508C>T and c.2712C>G in 142 MTC patients and controls. We demonstrated considerable differences in the genotypes distribution within c.73+9277T>C, c.135G>A and c.2307T>C\n loci<\/jats:italic>\n . Our results show that the c.73+9277T variant associated with a decreased activity of the MCS+9.7\n RET<\/jats:italic>\n enhancer is rare in hereditary MTC patients with primary hyperparathyroidism, and thus, may influence the MTC clinical picture. The decreased activity of the\n RET<\/jats:italic>\n promoter enhancer reduces\n RET<\/jats:italic>\n expression level and may counterbalance the activating mutation in this gene. Frequent co-occurrence of the c.73+9277T allele with p.E768D, p.Y791F, p.V804M or p.R844Q\n RET<\/jats:italic>\n mutations may be associated with their attenuation and milder clinical picture of the disease. Haplotypes analysis showed that C-G-A-G-T-(C)-C (c.73+9277T>C \u2013 c.135G>A \u2013 c.1296A>G \u2013 c.2071G>A \u2013 c.2307T>G \u2013 (c.2508C>T) \u2013 c.2712C>G) alleles combination predisposes to pheochromocytomas and primary hyperparathyroidism. We consider that\n RET<\/jats:italic>\n haplotypes defining may become an auxiliary diagnostic tool in MTC patients.\n <\/jats:p>","DOI":"10.1530\/erc-17-0452","type":"journal-article","created":{"date-parts":[[2018,1,31]],"date-time":"2018-01-31T20:10:38Z","timestamp":1517429438000},"page":"421-436","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":13,"title":["Modifying impact of RET gene haplotypes on medullary thyroid carcinoma clinical course"],"prefix":"10.1530","volume":"25","author":[{"given":"Marta","family":"Kaczmarek-Ry\u015b","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Ziemnicka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"P\u0142awski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart\u0142omiej","family":"Budny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u0142","family":"Michalak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szymon","family":"Hryhorowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Hoppe-Go\u0142\u0119biewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawe\u0142","family":"Boru\u0144","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Go\u0142\u0105b","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Czetwerty\u0144ska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Sromek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlena","family":"Szalata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Rucha\u0142a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryszard","family":"S\u0142omski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"ref181","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1089\/thy.2006.16.411","article-title":"Analysis 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Poland","volume":"21","year":"2010","journal-title":"Endocrine Pathology"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"5438","DOI":"10.1210\/jc.2003-030997","article-title":"A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma","volume":"88","year":"2003","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref131","doi-asserted-by":"crossref","first-page":"3579","DOI":"10.1210\/jc.2003-031898","article-title":"RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population","volume":"89","year":"2004","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref291","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1111\/j.1365-2265.2012.04462.x","article-title":"High prevalence of exon 8 G533C mutation in apparently sporadic medullary thyroid carcinoma in 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patients.","volume":"7","year":"2016","journal-title":"Oncotarget"},{"key":"ref211","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1038\/sj.onc.1202418","article-title":"Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation","volume":"18","year":"1999","journal-title":"Oncogene"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1136\/jmg.36.10.771","article-title":"Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression","volume":"36","year":"1999","journal-title":"Journal of Medical Genetics"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1111\/j.0009-9163.2004.00172.x","article-title":"Germline-sequence variants S836S and L769L in the RE arranged during Transfection (RET) proto-oncogene are not associated with predisposition to 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medullary thyroid carcinoma.","volume":"25","year":"2015","journal-title":"Thyroid"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/jhg.2012.54","article-title":"Hirschsprung\u2019s disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation","volume":"57","year":"2012","journal-title":"Journal of Human Genetics"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"e0147840","DOI":"10.1371\/journal.pone.0147840","article-title":"Effect of 3\u2032UTR RET variants on RET mRNA secondary structure and disease presentation in medullary thyroid carcinoma","volume":"11","year":"2016","journal-title":"PLoS ONE"},{"key":"ref81","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1530\/EJE-11-1060","article-title":"Additive effect of RET polymorphisms on sporadic medullary thyroid carcinoma susceptibility and tumor aggressiveness","volume":"166","year":"2012","journal-title":"European Journal of Endocrinology"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1007\/s00268-008-9826-z","article-title":"CXCR2 and RET single nucleotide polymorphisms in pancreatic cancer","volume":"33","year":"2009","journal-title":"World Journal of Surgery"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1111\/j.1365-2265.2008.03230.x","article-title":"Does the RET variant G691S influence the features of sporadic medullary thyroid carcinoma?","volume":"69","year":"2008","journal-title":"Clinical Endocrinology"}],"container-title":["Endocrine-Related 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