title: Thyroid cancer and co-occurring RET mutations in Hirschsprung disease.
abstract: 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; n=1) and 13 (Y791F, n=3) 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 ∼5% 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.
authors.affiliation: Section of Pediatric Surgery, Hospital for Children and Adolescents, University of Helsinki, Stenbäckinkatu 11, Helsinki, Finland. valtter.virtanen@helsinki.fi
authors.forename: Valtter B
authors.initials: VB
authors.lastname: Virtanen
authors.forename: Eero
authors.initials: E
authors.lastname: Pukkala
authors.forename: Reetta
authors.initials: R
authors.lastname: Kivisaari
authors.forename: Perttu P
authors.initials: PP
authors.lastname: Salo
authors.forename: Antti
authors.initials: A
authors.lastname: Koivusalo
authors.forename: Johanna
authors.initials: J
authors.lastname: Arola
authors.forename: Päivi J
authors.initials: PJ
authors.lastname: Miettinen
authors.forename: Risto J
authors.initials: RJ
authors.lastname: Rintala
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Mikko P
authors.initials: MP
authors.lastname: Pakarinen
mesh_terms: D000328:Adult; D000368:Aged; D002116:Calcitonin / Q000097:blood; D005091:Exons / Q000235:genetics; D005260:Female; D006627:Hirschsprung Disease / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013961:Thyroid Gland / Q000000981:diagnostic imaging; D013964:Thyroid Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics*; D014463:Ultrasonography
chemical_list: D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret
keywords: hirschsprung disease; multiple endocrine neoplasia; oncology; thyroid cancer