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V Häyry, K Salmenkivi, J Arola, P Heikkilä, C Haglund and H Sariola

Phaeochromocytomas are uncommon tumours of adrenal or extra-adrenal chromaffin tissue. About 2–26% of these have been reported to metastasize, but, on histological criteria, it is virtually impossible to predict malignant behaviour of the tumour. Using immunohistochemistry, we analysed the protein expression of SNAIL, a zinc-finger transcription factor, in a series of 50 phaeochromocytoma specimens from 42 patients. We found that SNAIL-expressing cells are frequent in metastatic primary tumours and their metastases, whereas in tumours without metastases, SNAIL expression is commonly absent. We conclude that the expression of SNAIL may be of use in predicting the metastatic potential of phaeochromocytoma.

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A Raitila, M Georgitsi, A Karhu, K Tuppurainen, M J Mäkinen, K Birkenkamp-Demtröder, K Salmenkivi, T F Ørntoft, J Arola, V Launonen, P Vahteristo and L A Aaltonen

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently observed in patients with pituitary adenoma predisposition (PAP). Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas. Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X) with a complete loss of the wild-type allele in the tumors. These results are in agreement with previous studies in that prolactin-producing adenomas are component tumors in PAP. The data also support the previous finding that somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well.

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

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.