Mutation screening in a Norwegian cohort with pheochromocytoma

Abstract

Pheochromocytomas (PHEOs) are neuroendocrine tumours, originating from chromaffin cells in the adrenal medulla. They are either sporadic or hereditary. It is important to identify the hereditary cases, so that patients and relatives with germline mutations can be offered regular surveillance. The objective of this study was the detection of pathogenic germline mutations in a cohort of Norwegian PHEO patients. Blood samples and/or formalin-fixed, paraffin-embedded tissue specimens, were collected from 60 patients who were operated upon between 1986 and 2004 at two university hospitals in Norway. DNA mutation analyses were performed successfully in the 42 blood samples and in one of the paraffin-embedded tissue specimen in VHL, RET, SDHB, SDHC, SDHD and NF1. In all, 32 different DNA variants were observed, of which 8 were classified as pathogenic (19 %), or possibly pathogenic; three in NF1, two in RET and VHL and one in SDHB. Two variants were observed in one patient, one in SDHB and one in NF1. Three of these variants are, to the best of our knowledge, new ones; two in NF1 [c.950_51insGCTGA, (p.Glu318LeufsX59) and c.1588G > A, (p.Val530Ile)] and one in VHL (c.308C > T, p.Pro103Leu). In conclusion the overall incidence of germline mutations in genes associated with familial PHEO was found to be of the same order of magnitude in the present Norwegian series as in those from other countries. Two new NF1 variants and one new VHL gene variant were detected.

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T)

“…8,10,11,58,59 Loss of SDHB protein expression is seen in pheochromocytomas/paragangliomas either harboring a mutation in any of the SDH genes or with somatic hypermethylation of the SDHC promoter region, 42 whereas loss of both SDHB and SDHA immunoreactivity is demonstrated only in the context of an SDHA mutation. [8][9][10][11][12][13][14][15][16][17][18][19][20] In agreement with previous studies, 8,10,11,[17][18][19][20] SDHB-/C-/D-and SDHAmutated tumors displayed the aforementioned and NF1 mutations, 8,10 respectively. By using a mouse monoclonal (21A11) SDHB antibody at a low concentration (1 in 1000), Gill et al 10 suggested that VHL-associated tumors could be classified as negative or weak diffuse rather than positive as demonstrated by a high concentration approach of two SDHB antibodies.…”

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

“…51,52 Another one was in SDHC (c.380A>G; p.His127Arg), and the last three were in SDHD (c.14G>A; p.Trp5*, c.149A>G; p.His50Arg, and c.274G>T; p.Asp92Tyr). 46,[53][54][55] Among these SDHD mutations, one resulted in a stop codon (p.Trp5*), which cannot be managed by the prediction tools we used but can be considered to Review be damaging because the mutation results in a severely truncated protein. This nonsense variant was identified in a patient suffering from Carney-Stratakis syndrome, with the PGL showing positive SDHB on IHC and the GIST presenting with a negative SDHB on IHC, potentially indicating two different second hit events in the SDHD gene.…”

A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma

“…has not routinely been analyzed before autumn 2016. The method has been described by Sjursen et al (240).…”