The Journal of clinical endocrinology and metabolism · 2015
Complex MAX Rearrangement in a Family With Malignant Pheochromocytoma, Renal Oncocytoma, and Erythrocytosis.
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Korpershoek Esther, Koffy Djamailys, Eussen Bert H, Oudijk Lindsey, Papathomas Thomas G, van Nederveen Francien H, Belt Eric J T, Franssen Gaston J H, Restuccia David F J, Krol Niels M G, van der Luijt Rob B, Feelders Richard A, Oldenburg Rogier A, van Ijcken Wilfred F J, de Klein Annelies, de Herder Wouter W, de Krijger Ronald R, Dinjens Winand N M
Аннотация
CONTEXT: Familial pheochromocytoma (PCC) has been associated with germline mutations in 16 genes. Here we investigated three siblings presenting with bilateral pheochromocytomas. In addition, the index patient also exhibited renal oncocytoma and erythrocytosis, whereas the second sibling presented with a lymph node metastasis.
DESIGN: First, single-nucleotide polymorphism array and exome sequencing were performed on germline and PCC-derived DNA to identify genomic alterations in the index patient. Second, alterations were confirmed and validated by Sanger sequencing, analyzed by (multiplexed) PCR to determine the loss of the wild-type allele, and investigated by immunohistochemistry in the tumors of the three siblings.
RESULTS: The index patient's germline DNA revealed a large complex genomic alteration encompassing the intragenic and promoter regions of Myc-associated factor X (MAX) and alpha-(1,6)-fucosyltransferase (FUT8). In all three siblings the MAX alteration was confirmed, and the loss of the wild-type MAX and FUT8 alleles was demonstrated in all tumors. Uniparental disomy of chromosome 14q, previously demonstrated as a hallmark for MAX-related PCC, was shown in the index patient's PCC by single-nucleotide polymorphism array. Loss of MAX and FUT8 protein expression was demonstrated by immunohistochemistry in the tumors from the three siblings.
CONCLUSIONS: Our results indicate that large genomic deletions of MAX should be considered in familial and bilateral PCC with prior negative testing for gene mutations. In addition, our results confirm that MAX is a tumor suppressor gene for renal oncocytomas.
DESIGN: First, single-nucleotide polymorphism array and exome sequencing were performed on germline and PCC-derived DNA to identify genomic alterations in the index patient. Second, alterations were confirmed and validated by Sanger sequencing, analyzed by (multiplexed) PCR to determine the loss of the wild-type allele, and investigated by immunohistochemistry in the tumors of the three siblings.
RESULTS: The index patient's germline DNA revealed a large complex genomic alteration encompassing the intragenic and promoter regions of Myc-associated factor X (MAX) and alpha-(1,6)-fucosyltransferase (FUT8). In all three siblings the MAX alteration was confirmed, and the loss of the wild-type MAX and FUT8 alleles was demonstrated in all tumors. Uniparental disomy of chromosome 14q, previously demonstrated as a hallmark for MAX-related PCC, was shown in the index patient's PCC by single-nucleotide polymorphism array. Loss of MAX and FUT8 protein expression was demonstrated by immunohistochemistry in the tumors from the three siblings.
CONCLUSIONS: Our results indicate that large genomic deletions of MAX should be considered in familial and bilateral PCC with prior negative testing for gene mutations. In addition, our results confirm that MAX is a tumor suppressor gene for renal oncocytomas.
Предметные рубрики MeSH
Adenoma, OxyphilicAdrenal Gland NeoplasmsAdultBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsChromosomes, Human, Pair 14ExomeFucosyltransferasesGene RearrangementGerm-Line MutationHumansLymphatic MetastasisMaleMiddle AgedPedigreePheochromocytomaPolycythemiaPolymorphism, Single NucleotideUniparental Disomy