title: Complex MAX Rearrangement in a Family With Malignant Pheochromocytoma, Renal Oncocytoma, and Erythrocytosis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Djamailys
authors.initials: D
authors.lastname: Koffy
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Bert H
authors.initials: BH
authors.lastname: Eussen
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Oudijk
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Papathomas
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Francien H
authors.initials: FH
authors.lastname: van Nederveen
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Eric J T
authors.initials: EJ
authors.lastname: Belt
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Gaston J H
authors.initials: GJ
authors.lastname: Franssen
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: David F J
authors.initials: DF
authors.lastname: Restuccia
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Niels M G
authors.initials: NM
authors.lastname: Krol
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Rob B
authors.initials: RB
authors.lastname: van der Luijt
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Oldenburg
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van Ijcken
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.affiliation: Departments of Pathology (E.K., D.K., L.O., T.G.P., D.F.J.R., N.M.G.K., R.R.d.K., W.N.M.D.), Internal Medicine (R.A.F., W.W.d.H.), and Biomics (W.F.J.v.I.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 CA Rotterdam, The Netherlands; Departments of Clinical Genetics (B.H.E., R.A.O., A.d.K.), and Surgery (E.J.T.B., G.J.H.F.), Erasmus Medical Center Cancer Institute, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Histopathology (T.G.P.), King's College Hospital, London, SE5 9RS, United Kingdom; Laboratory for Pathology (F.H.v.N.), Pathologisch Laboratorium Dordrecht, 3317 DA Dordrecht, The Netherlands; Division of Biomedical Genetics (R.B.v.d.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
mesh_terms: D018249:Adenoma, Oxyphilic / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D000310:Adrenal Gland Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D059472:Exome; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism; D015321:Gene Rearrangement; D018095:Germ-Line Mutation; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010673:Pheochromocytoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D011086:Polycythemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D024182:Uniparental Disomy
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499330:MAX protein, human; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase