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A germline mutation of the KIF1Bβ gene on 1p36 in a family with neural and nonneural tumors


Recently, the KIF1Bβ gene on 1p36, a region commonly deleted in neural crest cancers, was found to be a proapoptotic factor for sympathetic precursors. KIF1Bβ mutations were detected in pheochromocytomas and neuroblastomas, two sympathetic lineage tumors, suggesting a role for this gene in cancer. Here, we studied five individuals from a three-generation cancer-prone family with a KIF1Bβ germline variant and seven of their tumors, both of neural crest and nonneural origin. Genetic studies including sequencing, copy number analysis and fluorescence in situ-hybridization (FISH) showed retention of both KIF1Bβ alleles in all neural crest-derived tumors in this family, consistent with haploinsufficiency or methylation of the wild-type allele. In contrast, the lung adenocarcinoma from one mutation carrier had somatic loss of the wild-type allele in agreement with a classical two-hit inactivation. Global transcription analysis of KIF1Bβ mutant pheochromocytomas revealed that these tumors are transcriptionally related to pheochromocytomas with RET and NF1 mutations but independent from SDH- and VHL-associated tumors. Furthermore, KIF1Bβ-mutant tumors are uniquely enriched for pathways related to glutamate metabolism and the oxidative stress response. Our data start to delineate the signals that are disrupted by KIF1Bβ dysfunction in pheochromocytomas and suggest that loss of this gene may also be permissive to the development of nonneural crest malignancies. This may imply the existence of a tissue-specific gene dosage requirement for its tumorigenesis.

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  1. Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP (2005) Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23:8812–8818

  2. Bauters C, Vantyghem MC, Leteurtre E, Odou MF, Mouton C, Porchet N, Wemeau JL, Proye C, Pigny P (2003) Hereditary phaeochromocytomas and paragangliomas: a study of five susceptibility genes. J Med Genet 40:e75

  3. Creighton C, Hanash S, Beer D (2003) Gene expression patterns define pathways correlated with loss of differentiation in lung adenocarcinomas. FEBS Lett 540:167–170

  4. Dahia PLM, Hao K, Rogus J, Colin C, Pujana MAG, Ross K, Magoffin D, Aronin N, Cascon A, Hayashida CY, Li C, Toledo SPA, Stiles CD, Consortium. ftFP (2005a) Novel pheochromocytoma susceptibility loci identified by integrative genomics. Cancer Res 65:9651–9658

  5. Dahia PLM, Ross K, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore Jr F, Dluhy R, Sosa JA, IT O, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SPA, Nosé V, Li C, Stiles CD (2005b) A HIF1a regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 1:e8

  6. Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, Raza A, Root DE, Attar E, Ellis SR, Golub TR (2008) Identification of RPS14 as a 5q-syndrome gene by RNA interference screen 451:335–339

  7. Henderson TO, Whitton J, Stovall M, Mertens AC, Mitby P, Friedman D, Strong LC, Hammond S, Neglia JP, Meadows AT, Robison L, Diller L (2007) Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 99:300–308

  8. Ishiuchi S, Tsuzuki K, Yoshida Y, Yamada N, Hagimura N, Okado H, Miwa A, Kurihara H, Nakazato Y, Tamura M, Sasaki T, Ozawa S (2002) Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat Med 8:971–978

  9. Ishiuchi S, Yoshida Y, Sugawara K, Aihara M, Ohtani T, Watanabe T, Saito N, Tsuzuki K, Okado H, Miwa A, Nakazato Y, Ozawa S (2007) Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J Neurosci 27:7987–8001

  10. Knudson AG (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823

  11. Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG Jr, Schlisio S (2005) Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 8:155–167

  12. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB, Su X, Pui CH, Relling MV, Evans WE, Shurtleff SA, Downing JR (2007) Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446:758–764

  13. Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E, Chompret A, Ellison JW, Briere JJ, Rustin P, Gimenez-Roqueplo AP, Eng C, Carney JA, Stratakis CA (2008) Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16:79–88

  14. Ramanujan VK, Biener-Ramanujan E, Armmer K, Centonze VE, Herman BA (2006) Spectral kinetics ratiometry: a simple approach for real-time monitoring of fluorophore distributions in living cells. Cytometry A 69:912–919

  15. Schlisio S, Kenchappa RS, Vredeveld LC, George RE, Stewart R, Greulich H, Shahriari K, Nguyen NV, Pigny P, Dahia PL, Pomeroy SL, Maris JM, Look AT, Meyerson M, Peeper DS, Carter BD, Kaelin WG Jr (2008) The kinesin KIF1B{beta} acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev

  16. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) From the cover: gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550

  17. Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, Province MA, Kraja A, Johnson LA, Shah K, Sato M, Thomas RK, Barletta JA, Borecki IB, Broderick S, Chang AC, Chiang DY, Chirieac LR, Cho J, Fujii Y, Gazdar AF, Giordano T, Greulich H, Hanna M, Johnson BE, Kris MG, Lash A, Lin L, Lindeman N, Mardis ER, McPherson JD, Minna JD, Morgan MB, Nadel M, Orringer MB, Osborne JR, Ozenberger B, Ramos AH, Robinson J, Roth JA, Rusch V, Sasaki H, Shepherd F, Sougnez C, Spitz MR, Tsao MS, Twomey D, Verhaak RG, Weinstock GM, Wheeler DA, Winckler W, Yoshizawa A, Yu S, Zakowski MF, Zhang Q, Beer DG, Wistuba II, Watson MA, Garraway LA, Ladanyi M, Travis WD, Pao W, Rubin MA, Gabriel SB, Gibbs RA, Varmus HE, Wilson RK, Lander ES, Meyerson M (2007) Characterizing the cancer genome in lung adenocarcinoma. Nature 450:893–898

  18. Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y, Saito M, Tsuji S, Hayashi Y, Hirokawa N (2001) Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 105:587–597

  19. Zuchner S, Vance JM (2006) Molecular genetics of autosomal-dominant axonal Charcot-Marie-Tooth disease. Neuromolecular Med 8:63–74

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We thank Ricardo C. Aguiar for insightful comments, William G. Kaelin Jr and Susanne Schlisio for discussions, and Natalie Vena for technical assistance with the FISH analysis. P.L.M.D. is supported by grants from the Sidney Kimmel Cancer Foundation and the Cancer Therapy and Research Center (CTRC) at the University of Texas Health Science Center at San Antonio (NIH-P30 CA541). Authors’ contributions: I-T.Y. performed and analyzed experiments and made conceptual contributions, R.L., Y.Q. and K.B., performed experiments, A.H.L. designed experiments and interpreted data; C.D.C. and C.C.B. performed clinical analysis; E.L. and P.P. provided reagents and helped with data interpretation; P.L.M.D. designed experiments, supervised the project and wrote the manuscript.

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Correspondence to Patricia L. M. Dahia.

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Tumor DNA sequence traces of the region surrounding the mutation site on exon 41 of the KIF1bβ gene reveal wild-type (TGAGCGA) and/or mutant (TGAACGA) sequence (lower panel). Upper panel shows normal reference DNA. Resulting amino acid change (S to S/N) is displayed at the top of each image. Tumor carriers are identified according to pedigree labeling. All tumor sequences show a biallelic pattern except for the lung adenocarcinoma, where the mutant allele shows a predominant, but not exclusive, peak indicative of a heterogeneous cell population. (PPT 1294 kb)

Genomewide copy number display of the left pheochromocytoma of the index case. Affymetrix SNP 10K array based was used to determine LOH and copy number of the index case’s left pheochromocytoma (K1), along with two sporadic pheochromocytomas, S1 and S2, and two normal control DNAs (N1 and N2). Image was generated on dCHIP using normalized and modeled SNP array data and is displayed as inferred copy number. Columns represent samples and rows represent SNPs ordered by chromosomal location. Color scale (bottom) indicates copy number and SDs from the mean with intense red reflecting higher copy. Right panels display the copy number curve of each sample in blue juxtaposed to the normal copy (red line). Position of the KIF1Bβ gene is shown by an * and the corresponding copy number on K1 (normal or 2 copies) and S2 (hemizygous loss, left shift in relation to red line) are marked by arrows. Sample gender is also displayed on header (M or F) and is reflected by lower copy number on both normal male samples or by true allelic loss on tumor S2 (female with loss of X chromosome markers). (PPT 323 kb)

Leading edge genes of five pathways associated with the mutant KIF1Bβ transcription profile (DOC 77 kb)

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Yeh, I., Lenci, R.E., Qin, Y. et al. A germline mutation of the KIF1Bβ gene on 1p36 in a family with neural and nonneural tumors. Hum Genet 124, 279–285 (2008). https://doi.org/10.1007/s00439-008-0553-1

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  • Lung Adenocarcinoma
  • Leiomyosarcoma
  • Paragangliomas
  • Copy Number Analysis
  • Ganglioneuroma