Abstract
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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Acknowledgments
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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439_2008_553_MOESM1_ESM.ppt
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)
439_2008_553_MOESM2_ESM.ppt
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)
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Yeh, IT., 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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DOI: https://doi.org/10.1007/s00439-008-0553-1