A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors.
Recently, the KIF1B beta gene on 1p36, a region commonly deleted in neural crest cancers, was found to be a proapoptotic factor for sympathetic precursors. KIF1B beta 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 KIF1B beta 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 KIF1B beta 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 KIF1B beta 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, KIF1B beta-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 KIF1B beta 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.
Yeh
I-Tien
IT
Cancer Therapy and Research Center, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Lenci
Romina E
RE
Qin
Yuejuan
Y
Buddavarapu
Kalyan
K
Ligon
Azra H
AH
Leteurtre
Emmanuelle
E
Do Cao
Christine
C
Cardot-Bauters
Catherine
C
Pigny
Pascal
P
Dahia
Patricia L M
PL
D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D002878:Chromosomes, Human, Pair 1; D005192:Family Health; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D016547:Kinesins / Q000235:genetics* / Q000502:physiology; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009423:Nervous System Neoplasms / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010673:Pheochromocytoma / Q000235:genetics*
C091053:KIF1B protein, human; D016547:Kinesins