title: Characterization of DNA variants in the human kinome in breast cancer.
abstract: Kinases play a key role in cancer biology, and serve as potential clinically useful targets for designing cancer therapies. We examined nucleic acid variations in the human kinome and several known cancer-related genes in breast cancer. DNA was extracted from fine needle biopsies of 73 primary breast cancers and 19 metastatic lesions. Targeted sequencing of 518 kinases and 68 additional cancer related genes was performed using the SOLiD sequencing platform. We detected 1561 unique, non-synonymous variants in kinase genes in the 92 cases, and 74 unique variants in 43 kinases that were predicted to have major functional impact on the protein. Three kinase groups--CMGC, STE and TKL--showed greater mutational load in metastatic compared to primary cancer samples, however, after correction for multiple testing the difference was significant only for the TKL group (P = 0.04). We also observed that a higher proportion of histologic grade 1 and 2 cases had high functional impact variants in the SCYL2 gene compared with grade 3 cases. Our findings indicate that individual breast cancers harbor a substantial number of potentially functionally important nucleotide variations in kinase genes, most of which are present in unique combinations and include both somatic and germline functional variants.
authors.affiliation: Department of Breast Medical Oncology of Yale University, New Haven, CT, USA.|Molecular, Cellular and Developmental Biology of Yale University, New Haven, CT, USA.
authors.forename: Divyansh
authors.initials: D
authors.lastname: Agarwal
authors.affiliation: Department of Quantitative Sciences of the University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Breast Medical Oncology of Yale University, New Haven, CT, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Experimental Therapeutics of the University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Breast Medical Oncology of Yale University, New Haven, CT, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Breast Medical Oncology of Yale University, New Haven, CT, USA.
authors.forename: Vikram B
authors.initials: VB
authors.lastname: Wali
authors.affiliation: Department of Pharmacology of Yale University, New Haven, CT, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Turk
authors.affiliation: Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY, USA.|Foundation Medicine, Cambridge, MA, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Pathology of the University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Fraser Symmans
authors.affiliation: Department of Breast Medical Oncology of Yale University, New Haven, CT, USA.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: Department of Breast Medical Oncology of Yale University, New Haven, CT, USA.
authors.forename: Christos
authors.initials: C
authors.lastname: Hatzis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010770:Phosphotransferases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D010770:Phosphotransferases