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Characterization of DNA variants in the human kinome in breast cancer.

Agarwal D, Qi Y, Jiang T, Liu X, Shi W, Wali VB, Turk B, Ross JS, Fraser Symmans W, Pusztai L, Hatzis C - Sci Rep (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Medical Oncology of Yale University, New Haven, CT, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Single nucleotide kinase variants (SNVs) in 92 breast tumors.(A) Barplot of number of synonymous, non-synonymous and total SNVs for each of the 92 samples ordered by the total number of SNVs per sample. (B) Venn diagram showing the predicted functional impact of 3203 unique non-synonymous SNVs by 3 different functional prediction methods: SIFT scores, Mutation Assessor functional importance (FI) scores, and Kinase Specific functional effect score (KSS). The cutoff used for the three methods to categorize the variants as functionally important were: “high/medium” for Mutation Assessor, <0.05 for SIFT, and “Yes” for KSS deleterious prediction.
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f2: Single nucleotide kinase variants (SNVs) in 92 breast tumors.(A) Barplot of number of synonymous, non-synonymous and total SNVs for each of the 92 samples ordered by the total number of SNVs per sample. (B) Venn diagram showing the predicted functional impact of 3203 unique non-synonymous SNVs by 3 different functional prediction methods: SIFT scores, Mutation Assessor functional importance (FI) scores, and Kinase Specific functional effect score (KSS). The cutoff used for the three methods to categorize the variants as functionally important were: “high/medium” for Mutation Assessor, <0.05 for SIFT, and “Yes” for KSS deleterious prediction.

Mentions: Approximately 40 million nucleotide reads were acquired per sample, of which 61% could be mapped to the targeted kinase coding regions, resulting in a mean nucleotide coverage in the targeted regions of 369x. The mean number of nucleotide variants per sample was 1052, ranging from 493 to 1536 in individual cases, 97% of which were already cataloged in dbSNP138 or COSMIC databases. The remaining 3% of the variants were novel. The median number of synonymous variants per sample was 273 (range 119–396) and of non-synonymous variants 153 (range 75–223) (Fig. 2A). The raw data of variants for each patient, limited to only include non-synonymous changes, is provided in Supplementary Table 3.


Characterization of DNA variants in the human kinome in breast cancer.

Agarwal D, Qi Y, Jiang T, Liu X, Shi W, Wali VB, Turk B, Ross JS, Fraser Symmans W, Pusztai L, Hatzis C - Sci Rep (2015)

Single nucleotide kinase variants (SNVs) in 92 breast tumors.(A) Barplot of number of synonymous, non-synonymous and total SNVs for each of the 92 samples ordered by the total number of SNVs per sample. (B) Venn diagram showing the predicted functional impact of 3203 unique non-synonymous SNVs by 3 different functional prediction methods: SIFT scores, Mutation Assessor functional importance (FI) scores, and Kinase Specific functional effect score (KSS). The cutoff used for the three methods to categorize the variants as functionally important were: “high/medium” for Mutation Assessor, <0.05 for SIFT, and “Yes” for KSS deleterious prediction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588561&req=5

f2: Single nucleotide kinase variants (SNVs) in 92 breast tumors.(A) Barplot of number of synonymous, non-synonymous and total SNVs for each of the 92 samples ordered by the total number of SNVs per sample. (B) Venn diagram showing the predicted functional impact of 3203 unique non-synonymous SNVs by 3 different functional prediction methods: SIFT scores, Mutation Assessor functional importance (FI) scores, and Kinase Specific functional effect score (KSS). The cutoff used for the three methods to categorize the variants as functionally important were: “high/medium” for Mutation Assessor, <0.05 for SIFT, and “Yes” for KSS deleterious prediction.
Mentions: Approximately 40 million nucleotide reads were acquired per sample, of which 61% could be mapped to the targeted kinase coding regions, resulting in a mean nucleotide coverage in the targeted regions of 369x. The mean number of nucleotide variants per sample was 1052, ranging from 493 to 1536 in individual cases, 97% of which were already cataloged in dbSNP138 or COSMIC databases. The remaining 3% of the variants were novel. The median number of synonymous variants per sample was 273 (range 119–396) and of non-synonymous variants 153 (range 75–223) (Fig. 2A). The raw data of variants for each patient, limited to only include non-synonymous changes, is provided in Supplementary Table 3.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Medical Oncology of Yale University, New Haven, CT, USA.

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.

No MeSH data available.


Related in: MedlinePlus