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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

Average number of genomic aberrations per patient from the Foundation Medicine cohort.The first chart shows the results for identified mutations (variants), the second for copy number alterations (CNAs) and the third for genomic rearrangements. Each chart shows the average number of aberrations per patient in patients with metastatic (dark grey) or primary (light grey) tumors occurring in genes within each of the six kinase groups. The p-values are from the comparison of the means in the metastatic and primary groups using a T-test.
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f4: Average number of genomic aberrations per patient from the Foundation Medicine cohort.The first chart shows the results for identified mutations (variants), the second for copy number alterations (CNAs) and the third for genomic rearrangements. Each chart shows the average number of aberrations per patient in patients with metastatic (dark grey) or primary (light grey) tumors occurring in genes within each of the six kinase groups. The p-values are from the comparison of the means in the metastatic and primary groups using a T-test.

Mentions: We assessed the overall mutational load and potential specificity of kinase mutations in the Foundation Medicine cohort that included mutational profiles from 185 metastatic breast cancers. Among the 49 kinases present in the Foundation One gene panel, genes in the Atypical kinase group (AKT1, AKT2, AKT3, PDK1) had the highest mutation frequently in both primary (88%) and metastatic cancers (96%), followed by genes in the STE kinase group (MAP2K1, MAP2K2, MAP2K4, MAP3K1, PAK3) which were mutated in 83% of the primary and 81% of the metastatic cancers. Genes in the CMCG group (CDK4, CDK6, CDK8, GSK3B) had the most frequent copy number alterations in 86% of the primary and 65% of the metastatic cancers. However, neither difference was statistically significant. Interestingly, both primary and metastatic cancers had at least 1 mutation per patient on average in genes in the Atypical, STE and TK kinase groups (Fig. 4), suggesting that many of these kinases may be important cancer driver genes. Furthermore, about 70–80% of the primary and metastatic tumors appear to have a copy number aberration in genes in CMGC and TK kinase groups (Fig. 4). When comparing the relative mutational load in primary vs metastatic cancers, kinases in the TK group had a borderline significantly greater mutational load in metastatic cancers (P = 0.05) and a higher CNA load compared to primary tumors (Fig. 4). Overall these findings are significant and may warrant further investigation.


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)

Average number of genomic aberrations per patient from the Foundation Medicine cohort.The first chart shows the results for identified mutations (variants), the second for copy number alterations (CNAs) and the third for genomic rearrangements. Each chart shows the average number of aberrations per patient in patients with metastatic (dark grey) or primary (light grey) tumors occurring in genes within each of the six kinase groups. The p-values are from the comparison of the means in the metastatic and primary groups using a T-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Average number of genomic aberrations per patient from the Foundation Medicine cohort.The first chart shows the results for identified mutations (variants), the second for copy number alterations (CNAs) and the third for genomic rearrangements. Each chart shows the average number of aberrations per patient in patients with metastatic (dark grey) or primary (light grey) tumors occurring in genes within each of the six kinase groups. The p-values are from the comparison of the means in the metastatic and primary groups using a T-test.
Mentions: We assessed the overall mutational load and potential specificity of kinase mutations in the Foundation Medicine cohort that included mutational profiles from 185 metastatic breast cancers. Among the 49 kinases present in the Foundation One gene panel, genes in the Atypical kinase group (AKT1, AKT2, AKT3, PDK1) had the highest mutation frequently in both primary (88%) and metastatic cancers (96%), followed by genes in the STE kinase group (MAP2K1, MAP2K2, MAP2K4, MAP3K1, PAK3) which were mutated in 83% of the primary and 81% of the metastatic cancers. Genes in the CMCG group (CDK4, CDK6, CDK8, GSK3B) had the most frequent copy number alterations in 86% of the primary and 65% of the metastatic cancers. However, neither difference was statistically significant. Interestingly, both primary and metastatic cancers had at least 1 mutation per patient on average in genes in the Atypical, STE and TK kinase groups (Fig. 4), suggesting that many of these kinases may be important cancer driver genes. Furthermore, about 70–80% of the primary and metastatic tumors appear to have a copy number aberration in genes in CMGC and TK kinase groups (Fig. 4). When comparing the relative mutational load in primary vs metastatic cancers, kinases in the TK group had a borderline significantly greater mutational load in metastatic cancers (P = 0.05) and a higher CNA load compared to primary tumors (Fig. 4). Overall these findings are significant and may warrant further investigation.

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