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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

Distribution of high functional-importance (HFI) kinase variants across 92 breast cancers.A total of 295 unique HFI NVs (coverage >20x) in 148 kinase genes are shown at gene level, and the clinical variable status is shown on the top. The samples were ordered hierarchically by ER status, HER2 status, tumor grade, tumor node status (N), tumor size (T-stage), and pathologic complete response (pCR) status (white: missing values for clinical variables, blue: negative; yellow: positive). For Grade and T levels, yellow: 1, orange: 2, pink: 3, red: 4. The legend representing multiple colors, scored from 0–7, in the heatmap correspond to the frequency of HFI variants in a particular gene for a given patient.
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f3: Distribution of high functional-importance (HFI) kinase variants across 92 breast cancers.A total of 295 unique HFI NVs (coverage >20x) in 148 kinase genes are shown at gene level, and the clinical variable status is shown on the top. The samples were ordered hierarchically by ER status, HER2 status, tumor grade, tumor node status (N), tumor size (T-stage), and pathologic complete response (pCR) status (white: missing values for clinical variables, blue: negative; yellow: positive). For Grade and T levels, yellow: 1, orange: 2, pink: 3, red: 4. The legend representing multiple colors, scored from 0–7, in the heatmap correspond to the frequency of HFI variants in a particular gene for a given patient.

Mentions: The mean number of HFI variants per sample was 24 (range 5 to 40), with each tumor appearing to harbor a unique assortment of variants (Fig. 3). These variants fall into 3 categories: known polymorphisms already reported in dbSNP138; known cancer-associated mutations reported in COSMIC; and low frequency variants with currently unknown role in cancer (Supplementary Table 4). We note that important hotspot mutations in genes like PIK3CA (e.g. E545K and H1047R) and ERBB2 (e.g. L755S) do not get classified as HFI as they were filtered out as low quality calls, and are therefore excluded from the analysis.


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)

Distribution of high functional-importance (HFI) kinase variants across 92 breast cancers.A total of 295 unique HFI NVs (coverage >20x) in 148 kinase genes are shown at gene level, and the clinical variable status is shown on the top. The samples were ordered hierarchically by ER status, HER2 status, tumor grade, tumor node status (N), tumor size (T-stage), and pathologic complete response (pCR) status (white: missing values for clinical variables, blue: negative; yellow: positive). For Grade and T levels, yellow: 1, orange: 2, pink: 3, red: 4. The legend representing multiple colors, scored from 0–7, in the heatmap correspond to the frequency of HFI variants in a particular gene for a given patient.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Distribution of high functional-importance (HFI) kinase variants across 92 breast cancers.A total of 295 unique HFI NVs (coverage >20x) in 148 kinase genes are shown at gene level, and the clinical variable status is shown on the top. The samples were ordered hierarchically by ER status, HER2 status, tumor grade, tumor node status (N), tumor size (T-stage), and pathologic complete response (pCR) status (white: missing values for clinical variables, blue: negative; yellow: positive). For Grade and T levels, yellow: 1, orange: 2, pink: 3, red: 4. The legend representing multiple colors, scored from 0–7, in the heatmap correspond to the frequency of HFI variants in a particular gene for a given patient.
Mentions: The mean number of HFI variants per sample was 24 (range 5 to 40), with each tumor appearing to harbor a unique assortment of variants (Fig. 3). These variants fall into 3 categories: known polymorphisms already reported in dbSNP138; known cancer-associated mutations reported in COSMIC; and low frequency variants with currently unknown role in cancer (Supplementary Table 4). We note that important hotspot mutations in genes like PIK3CA (e.g. E545K and H1047R) and ERBB2 (e.g. L755S) do not get classified as HFI as they were filtered out as low quality calls, and are therefore excluded from the analysis.

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