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3. Comprehensive analysis of the functional impact of single nucleotide variants of human CHEK2.

Author

McCarthy-Leo, Claire E., Brush, George S., Pique-Regi, Roger, Luca, Francesca, Tainsky, Michael A., and Finley Jr, Russell L.

Subjects
SINGLE nucleotide polymorphisms, PROTEIN kinases, CHECKPOINT kinase 2, CANCER genes, DISEASE risk factors
Abstract

Loss of function mutations in the checkpoint kinase gene CHEK2 are associated with increased risk of breast and other cancers. Most of the 3,188 unique amino acid changes that can result from non-synonymous single nucleotide variants (SNVs) of CHEK2, however, have not been tested for their impact on the function of the CHEK2-enocded protein (CHK2). One successful approach to testing the function of variants has been to test for their ability to complement mutations in the yeast ortholog of CHEK2, RAD53. This approach has been used to provide functional information on over 100 CHEK2 SNVs and the results align with functional assays in human cells and known pathogenicity. Here we tested all but two of the 4,887 possible SNVs in the CHEK2 open reading frame for their ability to complement RAD53 mutants using a high throughput technique of deep mutational scanning (DMS). Among the non-synonymous changes, 770 were damaging to protein function while 2,417 were tolerated. The results correlate well with previous structure and function data and provide a first or additional functional assay for all the variants of uncertain significance identified in clinical databases. Combined, this approach can be used to help predict the pathogenicity of CHEK2 variants of uncertain significance that are found in susceptibility screening and could be applied to other cancer risk genes. Author summary: Variations in gene sequences account for many of the phenotypic differences between individuals, including different susceptibilities to diseases like cancer. Individuals who inherit specific variants in the CHEK2 gene, for example, have increased risk of developing breast cancer and other cancers. These cancer-associated variants all abolish the normal activity of the CHEK2-encoded protein, a protein kinase called Chk2. Most of the CHEK2 variants found in individuals, however, have an unknown effect on the function of the Chk2 protein, and therefore an unknown potential role in cancer. This is because it is cumbersome to individually make and test each newly identified variant to see whether it affects protein function. Here we use an efficient version of a technique called deep mutational scanning to test nearly all possible CHEK2 single nucleotide variants for their impact on Chk2 protein function. Analyses of the resulting data indicate that it will be useful for developing models to predict the cancer risk in individuals who inherit any CHEK2 variants. This study also demonstrates a viable efficient approach to study variants of other genes, including other cancer related genes. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Data from Germline and Somatic NF1 Alterations Are Linked to Increased HER2 Expression in Breast Cancer

Author

Wang, Xia, primary, Kallionpää, Roope A., primary, Gonzales, Patrick R., primary, Chitale, Dhananjay A., primary, Tousignant, Renee N., primary, Crowley, Jacob P., primary, Chen, Zhihua, primary, Yoder, Sean J., primary, Blakeley, Jaishri O., primary, Acosta, Maria T., primary, Korf, Bruce R., primary, Messiaen, Ludwine M., primary, and Tainsky, Michael A., primary

Published
2023
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10. Supplement 1 from Germline and Somatic NF1 Alterations Are Linked to Increased HER2 Expression in Breast Cancer

Author

Wang, Xia, primary, Kallionpää, Roope A., primary, Gonzales, Patrick R., primary, Chitale, Dhananjay A., primary, Tousignant, Renee N., primary, Crowley, Jacob P., primary, Chen, Zhihua, primary, Yoder, Sean J., primary, Blakeley, Jaishri O., primary, Acosta, Maria T., primary, Korf, Bruce R., primary, Messiaen, Ludwine M., primary, and Tainsky, Michael A., primary

Published
2023
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19. Supplement 2 from Germline and Somatic NF1 Alterations Are Linked to Increased HER2 Expression in Breast Cancer

Author

Wang, Xia, primary, Kallionpää, Roope A., primary, Gonzales, Patrick R., primary, Chitale, Dhananjay A., primary, Tousignant, Renee N., primary, Crowley, Jacob P., primary, Chen, Zhihua, primary, Yoder, Sean J., primary, Blakeley, Jaishri O., primary, Acosta, Maria T., primary, Korf, Bruce R., primary, Messiaen, Ludwine M., primary, and Tainsky, Michael A., primary

Published
2023
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20. Supplemental Tables 1-3 from Germline and Somatic NF1 Alterations Are Linked to Increased HER2 Expression in Breast Cancer

Author

Wang, Xia, primary, Kallionpää, Roope A., primary, Gonzales, Patrick R., primary, Chitale, Dhananjay A., primary, Tousignant, Renee N., primary, Crowley, Jacob P., primary, Chen, Zhihua, primary, Yoder, Sean J., primary, Blakeley, Jaishri O., primary, Acosta, Maria T., primary, Korf, Bruce R., primary, Messiaen, Ludwine M., primary, and Tainsky, Michael A., primary

Published
2023
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21. Supplementary Tables 1-4 from Diagnostic Markers of Ovarian Cancer by High-Throughput Antigen Cloning and Detection on Arrays

Author

Chatterjee, Madhumita, primary, Mohapatra, Saroj, primary, Ionan, Alexei, primary, Bawa, Gagandeep, primary, Ali-Fehmi, Rouba, primary, Wang, Xiaoju, primary, Nowak, James, primary, Ye, Bin, primary, Nahhas, Fatimah A., primary, Lu, Karen, primary, Witkin, Steven S., primary, Fishman, David, primary, Munkarah, Adnan, primary, Morris, Robert, primary, Levin, Nancy K., primary, Shirley, Natalie N., primary, Tromp, Gerard, primary, Abrams, Judith, primary, Draghici, Sorin, primary, and Tainsky, Michael A., primary

Published
2023
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23. Data from Racial Disparity in Breast Cancer and Functional Germ Line Mutation in Galectin-3 (rs4644): A Pilot Study

Author

Balan, Vitaly, primary, Nangia-Makker, Pratima, primary, Schwartz, Ann G., primary, Jung, Young Suk, primary, Tait, Larry, primary, Hogan, Victor, primary, Raz, Tirza, primary, Wang, Yi, primary, Yang, Zeng Quan, primary, Wu, Gen Sheng, primary, Guo, Yongjun, primary, Li, Huixiang, primary, Abrams, Judith, primary, Couch, Fergus J., primary, Lingle, Wilma L., primary, Lloyd, Ricardo V., primary, Ethier, Stephen P., primary, Tainsky, Michael A., primary, and Raz, Avraham, primary

Published
2023
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24. Supplementary Tables 1-2 from Racial Disparity in Breast Cancer and Functional Germ Line Mutation in Galectin-3 (rs4644): A Pilot Study

Author

Balan, Vitaly, primary, Nangia-Makker, Pratima, primary, Schwartz, Ann G., primary, Jung, Young Suk, primary, Tait, Larry, primary, Hogan, Victor, primary, Raz, Tirza, primary, Wang, Yi, primary, Yang, Zeng Quan, primary, Wu, Gen Sheng, primary, Guo, Yongjun, primary, Li, Huixiang, primary, Abrams, Judith, primary, Couch, Fergus J., primary, Lingle, Wilma L., primary, Lloyd, Ricardo V., primary, Ethier, Stephen P., primary, Tainsky, Michael A., primary, and Raz, Avraham, primary

Published
2023
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25. Data from Diagnostic Markers of Ovarian Cancer by High-Throughput Antigen Cloning and Detection on Arrays

Author

Chatterjee, Madhumita, primary, Mohapatra, Saroj, primary, Ionan, Alexei, primary, Bawa, Gagandeep, primary, Ali-Fehmi, Rouba, primary, Wang, Xiaoju, primary, Nowak, James, primary, Ye, Bin, primary, Nahhas, Fatimah A., primary, Lu, Karen, primary, Witkin, Steven S., primary, Fishman, David, primary, Munkarah, Adnan, primary, Morris, Robert, primary, Levin, Nancy K., primary, Shirley, Natalie N., primary, Tromp, Gerard, primary, Abrams, Judith, primary, Draghici, Sorin, primary, and Tainsky, Michael A., primary

Published
2023
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31. Telomere dysfunction and chromothripsis

Author

Ernst, Aurélie, Jones, David T.W., Maass, Kendra K., Rode, Agata, Deeg, Katharina I., Jebaraj, Billy Michael Chelliah, Korshunov, Andrey, Hovestadt, Volker, Tainsky, Michael A., Pajtler, Kristian W., Bender, Sebastian, Brabetz, Sebastian, Gröbner, Susanne, Kool, Marcel, Devens, Frauke, Edelmann, Jennifer, Zhang, Cindy, Castelo-Branco, Pedro, Tabori, Uri, Malkin, David, Rippe, Karsten, Stilgenbauer, Stephan, Pfister, Stefan M., Zapatka, Marc, and Lichter, Peter

Published
2016
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40. Expression profiling identifies three pathways altered in cellular immortalization: interferon, cell cycle, and cytoskeleton

Author

Fridman, Aviva Levine, Tang, Lin, Kulaeva, Olga I., Ye, Bin, Li, Qunfang, Nahhas, Fatimah, Roberts, Paul C., Land, Susan J., Abrams, Judith, and Tainsky, Michael A.

Subjects
Gerontology -- Research, Immortality -- Research, Li-Fraumeni syndrome -- Research, Health, Seniors
Abstract

Abrogation of cellular senescence, resulting in immortalization, is a necessary step in the tumorigenic transformation of a cell. Four independent, spontaneously immortalized Li-Fraumeni syndrome (LFS) cell lines were used to analyze the gene expression changes that may have given these cell lines the growth advantage required to become immortal. A cellular senescence-like phenotype can be induced in immortal LFS cells by treating them with the DNA methyltransferase (DNMT) inhibitor 5-aza-deoxycytidine. We hypothesized, therefore, that genes epigenetically silenced by promoter methylation are potentially key regulators of senescence. We used microarrays to compare the epigenetic gene expression profiles of precrisis LFS cells with immortal LFS cells. Gene ontology analysis of the expression data revealed a statistically significant contribution of interferon pathway, cell cycle, and cytoskeletal genes in the process of immortalization. The identification of the genes and pathways regulating immortalization will lead to a better understanding of cellular immortalization and molecular targets in cancer and aging.

Published
2006

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