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2. Comprehensive Analysis of Hypermutation in Human Cancer

Author

Campbell, Brittany B, Light, Nicholas, Fabrizio, David, Zatzman, Matthew, Fuligni, Fabio, de Borja, Richard, Davidson, Scott, Edwards, Melissa, Elvin, Julia A, Hodel, Karl P, Zahurancik, Walter J, Suo, Zucai, Lipman, Tatiana, Wimmer, Katharina, Kratz, Christian P, Bowers, Daniel C, Laetsch, Theodore W, Dunn, Gavin P, Johanns, Tanner M, Grimmer, Matthew R, Smirnov, Ivan V, Larouche, Valérie, Samuel, David, Bronsema, Annika, Osborn, Michael, Stearns, Duncan, Raman, Pichai, Cole, Kristina A, Storm, Phillip B, Yalon, Michal, Opocher, Enrico, Mason, Gary, Thomas, Gregory A, Sabel, Magnus, George, Ben, Ziegler, David S, Lindhorst, Scott, Issai, Vanan Magimairajan, Constantini, Shlomi, Toledano, Helen, Elhasid, Ronit, Farah, Roula, Dvir, Rina, Dirks, Peter, Huang, Annie, Galati, Melissa A, Chung, Jiil, Ramaswamy, Vijay, Irwin, Meredith S, Aronson, Melyssa, Durno, Carol, Taylor, Michael D, Rechavi, Gideon, Maris, John M, Bouffet, Eric, Hawkins, Cynthia, Costello, Joseph F, Meyn, M Stephen, Pursell, Zachary F, Malkin, David, Tabori, Uri, and Shlien, Adam

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Human Genome, Cancer, Rare Diseases, Cancer Genomics, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Child, Cluster Analysis, DNA Polymerase II, DNA Polymerase III, DNA Replication, Humans, Mutation, Neoplasms, Poly-ADP-Ribose Binding Proteins, DNA repair, DNA replication, cancer genomics, cancer predisposition, hypermutation, immune checkpoint inhibitors, mismatch repair, mutator, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.

Published
2017

3. Data from Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade

Author

Galati, Melissa A., primary, Hodel, Karl P., primary, Gams, Miki S., primary, Sudhaman, Sumedha, primary, Bridge, Taylor, primary, Zahurancik, Walter J., primary, Ungerleider, Nathan A., primary, Park, Vivian S., primary, Ercan, Ayse B., primary, Joksimovic, Lazar, primary, Siddiqui, Iram, primary, Siddaway, Robert, primary, Edwards, Melissa, primary, de Borja, Richard, primary, Elshaer, Dana, primary, Chung, Jiil, primary, Forster, Victoria J., primary, Nunes, Nuno M., primary, Aronson, Melyssa, primary, Wang, Xia, primary, Ramdas, Jagadeesh, primary, Seeley, Andrea, primary, Sarosiek, Tomasz, primary, Dunn, Gavin P., primary, Byrd, Jonathan N., primary, Mordechai, Oz, primary, Durno, Carol, primary, Martin, Alberto, primary, Shlien, Adam, primary, Bouffet, Eric, primary, Suo, Zucai, primary, Jackson, James G., primary, Hawkins, Cynthia E., primary, Guidos, Cynthia J., primary, Pursell, Zachary F., primary, and Tabori, Uri, primary

Published
2023
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4. Supplementary Table S3 from Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade

Author

Galati, Melissa A., primary, Hodel, Karl P., primary, Gams, Miki S., primary, Sudhaman, Sumedha, primary, Bridge, Taylor, primary, Zahurancik, Walter J., primary, Ungerleider, Nathan A., primary, Park, Vivian S., primary, Ercan, Ayse B., primary, Joksimovic, Lazar, primary, Siddiqui, Iram, primary, Siddaway, Robert, primary, Edwards, Melissa, primary, de Borja, Richard, primary, Elshaer, Dana, primary, Chung, Jiil, primary, Forster, Victoria J., primary, Nunes, Nuno M., primary, Aronson, Melyssa, primary, Wang, Xia, primary, Ramdas, Jagadeesh, primary, Seeley, Andrea, primary, Sarosiek, Tomasz, primary, Dunn, Gavin P., primary, Byrd, Jonathan N., primary, Mordechai, Oz, primary, Durno, Carol, primary, Martin, Alberto, primary, Shlien, Adam, primary, Bouffet, Eric, primary, Suo, Zucai, primary, Jackson, James G., primary, Hawkins, Cynthia E., primary, Guidos, Cynthia J., primary, Pursell, Zachary F., primary, and Tabori, Uri, primary

Published
2023
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5. Supplementary Data Figures 1-8 from Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade

Author

Galati, Melissa A., primary, Hodel, Karl P., primary, Gams, Miki S., primary, Sudhaman, Sumedha, primary, Bridge, Taylor, primary, Zahurancik, Walter J., primary, Ungerleider, Nathan A., primary, Park, Vivian S., primary, Ercan, Ayse B., primary, Joksimovic, Lazar, primary, Siddiqui, Iram, primary, Siddaway, Robert, primary, Edwards, Melissa, primary, de Borja, Richard, primary, Elshaer, Dana, primary, Chung, Jiil, primary, Forster, Victoria J., primary, Nunes, Nuno M., primary, Aronson, Melyssa, primary, Wang, Xia, primary, Ramdas, Jagadeesh, primary, Seeley, Andrea, primary, Sarosiek, Tomasz, primary, Dunn, Gavin P., primary, Byrd, Jonathan N., primary, Mordechai, Oz, primary, Durno, Carol, primary, Martin, Alberto, primary, Shlien, Adam, primary, Bouffet, Eric, primary, Suo, Zucai, primary, Jackson, James G., primary, Hawkins, Cynthia E., primary, Guidos, Cynthia J., primary, Pursell, Zachary F., primary, and Tabori, Uri, primary

Published
2023
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6. Supplementary Data from Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade

Author

Galati, Melissa A., primary, Hodel, Karl P., primary, Gams, Miki S., primary, Sudhaman, Sumedha, primary, Bridge, Taylor, primary, Zahurancik, Walter J., primary, Ungerleider, Nathan A., primary, Park, Vivian S., primary, Ercan, Ayse B., primary, Joksimovic, Lazar, primary, Siddiqui, Iram, primary, Siddaway, Robert, primary, Edwards, Melissa, primary, de Borja, Richard, primary, Elshaer, Dana, primary, Chung, Jiil, primary, Forster, Victoria J., primary, Nunes, Nuno M., primary, Aronson, Melyssa, primary, Wang, Xia, primary, Ramdas, Jagadeesh, primary, Seeley, Andrea, primary, Sarosiek, Tomasz, primary, Dunn, Gavin P., primary, Byrd, Jonathan N., primary, Mordechai, Oz, primary, Durno, Carol, primary, Martin, Alberto, primary, Shlien, Adam, primary, Bouffet, Eric, primary, Suo, Zucai, primary, Jackson, James G., primary, Hawkins, Cynthia E., primary, Guidos, Cynthia J., primary, Pursell, Zachary F., primary, and Tabori, Uri, primary

Published
2023
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10. DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'hématologie, Chung, Jiil, Maruvka, Yosef E, Sudhaman, Sumedha, Kelly, Jacalyn, Haradhvala, Nicholas J, Bianchi, Vanessa, Edwards, Melissa, Forster, Victoria J, Nunes, Nuno M, Galati, Melissa A, Komosa, Martin, Deshmukh, Shriya, Cabric, Vanja, Davidson, Scott, Zatzman, Matthew, Light, Nicholas, Hayes, Reid, Brunga, Ledia, Anderson, Nathaniel D, Ho, Ben, Hodel, Karl P, Siddaway, Robert, Morrissy, A Sorana, Bowers, Daniel C, Larouche, Valérie, Bronsema, Annika, Osborn, Michael, Cole, Kristina A, Opocher, Enrico, Mason, Gary, Thomas, Gregory A, George, Ben, Ziegler, David S, Lindhorst, Scott, Vanan, Magimairajan, Yalon-Oren, Michal, Reddy, Alyssa T, Massimino, Maura, Tomboc, Patrick, Van Damme, An, Lossos, Alexander, Durno, Carol, Aronson, Melyssa, Morgenstern, Daniel A, Bouffet, Eric, Huang, Annie, Taylor, Michael D, Villani, Anita, Malkin, David, Hawkins, Cynthia E, Pursell, Zachary F, Shlien, Adam, Kunkel, Thomas A, Getz, Gad, Tabori, Uri, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'hématologie, Chung, Jiil, Maruvka, Yosef E, Sudhaman, Sumedha, Kelly, Jacalyn, Haradhvala, Nicholas J, Bianchi, Vanessa, Edwards, Melissa, Forster, Victoria J, Nunes, Nuno M, Galati, Melissa A, Komosa, Martin, Deshmukh, Shriya, Cabric, Vanja, Davidson, Scott, Zatzman, Matthew, Light, Nicholas, Hayes, Reid, Brunga, Ledia, Anderson, Nathaniel D, Ho, Ben, Hodel, Karl P, Siddaway, Robert, Morrissy, A Sorana, Bowers, Daniel C, Larouche, Valérie, Bronsema, Annika, Osborn, Michael, Cole, Kristina A, Opocher, Enrico, Mason, Gary, Thomas, Gregory A, George, Ben, Ziegler, David S, Lindhorst, Scott, Vanan, Magimairajan, Yalon-Oren, Michal, Reddy, Alyssa T, Massimino, Maura, Tomboc, Patrick, Van Damme, An, Lossos, Alexander, Durno, Carol, Aronson, Melyssa, Morgenstern, Daniel A, Bouffet, Eric, Huang, Annie, Taylor, Michael D, Villani, Anita, Malkin, David, Hawkins, Cynthia E, Pursell, Zachary F, Shlien, Adam, Kunkel, Thomas A, Getz, Gad, and Tabori, Uri

Abstract

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction..

Published
2021

11. DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells

Author

Chung, Jiil, primary, Maruvka, Yosef E., additional, Sudhaman, Sumedha, additional, Kelly, Jacalyn, additional, Haradhvala, Nicholas J., additional, Bianchi, Vanessa, additional, Edwards, Melissa, additional, Forster, Victoria J., additional, Nunes, Nuno M., additional, Galati, Melissa A., additional, Komosa, Martin, additional, Deshmukh, Shriya, additional, Cabric, Vanja, additional, Davidson, Scott, additional, Zatzman, Matthew, additional, Light, Nicholas, additional, Hayes, Reid, additional, Brunga, Ledia, additional, Anderson, Nathaniel D., additional, Ho, Ben, additional, Hodel, Karl P., additional, Siddaway, Robert, additional, Morrissy, A. Sorana, additional, Bowers, Daniel C., additional, Larouche, Valérie, additional, Bronsema, Annika, additional, Osborn, Michael, additional, Cole, Kristina A., additional, Opocher, Enrico, additional, Mason, Gary, additional, Thomas, Gregory A., additional, George, Ben, additional, Ziegler, David S., additional, Lindhorst, Scott, additional, Vanan, Magimairajan, additional, Yalon-Oren, Michal, additional, Reddy, Alyssa T., additional, Massimino, Maura, additional, Tomboc, Patrick, additional, Van Damme, An, additional, Lossos, Alexander, additional, Durno, Carol, additional, Aronson, Melyssa, additional, Morgenstern, Daniel A., additional, Bouffet, Eric, additional, Huang, Annie, additional, Taylor, Michael D., additional, Villani, Anita, additional, Malkin, David, additional, Hawkins, Cynthia E., additional, Pursell, Zachary F., additional, Shlien, Adam, additional, Kunkel, Thomas A., additional, Getz, Gad, additional, and Tabori, Uri, additional

Published
2020
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12. Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade

Author

Galati, Melissa A., primary, Hodel, Karl P., additional, Gams, Miki S., additional, Sudhaman, Sumedha, additional, Bridge, Taylor, additional, Zahurancik, Walter J., additional, Ungerleider, Nathan A., additional, Park, Vivian S., additional, Ercan, Ayse B., additional, Joksimovic, Lazar, additional, Siddiqui, Iram, additional, Siddaway, Robert, additional, Edwards, Melissa, additional, de Borja, Richard, additional, Elshaer, Dana, additional, Chung, Jiil, additional, Forster, Victoria J., additional, Nunes, Nuno M., additional, Aronson, Melyssa, additional, Wang, Xia, additional, Ramdas, Jagadeesh, additional, Seeley, Andrea, additional, Sarosiek, Tomasz, additional, Dunn, Gavin P., additional, Byrd, Jonathan N., additional, Mordechai, Oz, additional, Durno, Carol, additional, Martin, Alberto, additional, Shlien, Adam, additional, Bouffet, Eric, additional, Suo, Zucai, additional, Jackson, James G., additional, Hawkins, Cynthia E., additional, Guidos, Cynthia J., additional, Pursell, Zachary F., additional, and Tabori, Uri, additional

Published
2020
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13. POLE Mutation Spectra Are Shaped by the Mutant Allele Identity, Its Abundance, and Mismatch Repair Status

Author

Hodel, Karl P., primary, Sun, Meijuan J.S., additional, Ungerleider, Nathan, additional, Park, Vivian S., additional, Williams, Leonard G., additional, Bauer, David L., additional, Immethun, Victoria E., additional, Wang, Jieqiong, additional, Suo, Zucai, additional, Lu, Hua, additional, McLachlan, James B., additional, and Pursell, Zachary F., additional

Published
2020
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14. Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

Author

Hodel, Karl P, primary, de Borja, Richard, additional, Henninger, Erin E, additional, Campbell, Brittany B, additional, Ungerleider, Nathan, additional, Light, Nicholas, additional, Wu, Tong, additional, LeCompte, Kimberly G, additional, Goksenin, A Yasemin, additional, Bunnell, Bruce A, additional, Tabori, Uri, additional, Shlien, Adam, additional, and Pursell, Zachary F, additional

Published
2018
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15. Author response: Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

Author

Hodel, Karl P, primary, de Borja, Richard, additional, Henninger, Erin E, additional, Campbell, Brittany B, additional, Ungerleider, Nathan, additional, Light, Nicholas, additional, Wu, Tong, additional, LeCompte, Kimberly G, additional, Goksenin, A Yasemin, additional, Bunnell, Bruce A, additional, Tabori, Uri, additional, Shlien, Adam, additional, and Pursell, Zachary F, additional

Published
2018
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17. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.

Author

Shlien, Adam, Meier, Bettina, Hong, Ye, Gartner, Anton, Remke, Marc, Thakkar, Neha P, Pearson, Christopher E, Hodel, Karl P, Henninger, Erin E, Göksenin, A Yasemin, Pursell, Zachary F, Bakry, Doua, Grant, Ronald, Nathan, Paul C, Alexander, Sarah, Charames, George S, Druker, Harriet, Lerner-Ellis, Jordan, Dvir, Rina, and Elhasid, Ronit

Subjects
SOMATIC mutation, DNA replication, POLYMERASES, GENOMES, BRAIN tumors, CANCER
Abstract

DNA replication−associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10−13). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair. [ABSTRACT FROM AUTHOR]

Published
2015
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18. DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Author

Chung J, Maruvka YE, Sudhaman S, Kelly J, Haradhvala NJ, Bianchi V, Edwards M, Forster VJ, Nunes NM, Galati MA, Komosa M, Deshmukh S, Cabric V, Davidson S, Zatzman M, Light N, Hayes R, Brunga L, Anderson ND, Ho B, Hodel KP, Siddaway R, Morrissy AS, Bowers DC, Larouche V, Bronsema A, Osborn M, Cole KA, Opocher E, Mason G, Thomas GA, George B, Ziegler DS, Lindhorst S, Vanan M, Yalon-Oren M, Reddy AT, Massimino M, Tomboc P, Van Damme A, Lossos A, Durno C, Aronson M, Morgenstern DA, Bouffet E, Huang A, Taylor MD, Villani A, Malkin D, Hawkins CE, Pursell ZF, Shlien A, Kunkel TA, Getz G, and Tabori U

Subjects
Humans, Exome Sequencing, Cell Transformation, Neoplastic, DNA Mismatch Repair, DNA-Directed DNA Polymerase, Gene Expression Regulation, Neoplastic, Microsatellite Instability, Neoplasms genetics
Abstract

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction. This article is highlighted in the In This Issue feature, p. 995 ., (©2020 American Association for Cancer Research.)

Published
2021
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