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1. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Author

Cortes-Ciriano, I, Lee, JJ-K, Xi, R, Jain, D, Jung, YL, Yang, L, Gordenin, D, Klimczak, LJ, Zhang, C-Z, Pellman, DS, Park, PJ, Akdemir, KC, Alvarez, EG, Baez-Ortega, A, Beroukhim, R, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Campbell, PJ, Chan, K, Chen, K, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Frenkel-Morgenstern, M, Garsed, DW, Gerstein, M, Gordenin, DA, Haan, D, Haber, JE, Hess, JM, Hutter, B, Imielinski, M, Jones, DTW, Ju, YS, Kazanov, MD, Koh, Y, Korbel, JO, Kumar, K, Lee, EA, Li, Y, Lynch, AG, Macintyre, G, Markowetz, F, Martincorena, I, Martinez-Fundichely, A, Miyano, S, Nakagawa, H, Navarro, FCP, Ossowski, S, Pearson, J, Puiggros, M, Rippe, K, Roberts, ND, Roberts, SA, Rodriguez-Martin, B, Schumacher, SE, Scully, R, Shackleton, M, Sidiropoulos, N, Sieverling, L, Stewart, C, Torrents, D, Tubio, JMC, Villasante, I, Waddell, N, Wala, JA, Weischenfeldt, J, Yao, X, Yoon, S-S, Zamora, J, Cortes-Ciriano, I, Lee, JJ-K, Xi, R, Jain, D, Jung, YL, Yang, L, Gordenin, D, Klimczak, LJ, Zhang, C-Z, Pellman, DS, Park, PJ, Akdemir, KC, Alvarez, EG, Baez-Ortega, A, Beroukhim, R, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Campbell, PJ, Chan, K, Chen, K, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Frenkel-Morgenstern, M, Garsed, DW, Gerstein, M, Gordenin, DA, Haan, D, Haber, JE, Hess, JM, Hutter, B, Imielinski, M, Jones, DTW, Ju, YS, Kazanov, MD, Koh, Y, Korbel, JO, Kumar, K, Lee, EA, Li, Y, Lynch, AG, Macintyre, G, Markowetz, F, Martincorena, I, Martinez-Fundichely, A, Miyano, S, Nakagawa, H, Navarro, FCP, Ossowski, S, Pearson, J, Puiggros, M, Rippe, K, Roberts, ND, Roberts, SA, Rodriguez-Martin, B, Schumacher, SE, Scully, R, Shackleton, M, Sidiropoulos, N, Sieverling, L, Stewart, C, Torrents, D, Tubio, JMC, Villasante, I, Waddell, N, Wala, JA, Weischenfeldt, J, Yao, X, Yoon, S-S, and Zamora, J

Abstract

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.

Published
2020

2. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

Author

Rheinbay, E, Nielsen, MM, Abascal, F, Wala, JA, Shapira, O, Tiao, G, Hornshoj, H, Hess, JM, Juul, RI, Lin, Z, Feuerbach, L, Sabarinathan, R, Madsen, T, Kim, J, Mularoni, L, Shuai, S, Lanzos, A, Herrmann, C, Maruvka, YE, Shen, C, Amin, SB, Bandopadhayay, P, Bertl, J, Boroevich, KA, Busanovich, J, Carlevaro-Fita, J, Chakravarty, D, Chan, CWY, Craft, D, Dhingra, P, Diamanti, K, Fonseca, NA, Gonzalez-Perez, A, Guo, Q, Hamilton, MP, Haradhvala, NJ, Hong, C, Isaev, K, Johnson, TA, Juul, M, Kahles, A, Kahraman, A, Kim, Y, Komorowski, J, Kumar, K, Kumar, S, Lee, D, Lehmann, K-V, Li, Y, Liu, EM, Lochovsky, L, Park, K, Pich, O, Roberts, ND, Saksena, G, Schumacher, SE, Sidiropoulos, N, Sieverling, L, Sinnott-Armstrong, N, Stewart, C, Tamborero, D, Tubio, JMC, Umer, HM, Uuskula-Reimand, L, Wadelius, C, Wadi, L, Yao, X, Zhang, C-Z, Zhang, J, Haber, JE, Hobolth, A, Imielinski, M, Kellis, M, Lawrence, MS, von Mering, C, Nakagawa, H, Raphael, BJ, Rubin, MA, Sander, C, Stein, LD, Stuart, JM, Tsunoda, T, Wheeler, DA, Johnson, R, Reimand, J, Gerstein, M, Khurana, E, Campbell, PJ, Lopez-Bigas, N, Weischenfeldt, J, Beroukhim, R, Martincorena, I, Pedersen, JS, Getz, G, Bader, GD, Barenboim, J, Brunak, S, Chen, K, Choi, JK, Deu-Pons, J, Fink, JL, Frigola, J, Gambacorti-Passerini, C, Garsed, DW, Gut, IG, Haan, D, Harmanci, AO, Helmy, M, Hodzic, E, Izarzugaza, JMG, Kim, JK, Korbel, JO, Larsson, E, Li, S, Li, X, Lou, S, Marchal, K, Martinez-Fundichely, A, McGillivray, PD, Meyerson, W, Muinos, F, Paczkowska, M, Pons, T, Pulido-Tamayo, S, Reyes-Salazar, I, Reyna, MA, Rubio-Perez, C, Sahinalp, SC, Salichos, L, Shackleton, M, Shrestha, R, Valencia, A, Vazquez, M, Verbeke, LPC, Wang, J, Warrell, J, Waszak, SM, Wu, G, Yu, J, Zhang, X, Zhang, Y, Zhao, Z, Zou, L, Akdemir, KC, Alvarez, EG, Baez-Ortega, A, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Chan, K, CortesCiriano, I, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Frenkel-Morgenstern, M, Gordenin, DA, Hutter, B, Jones, DTW, Ju, YS, Kazanov, MD, Klimczak, LJ, Koh, Y, Lee, EA, Lee, JJ-K, Lynch, AG, Macintyre, G, Markowetz, F, Meyerson, M, Miyano, S, Navarro, FCP, Ossowski, S, Park, PJ, Pearson, J, Puiggros, M, Rippe, K, Roberts, SA, RodriguezMartin, B, Scully, R, Torrents, D, Villasante, I, Waddell, N, Yang, L, Yoon, S-S, Zamora, J, Rheinbay, E, Nielsen, MM, Abascal, F, Wala, JA, Shapira, O, Tiao, G, Hornshoj, H, Hess, JM, Juul, RI, Lin, Z, Feuerbach, L, Sabarinathan, R, Madsen, T, Kim, J, Mularoni, L, Shuai, S, Lanzos, A, Herrmann, C, Maruvka, YE, Shen, C, Amin, SB, Bandopadhayay, P, Bertl, J, Boroevich, KA, Busanovich, J, Carlevaro-Fita, J, Chakravarty, D, Chan, CWY, Craft, D, Dhingra, P, Diamanti, K, Fonseca, NA, Gonzalez-Perez, A, Guo, Q, Hamilton, MP, Haradhvala, NJ, Hong, C, Isaev, K, Johnson, TA, Juul, M, Kahles, A, Kahraman, A, Kim, Y, Komorowski, J, Kumar, K, Kumar, S, Lee, D, Lehmann, K-V, Li, Y, Liu, EM, Lochovsky, L, Park, K, Pich, O, Roberts, ND, Saksena, G, Schumacher, SE, Sidiropoulos, N, Sieverling, L, Sinnott-Armstrong, N, Stewart, C, Tamborero, D, Tubio, JMC, Umer, HM, Uuskula-Reimand, L, Wadelius, C, Wadi, L, Yao, X, Zhang, C-Z, Zhang, J, Haber, JE, Hobolth, A, Imielinski, M, Kellis, M, Lawrence, MS, von Mering, C, Nakagawa, H, Raphael, BJ, Rubin, MA, Sander, C, Stein, LD, Stuart, JM, Tsunoda, T, Wheeler, DA, Johnson, R, Reimand, J, Gerstein, M, Khurana, E, Campbell, PJ, Lopez-Bigas, N, Weischenfeldt, J, Beroukhim, R, Martincorena, I, Pedersen, JS, Getz, G, Bader, GD, Barenboim, J, Brunak, S, Chen, K, Choi, JK, Deu-Pons, J, Fink, JL, Frigola, J, Gambacorti-Passerini, C, Garsed, DW, Gut, IG, Haan, D, Harmanci, AO, Helmy, M, Hodzic, E, Izarzugaza, JMG, Kim, JK, Korbel, JO, Larsson, E, Li, S, Li, X, Lou, S, Marchal, K, Martinez-Fundichely, A, McGillivray, PD, Meyerson, W, Muinos, F, Paczkowska, M, Pons, T, Pulido-Tamayo, S, Reyes-Salazar, I, Reyna, MA, Rubio-Perez, C, Sahinalp, SC, Salichos, L, Shackleton, M, Shrestha, R, Valencia, A, Vazquez, M, Verbeke, LPC, Wang, J, Warrell, J, Waszak, SM, Wu, G, Yu, J, Zhang, X, Zhang, Y, Zhao, Z, Zou, L, Akdemir, KC, Alvarez, EG, Baez-Ortega, A, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Chan, K, CortesCiriano, I, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Frenkel-Morgenstern, M, Gordenin, DA, Hutter, B, Jones, DTW, Ju, YS, Kazanov, MD, Klimczak, LJ, Koh, Y, Lee, EA, Lee, JJ-K, Lynch, AG, Macintyre, G, Markowetz, F, Meyerson, M, Miyano, S, Navarro, FCP, Ossowski, S, Park, PJ, Pearson, J, Puiggros, M, Rippe, K, Roberts, SA, RodriguezMartin, B, Scully, R, Torrents, D, Villasante, I, Waddell, N, Yang, L, Yoon, S-S, and Zamora, J

Abstract

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

Published
2020

3. Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer

Author

Akdemir, KC, Le, VT, Chandran, S, Li, Y, Verhaak, RG, Beroukhim, R, Campbell, PJ, Chin, L, Dixon, JR, Futreal, PA, Alvarez, EG, Baez-Ortega, A, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Chan, K, Chen, K, Cortes-Ciriano, I, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Frenkel-Morgenstern, M, Garsed, DW, Gerstein, M, Gordenin, DA, Haan, D, Haber, JE, Hess, JM, Hutter, B, Imielinski, M, Jones, DTW, Ju, YS, Kazanov, MD, Klimczak, LJ, Koh, Y, Korbel, JO, Kumar, K, Lee, EA, Lee, JJ-K, Lynch, AG, Macintyre, G, Markowetz, F, Martincorena, I, Martinez-Fundichely, A, Meyerson, M, Miyano, S, Nakagawa, H, Navarro, FCP, Ossowski, S, Park, PJ, Pearson, JV, Puiggros, M, Rippe, K, Roberts, ND, Roberts, SA, Rodriguez-Martin, B, Schumacher, SE, Scully, R, Shackleton, M, Sidiropoulos, N, Sieverling, L, Stewart, C, Torrents, D, Tubio, JMC, Villasante, I, Waddell, N, Wala, JA, Weischenfeldt, J, Yang, L, Yao, X, Yoon, S-S, Zamora, J, Zhang, C-Z, Akdemir, KC, Le, VT, Chandran, S, Li, Y, Verhaak, RG, Beroukhim, R, Campbell, PJ, Chin, L, Dixon, JR, Futreal, PA, Alvarez, EG, Baez-Ortega, A, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Chan, K, Chen, K, Cortes-Ciriano, I, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Frenkel-Morgenstern, M, Garsed, DW, Gerstein, M, Gordenin, DA, Haan, D, Haber, JE, Hess, JM, Hutter, B, Imielinski, M, Jones, DTW, Ju, YS, Kazanov, MD, Klimczak, LJ, Koh, Y, Korbel, JO, Kumar, K, Lee, EA, Lee, JJ-K, Lynch, AG, Macintyre, G, Markowetz, F, Martincorena, I, Martinez-Fundichely, A, Meyerson, M, Miyano, S, Nakagawa, H, Navarro, FCP, Ossowski, S, Park, PJ, Pearson, JV, Puiggros, M, Rippe, K, Roberts, ND, Roberts, SA, Rodriguez-Martin, B, Schumacher, SE, Scully, R, Shackleton, M, Sidiropoulos, N, Sieverling, L, Stewart, C, Torrents, D, Tubio, JMC, Villasante, I, Waddell, N, Wala, JA, Weischenfeldt, J, Yang, L, Yao, X, Yoon, S-S, Zamora, J, and Zhang, C-Z

Abstract

Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.

Published
2020

4. Patterns of somatic structural variation in human cancer genomes

Author

Li, Y, Roberts, ND, Wala, JA, Shapira, O, Schumacher, SE, Kumar, K, Khurana, E, Waszak, S, Korbel, JO, Haber, JE, Imielinski, M, Weischenfeldt, J, Beroukhim, R, Campbell, PJ, Akdemir, KC, Alvarez, EG, Baez-Ortega, A, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Chan, K, Chen, K, Cortes-Ciriano, I, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Frenkel-Morgenstern, M, Garsed, DW, Gerstein, M, Gordenin, DA, Haan, D, Hess, JM, Hutter, B, Jones, DTW, Ju, YS, Kazanov, MD, Klimczak, LJ, Koh, Y, Lee, EA, Lee, JJ-K, Lynch, AG, Macintyre, G, Markowetz, F, Martincorena, I, Martinez-Fundichely, A, Meyerson, M, Miyano, S, Nakagawa, H, Navarro, FCP, Ossowski, S, Park, PJ, Pearson, J, Puiggros, M, Rippe, K, Roberts, SA, Rodriguez-Martin, B, Scully, R, Shackleton, M, Sidiropoulos, N, Sieverling, L, Stewart, C, Torrents, D, Tubio, JMC, Villasante, I, Waddell, N, Yang, L, Yao, X, Yoon, S-S, Zamora, J, Zhang, C-Z, Li, Y, Roberts, ND, Wala, JA, Shapira, O, Schumacher, SE, Kumar, K, Khurana, E, Waszak, S, Korbel, JO, Haber, JE, Imielinski, M, Weischenfeldt, J, Beroukhim, R, Campbell, PJ, Akdemir, KC, Alvarez, EG, Baez-Ortega, A, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Chan, K, Chen, K, Cortes-Ciriano, I, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Frenkel-Morgenstern, M, Garsed, DW, Gerstein, M, Gordenin, DA, Haan, D, Hess, JM, Hutter, B, Jones, DTW, Ju, YS, Kazanov, MD, Klimczak, LJ, Koh, Y, Lee, EA, Lee, JJ-K, Lynch, AG, Macintyre, G, Markowetz, F, Martincorena, I, Martinez-Fundichely, A, Meyerson, M, Miyano, S, Nakagawa, H, Navarro, FCP, Ossowski, S, Park, PJ, Pearson, J, Puiggros, M, Rippe, K, Roberts, SA, Rodriguez-Martin, B, Scully, R, Shackleton, M, Sidiropoulos, N, Sieverling, L, Stewart, C, Torrents, D, Tubio, JMC, Villasante, I, Waddell, N, Yang, L, Yao, X, Yoon, S-S, Zamora, J, and Zhang, C-Z

Abstract

A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes1-7. Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types8. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions-as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2-7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and-in liver cancer-frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

Published
2020

5. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

Author

Rodriguez-Martin, B, Alvarez, EG, Baez-Ortega, A, Zamora, J, Supek, F, Demeulemeester, J, Santamarina, M, Ju, YS, Temes, J, Garcia-Souto, D, Detering, H, Li, Y, Rodriguez-Castro, J, Dueso-Barroso, A, Bruzos, AL, Dentro, SC, Blanco, MG, Contino, G, Ardeljan, D, Tojo, M, Roberts, ND, Zumalave, S, Edwards, PAW, Weischenfeldt, J, Puiggros, M, Chong, Z, Chen, K, Lee, EA, Wala, JA, Raine, K, Butler, A, Waszak, SM, Navarro, FCP, Schumacher, SE, Monlong, J, Maura, F, Bolli, N, Bourque, G, Gerstein, M, Park, PJ, Wedge, DC, Beroukhim, R, Torrents, D, Korbel, JO, Martincorena, I, Fitzgerald, RC, Van Loo, P, Kazazian, HH, Burns, KH, Campbell, PJ, Tubio, JMC, Akdemir, KC, Boutros, PC, Bowtell, DDL, Brors, B, Chan, K, Cortes-Ciriano, I, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Frenkel-Morgenstern, M, Garsed, DW, Gordenin, DA, Haan, D, Haber, JE, Hess, JM, Hutter, B, Imielinski, M, Jones, DTW, Kazanov, MD, Klimczak, LJ, Koh, Y, Kumar, K, Lee, JJ-K, Lynch, AG, Macintyre, G, Markowetz, F, Martinez-Fundichely, A, Meyerson, M, Miyano, S, Nakagawa, H, Ossowski, S, Pearson, J, Rippe, K, Roberts, SA, Scully, R, Shackleton, M, Sidiropoulos, N, Sieverling, L, Stewart, C, Villasante, I, Waddell, N, Yang, L, Yao, X, Yoon, S-S, Zhang, C-Z, Rodriguez-Martin, B, Alvarez, EG, Baez-Ortega, A, Zamora, J, Supek, F, Demeulemeester, J, Santamarina, M, Ju, YS, Temes, J, Garcia-Souto, D, Detering, H, Li, Y, Rodriguez-Castro, J, Dueso-Barroso, A, Bruzos, AL, Dentro, SC, Blanco, MG, Contino, G, Ardeljan, D, Tojo, M, Roberts, ND, Zumalave, S, Edwards, PAW, Weischenfeldt, J, Puiggros, M, Chong, Z, Chen, K, Lee, EA, Wala, JA, Raine, K, Butler, A, Waszak, SM, Navarro, FCP, Schumacher, SE, Monlong, J, Maura, F, Bolli, N, Bourque, G, Gerstein, M, Park, PJ, Wedge, DC, Beroukhim, R, Torrents, D, Korbel, JO, Martincorena, I, Fitzgerald, RC, Van Loo, P, Kazazian, HH, Burns, KH, Campbell, PJ, Tubio, JMC, Akdemir, KC, Boutros, PC, Bowtell, DDL, Brors, B, Chan, K, Cortes-Ciriano, I, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Frenkel-Morgenstern, M, Garsed, DW, Gordenin, DA, Haan, D, Haber, JE, Hess, JM, Hutter, B, Imielinski, M, Jones, DTW, Kazanov, MD, Klimczak, LJ, Koh, Y, Kumar, K, Lee, JJ-K, Lynch, AG, Macintyre, G, Markowetz, F, Martinez-Fundichely, A, Meyerson, M, Miyano, S, Nakagawa, H, Ossowski, S, Pearson, J, Rippe, K, Roberts, SA, Scully, R, Shackleton, M, Sidiropoulos, N, Sieverling, L, Stewart, C, Villasante, I, Waddell, N, Yang, L, Yao, X, Yoon, S-S, and Zhang, C-Z

Abstract

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.

Published
2020

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