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1. Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin

Author

Ho, GY, Kyran, EL, Bedo, J, Wakefield, MJ, Ennis, DP, Mirza, HB, Vandenberg, CJ, Lieschke, E, Farrell, A, Hadla, A, Lim, R, Dall, G, Vince, JE, Chua, NK, Kondrashova, O, Upstill-Goddard, R, Bailey, U-M, Dowson, S, Roxburgh, P, Glasspool, RM, Bryson, G, Biankin, AV, Cooke, SL, Ratnayake, G, McNally, O, Traficante, N, DeFazio, A, Weroha, SJ, Bowtell, DD, McNeish, IA, Papenfuss, AT, Scott, CL, Barker, HE, Ho, GY, Kyran, EL, Bedo, J, Wakefield, MJ, Ennis, DP, Mirza, HB, Vandenberg, CJ, Lieschke, E, Farrell, A, Hadla, A, Lim, R, Dall, G, Vince, JE, Chua, NK, Kondrashova, O, Upstill-Goddard, R, Bailey, U-M, Dowson, S, Roxburgh, P, Glasspool, RM, Bryson, G, Biankin, AV, Cooke, SL, Ratnayake, G, McNally, O, Traficante, N, DeFazio, A, Weroha, SJ, Bowtell, DD, McNeish, IA, Papenfuss, AT, Scott, CL, and Barker, HE

Abstract

UNLABELLED: Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. SIGNIFICANCE: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indica

Published
2022

2. Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Author

Dreyer, SB, Upstill-Goddard, R, Paulus-Hock, V, Paris, C, Lampraki, EM, Dray, E, Serrels, B, Caligiuri, G, Rebus, S, Plenker, D, Galluzzo, Z, Brunton, H, Cunningham, R, Tesson, M, Nourse, C, Bailey, UM, Jones, MD, Moran-Jones, K, Wright, DW, Duthie, F, Oien, K, Evers, L, McKay, CJ, McGregor, GA, Gulati, A, Brough, R, Bajrami, I, Pettitt, S, Dziubinski, ML, Candido, J, Balkwill, F, Barry, ST, Grützmann, R, Rahib, L, Allison, S, Bailey, PJ, Biankin, AV, Beraldi, D, Cameron, E, Chang, DK, Cooke, SL, Grimwood, P, Kelly, S, Marshall, J, Martin, S, McDade, B, McElroy, D, Musgrove, EA, Ramsay, D, Wright, D, Hair, J, Jamieson, NB, Westwood, P, Williams, N, Johns, AL, Mawson, A, Scarlett, CJ, Brancato, MAL, Rowe, SJ, Simpson, SH, Martyn-Smith, M, Thomas, MT, Chantrill, LA, Chin, VT, Chou, A, Cowley, MJ, Humphris, JL, Mead, RS, Nagrial, AM, Pajic, M, Pettit, J, Pinese, M, Rooman, I, Wu, J, Tao, J, DiPietro, R, Watson, C, Steinmann, A, Lee, HC, Wong, R, Pinho, AV, Giry-Laterriere, M, Daly, RJ, Sutherland, RL, Grimmond, SM, Waddell, N, Kassahn, KS, Miller, DK, Wilson, PJ, Patch, AM, Song, S, Harliwong, I, Idrisoglu, S, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Anderson, M, Holmes, O, Leonard, C, Dreyer, SB, Upstill-Goddard, R, Paulus-Hock, V, Paris, C, Lampraki, EM, Dray, E, Serrels, B, Caligiuri, G, Rebus, S, Plenker, D, Galluzzo, Z, Brunton, H, Cunningham, R, Tesson, M, Nourse, C, Bailey, UM, Jones, MD, Moran-Jones, K, Wright, DW, Duthie, F, Oien, K, Evers, L, McKay, CJ, McGregor, GA, Gulati, A, Brough, R, Bajrami, I, Pettitt, S, Dziubinski, ML, Candido, J, Balkwill, F, Barry, ST, Grützmann, R, Rahib, L, Allison, S, Bailey, PJ, Biankin, AV, Beraldi, D, Cameron, E, Chang, DK, Cooke, SL, Grimwood, P, Kelly, S, Marshall, J, Martin, S, McDade, B, McElroy, D, Musgrove, EA, Ramsay, D, Wright, D, Hair, J, Jamieson, NB, Westwood, P, Williams, N, Johns, AL, Mawson, A, Scarlett, CJ, Brancato, MAL, Rowe, SJ, Simpson, SH, Martyn-Smith, M, Thomas, MT, Chantrill, LA, Chin, VT, Chou, A, Cowley, MJ, Humphris, JL, Mead, RS, Nagrial, AM, Pajic, M, Pettit, J, Pinese, M, Rooman, I, Wu, J, Tao, J, DiPietro, R, Watson, C, Steinmann, A, Lee, HC, Wong, R, Pinho, AV, Giry-Laterriere, M, Daly, RJ, Sutherland, RL, Grimmond, SM, Waddell, N, Kassahn, KS, Miller, DK, Wilson, PJ, Patch, AM, Song, S, Harliwong, I, Idrisoglu, S, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Anderson, M, Holmes, O, and Leonard, C

Abstract

Background & Aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient–derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P <.001) and PARP inhibitor therapy (P <.001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P <.018) and WEE1 inhibitor (P <.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P <.001) but was not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.

Published
2021

3. Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Author

Dreyer, SB, Upstill-Goddard, R, Paulus-Hock, V, Paris, C, Lampraki, E-M, Dray, E, Serrels, B, Caligiuri, G, Rebus, S, Plenker, D, Galluzzo, Z, Brunton, H, Cunningham, R, Tesson, M, Nourse, C, Bailey, U-M, Jones, M, Moran-Jones, K, Wright, DW, Duthie, F, Oien, K, Evers, L, McKay, CJ, McGregor, GA, Gulati, A, Brough, R, Bajrami, I, Pettitt, S, Dziubinski, ML, Candido, J, Balkwill, F, Barry, ST, Grutzmann, R, Rahib, L, Johns, A, Pajic, M, Froeling, FEM, Beer, P, Musgrove, EA, Petersen, GM, Ashworth, A, Frame, MC, Crawford, HC, Simeone, DM, Lord, C, Mukhopadhyay, D, Pilarsky, C, Tuveson, DA, Cooke, SL, Jamieson, NB, Morton, JP, Sansom, OJ, Bailey, PJ, Biankin, A, Chang, DK, Dreyer, SB, Upstill-Goddard, R, Paulus-Hock, V, Paris, C, Lampraki, E-M, Dray, E, Serrels, B, Caligiuri, G, Rebus, S, Plenker, D, Galluzzo, Z, Brunton, H, Cunningham, R, Tesson, M, Nourse, C, Bailey, U-M, Jones, M, Moran-Jones, K, Wright, DW, Duthie, F, Oien, K, Evers, L, McKay, CJ, McGregor, GA, Gulati, A, Brough, R, Bajrami, I, Pettitt, S, Dziubinski, ML, Candido, J, Balkwill, F, Barry, ST, Grutzmann, R, Rahib, L, Johns, A, Pajic, M, Froeling, FEM, Beer, P, Musgrove, EA, Petersen, GM, Ashworth, A, Frame, MC, Crawford, HC, Simeone, DM, Lord, C, Mukhopadhyay, D, Pilarsky, C, Tuveson, DA, Cooke, SL, Jamieson, NB, Morton, JP, Sansom, OJ, Bailey, PJ, Biankin, A, and Chang, DK

Abstract

BACKGROUND & AIMS: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. METHODS: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. RESULTS: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.

Published
2021

4. Sex differences in oncogenic mutational processes

Author

Li, CH, Prokopec, SD, Sun, RX, Yousif, F, Schmitz, N, Al-Shahrour, F, Atwal, G, Bailey, PJ, Biankin, AV, Boutros, PC, Campbell, PJ, Chang, DK, Cooke, SL, Deshpande, V, Faltas, BM, Faquin, WC, Garraway, L, Getz, G, Grimmond, SM, Haider, S, Hoadley, KA, Jiao, W, Kaiser, VB, Karlić, R, Kato, M, Kübler, K, Lazar, AJ, Louis, DN, Margolin, A, Martin, S, Nahal-Bose, HK, Nielsen, GP, Nik-Zainal, S, Omberg, L, P’ng, C, Perry, MD, Polak, P, Rheinbay, E, Rubin, MA, Semple, CA, Sgroi, DC, Shibata, T, Siebert, R, Smith, J, Stein, LD, Stobbe, MD, Thai, K, Wright, DW, Wu, CL, Yuan, K, Zhang, J, Aaltonen, LA, Abascal, F, Abeshouse, A, Aburatani, H, Adams, DJ, Agrawal, N, Ahn, KS, Ahn, SM, Aikata, H, Akbani, R, Akdemir, KC, Al-Ahmadie, H, Al-Sedairy, ST, Alawi, M, Albert, M, Aldape, K, Alexandrov, LB, Ally, A, Alsop, K, Alvarez, EG, Amary, F, Amin, SB, Aminou, B, Ammerpohl, O, Anderson, MJ, Ang, Y, Antonello, D, Anur, P, Aparicio, S, Appelbaum, EL, Arai, Y, Aretz, A, Arihiro, K, Ariizumi, SI, Armenia, J, Arnould, L, Asa, S, Assenov, Y, Aukema, S, Auman, JT, Aure, MR, Awadalla, P, Aymerich, M, Bader, GD, Baez-Ortega, A, Li, CH, Prokopec, SD, Sun, RX, Yousif, F, Schmitz, N, Al-Shahrour, F, Atwal, G, Bailey, PJ, Biankin, AV, Boutros, PC, Campbell, PJ, Chang, DK, Cooke, SL, Deshpande, V, Faltas, BM, Faquin, WC, Garraway, L, Getz, G, Grimmond, SM, Haider, S, Hoadley, KA, Jiao, W, Kaiser, VB, Karlić, R, Kato, M, Kübler, K, Lazar, AJ, Louis, DN, Margolin, A, Martin, S, Nahal-Bose, HK, Nielsen, GP, Nik-Zainal, S, Omberg, L, P’ng, C, Perry, MD, Polak, P, Rheinbay, E, Rubin, MA, Semple, CA, Sgroi, DC, Shibata, T, Siebert, R, Smith, J, Stein, LD, Stobbe, MD, Thai, K, Wright, DW, Wu, CL, Yuan, K, Zhang, J, Aaltonen, LA, Abascal, F, Abeshouse, A, Aburatani, H, Adams, DJ, Agrawal, N, Ahn, KS, Ahn, SM, Aikata, H, Akbani, R, Akdemir, KC, Al-Ahmadie, H, Al-Sedairy, ST, Alawi, M, Albert, M, Aldape, K, Alexandrov, LB, Ally, A, Alsop, K, Alvarez, EG, Amary, F, Amin, SB, Aminou, B, Ammerpohl, O, Anderson, MJ, Ang, Y, Antonello, D, Anur, P, Aparicio, S, Appelbaum, EL, Arai, Y, Aretz, A, Arihiro, K, Ariizumi, SI, Armenia, J, Arnould, L, Asa, S, Assenov, Y, Aukema, S, Auman, JT, Aure, MR, Awadalla, P, Aymerich, M, Bader, GD, and Baez-Ortega, A

Abstract

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.

Published
2020

5. Processed pseudogenes acquired somatically during cancer development

Author

Cooke, SL, Shlien, A, Marshall, J, Pipinikas, CP, Martincorena, I, Tubio, JMC, Li, Y, Menzies, A, Mudie, L, Ramakrishna, M, Yates, L, Davies, H, Bolli, N, Bignell, GR, Tarpey, PS, Behjati, S, Nik-Zainal, S, Papaemmanuil, E, Teixeira, VH, Raine, K, O'Meara, S, Dodoran, MS, Teague, JW, Butler, AP, Iacobuzio-Donahue, C, Santarius, T, Grundy, RG, Malkin, D, Greaves, M, Munshi, N, Flanagan, AM, Bowtell, D, Martin, S, Larsimont, D, Reis-Filho, JS, Boussioutas, A, Taylor, JA, Hayes, DN, Janes, SM, Futreal, PA, Stratton, MR, McDermott, U, Campbell, PJ, Cooke, SL, Shlien, A, Marshall, J, Pipinikas, CP, Martincorena, I, Tubio, JMC, Li, Y, Menzies, A, Mudie, L, Ramakrishna, M, Yates, L, Davies, H, Bolli, N, Bignell, GR, Tarpey, PS, Behjati, S, Nik-Zainal, S, Papaemmanuil, E, Teixeira, VH, Raine, K, O'Meara, S, Dodoran, MS, Teague, JW, Butler, AP, Iacobuzio-Donahue, C, Santarius, T, Grundy, RG, Malkin, D, Greaves, M, Munshi, N, Flanagan, AM, Bowtell, D, Martin, S, Larsimont, D, Reis-Filho, JS, Boussioutas, A, Taylor, JA, Hayes, DN, Janes, SM, Futreal, PA, Stratton, MR, McDermott, U, and Campbell, PJ

Abstract

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.

Published
2014

6. Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes

Author

McBride, DJ, Etemadmoghadam, D, Cooke, SL, Alsop, K, George, J, Butler, A, Cho, J, Galappaththige, D, Greenman, C, Howarth, KD, Lau, KW, Ng, CK, Raine, K, Teague, J, Wedge, DC, Caubit, X, Stratton, MR, Brenton, JD, Campbell, PJ, Futreal, PA, Bowtell, DDL, McBride, DJ, Etemadmoghadam, D, Cooke, SL, Alsop, K, George, J, Butler, A, Cho, J, Galappaththige, D, Greenman, C, Howarth, KD, Lau, KW, Ng, CK, Raine, K, Teague, J, Wedge, DC, Caubit, X, Stratton, MR, Brenton, JD, Campbell, PJ, Futreal, PA, and Bowtell, DDL

Abstract

The application of paired-end next generation sequencing approaches has made it possible to systematically characterize rearrangements of the cancer genome to base-pair level. Utilizing this approach, we report the first detailed analysis of ovarian cancer rearrangements, comparing high-grade serous and clear cell cancers, and these histotypes with other solid cancers. Somatic rearrangements were systematically characterized in eight high-grade serous and five clear cell ovarian cancer genomes and we report here the identification of > 600 somatic rearrangements. Recurrent rearrangements of the transcriptional regulator gene, TSHZ3, were found in three of eight serous cases. Comparison to breast, pancreatic and prostate cancer genomes revealed that a subset of ovarian cancers share a marked tandem duplication phenotype with triple-negative breast cancers. The tandem duplication phenotype was not linked to BRCA1/2 mutation, suggesting that other common mechanisms or carcinogenic exposures are operative. High-grade serous cancers arising in women with germline BRCA1 or BRCA2 mutation showed a high frequency of small chromosomal deletions. These findings indicate that BRCA1/2 germline mutation may contribute to widespread structural change and that other undefined mechanism(s), which are potentially shared with triple-negative breast cancer, promote tandem chromosomal duplications that sculpt the ovarian cancer genome.

Published
2012

7. Mutational Processes Molding the Genomes of 21 Breast Cancers

Author

Nik-Zainal, S, Alexandrov, LB, Wedge, DC, van Loo, PF, Greenman, CD, Raine, K, Jones, D, Hinton, J, Marshall, J, Stebbings, LA, Menzies, A, Martin, S, Leung, Esther, Chen, Lina, Leroy, C, Ramakrishna, M, Rance, R, Lau, KW, Mudie, LJ, Varela, I, McBride, DJ, Bignell, GR, Cooke, SL, Shlien, A, Gamble, J, Whitmore, I, Maddison, M, Tarpey, PS, Davies, HR, Papaemmanuil, E, Stephens, PJ, McLaren, S, Butler, AP, Teague, JW, Jonsson, G, Garber, JE, Silver, D, Miron, P, Fatima, A, Boyault, S, Langerod, A, Tutt, A, Martens, John, Aparicio, SAJR, Borg, A, Salomon, AV, Thomas, Giju, Borresen-Dale, AL, Richardson, AL, Neuberger, MS, Futreal, PA, Campbell, PJ, Stratton, MR, Nik-Zainal, S, Alexandrov, LB, Wedge, DC, van Loo, PF, Greenman, CD, Raine, K, Jones, D, Hinton, J, Marshall, J, Stebbings, LA, Menzies, A, Martin, S, Leung, Esther, Chen, Lina, Leroy, C, Ramakrishna, M, Rance, R, Lau, KW, Mudie, LJ, Varela, I, McBride, DJ, Bignell, GR, Cooke, SL, Shlien, A, Gamble, J, Whitmore, I, Maddison, M, Tarpey, PS, Davies, HR, Papaemmanuil, E, Stephens, PJ, McLaren, S, Butler, AP, Teague, JW, Jonsson, G, Garber, JE, Silver, D, Miron, P, Fatima, A, Boyault, S, Langerod, A, Tutt, A, Martens, John, Aparicio, SAJR, Borg, A, Salomon, AV, Thomas, Giju, Borresen-Dale, AL, Richardson, AL, Neuberger, MS, Futreal, PA, Campbell, PJ, and Stratton, MR

Abstract

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis,'' was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.

Published
2012

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