Intraductal papillary mucinous neoplasms arise from multiple independent clones, each with distinct mutations
Open accessAbstract
Background & aims Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis.Methods We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations.Results We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis.Conclusions In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.
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Cites
R: A Language and Environment for Statistical Computing
R Core Team (2000) · doi:10.32614/r.manuals · Cited by 355,706 · see citing works
Trimmomatic: a flexible trimmer for Illumina sequence data
Bolger, A. M., Lohse, M., & Usadel, B. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu170 · Cited by 65,548 · see citing works
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895 · see citing works
Siegel, R. L., Miller, K. D., & Jemal, A. (2018) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21442 · Cited by 16,632 · see citing works
Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1754 · Cited by 15,390 · see citing works
Fast and accurate long-read alignment with Burrows-Wheeler transform.
Li, H., & Durbin, R. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp698 · Cited by 12,063 · see citing works
Van der Auwera, G. A., Carneiro, M. O., Hartl, C., Poplin, R., del Angel, G., Levy‐Moonshine, A., Jordan, T., Shakir, K., Roazen, D., Thibault, J., et al. (2013) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi1110s43 · Cited by 6,687 · see citing works
Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples
Cibulskis, K., Lawrence, M. S., Carter, S. L., Sivachenko, A., Jaffe, D. B., Sougnez, C. L., Gabriel, S., Meyerson, M. M., Lander, E. S., & Getz, G. A. (2013) · Nature Biotechnology · doi:10.1038/nbt.2514 · Cited by 4,838 · see citing works
Zehir, A., Benayed, R., Shah, R. H., Syed, A., Middha, S., Kim, H. R., Srinivasan, P., Gao, J., Chakravarty, D., Devlin, S. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4333 · Cited by 3,380 · see citing works
(2012) · doi:10.1016/j.jmoldx.2011.08.002 · Cited by 2,567 · see citing works
International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas
Tanaka, M., Fernández-del Castillo, C., Adsay, V., Chari, S., Falconi, M., Jang, J.-Y., Kimura, W., Levy, P., Pitman, M. B., Schmidt, C. M., et al. (2012) · Pancreatology · doi:10.1016/j.pan.2012.04.004 · Cited by 2,354 · see citing works
Self-citationIntegrated genomic characterization of pancreatic ductal adenocarcinoma
Raphael, B. J., Hruban, R. H., Aguirre, A. J., Moffitt, R. A., Yeh, J. J., Stewart, C., Robertson, A. G., Cherniack, A. D., Gupta, M., Getz, G., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.07.007 · Cited by 2,019 · see citing works
Self-citationHigh burden and pervasive positive selection of somatic mutations in normal human skin
Martincorena, I., Roshan, A., Gerstung, M., Ellis, P., Van Loo, P., McLaren, S., Wedge, D. C., Fullam, A., Alexandrov, L. B., Tubio, J. M., et al. (2015) · Science · doi:10.1126/science.aaa6806 · Cited by 1,770 · see citing works
Strelka: accurate somatic small-variant calling from sequenced tumor–normal sample pairs
Saunders, C. T., Wong, W. S. W., Swamy, S., Becq, J., Murray, L. J., & Cheetham, R. K. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts271 · Cited by 1,589 · see citing works
Gerlinger, M., Horswell, S. D., Larkin, J., Rowan, A., Salm, M., Varela, I., Fisher, R. A., McGranahan, N., Matthews, N., Santos, C. R., et al. (2014) · Nature Genetics · doi:10.1038/ng.2891 · Cited by 1,211 · see citing works
Prevalence of Unsuspected Pancreatic Cysts on MDCT
Laffan, T. A., Horton, K. M., Klein, A. P., Berlanstein, B. P., Siegelman, S. S., Kawamoto, S., Johnson, P. T., Fishman, E. K., & Hruban, R. H. (2008) · American Journal of Roentgenology · doi:10.2214/ajr.07.3340 · Cited by 882 · see citing works
Self-citationBasturk, O., Hong, S.-M., Wood, L. D., Adsay, N. V., Albores-Saavedra, J., Biankin, A. V., Brosens, L. A. A., Fukushima, N., Goggins, M., Hruban, R. H., et al. (2015) · American Journal of Surgical Pathology · doi:10.1097/pas.0000000000000533 · Cited by 864 · see citing works
Self-citationSubclonal diversification of primary breast cancer revealed by multiregion sequencing
Yates, L. R., Gerstung, M., Knappskog, S., Desmedt, C., Gundem, G., Loo, P. V., Aas, T., Alexandrov, L. B., Larsimont, D., Davies, H., et al. (2015) · Nature Medicine · doi:10.1038/nm.3886 · Cited by 812 · see citing works
Chang, M. T., Asthana, S., Gao, S. P., Lee, B. H., Chapman, J. S., Kandoth, C., Gao, J., Socci, N. D., Solit, D. B., Olshen, A. B., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3391 · Cited by 808 · see citing works
Recurrent GNAS Mutations Define an Unexpected Pathway for Pancreatic Cyst Development
Wu, J., Matthaei, H., Maitra, A., Molin, M. D., Wood, L., Eshleman, J., Goggins, M., Canto, M., Schulick, R., Edil, B., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002543 · Cited by 786 · see citing works
Self-citationResistance to anti-EGFR therapy in colorectal cancer: From heterogeneity to convergent evolution
Misale, S., Di Nicolantonio, F., Sartore-Bianchi, A., Siena, S., & Bardelli, A. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0462 · Cited by 513 · see citing works
Springer, S., Wang, Y., Dal Molin, M., Masica, D. L., Jiao, Y., Kinde, I., Blackford, A., Raman, S. P., Wolfgang, C. L., Tomita, T., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.07.041 · Cited by 477 · see citing works
Self-citationFurukawa, T., Kuboki, Y., Tanji, E., Yoshida, S., Hatori, T., Yamamoto, M., Shibata, N., Shimizu, K., Kamatani, N., & Shiratori, K. (2011) · Scientific Reports · doi:10.1038/srep00161 · Cited by 442 · see citing works
Tomasetti, C., Vogelstein, B., & Parmigiani, G. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221068110 · Cited by 414 · see citing works
Singhi, A. D., McGrath, K., Brand, R. E., Khalid, A., Zeh, H. J., Chennat, J. S., Fasanella, K. E., Papachristou, G. I., Slivka, A., Bartlett, D. L., et al. (2018) · Gut · doi:10.1136/gutjnl-2016-313586 · Cited by 405 · see citing works
Makohon-Moore, A. P., Zhang, M., Reiter, J. G., Bozic, I., Allen, B., Kundu, D., Chatterjee, K., Wong, F., Jiao, Y., Kohutek, Z. A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3764 · Cited by 403 · see citing works
Paired exome analysis of Barrett's esophagus and adenocarcinoma
Stachler, M. D., Taylor-Weiner, A. N., Peng, S., McKenna, A., Agoston, A. T., Odze, R. D., Davison, J. M., Nason, K. S., Loda, M. F., Leshchiner, I., et al. (2015) · Nature Genetics · doi:10.1038/ng.3343 · Cited by 366 · see citing works
Amato, E., Molin, M. D., Mafficini, A., Yu, J. Q., Malleo, G., Rusev, B. C., Fassan, M., Antonello, D., Sadakari, Y., Castelli, P., et al. (2014) · The Journal of Pathology · doi:10.1002/path.4344 · Cited by 349 · see citing works
Self-citationRoss-Innes, C. S., Becq, J., Warren, A., Cheetham, R. K., Northen, H., O’Donovan, M., Malhotra, S., di Pietro, M., Ivakhno, S., He, M., et al. (2015) · Nature Genetics · doi:10.1038/ng.3357 · Cited by 299 · see citing works
Connor, A. A., Denroche, R. E., Jang, G. H., Lemire, M., Zhang, A. X. W., Chan‐Seng‐Yue, M., Wilson, G. W., Grant, R. C., Merico, D., Lungu, I. M., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2018.12.010 · Cited by 231 · see citing works
A multimodality test to guide the management of patients with a pancreatic cyst
Springer, S., Masica, D. L., Dal Molin, M., Douville, C., Thoburn, C. J., Afsari, B., Li, L., Cohen, J. D., Thompson, E., Allen, P. J., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aav4772 · Cited by 217 · see citing works
Self-citationTan, M. C. B., Baştürk, O., Brannon, R., Bhanot, U. K., Scott, S. N., Bouvier, N., LaFemina, J., Jarnagin, W. R., Berger, M. F., Klimstra, D. S., et al. (2015) · Journal of the American College of Surgeons · doi:10.1016/j.jamcollsurg.2014.11.029 · Cited by 202 · see citing works
Omori, Y., Ono, Y., Tanino, M. A., Karasaki, H., Yamaguchi, H., Furukawa, T., Enomoto, K., Ueda, J., Sumi, A., Katayama, J., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.10.029 · Cited by 189 · see citing works
Genevay, M., Mino-Kenudson, M., Yaeger, K., Konstantinidis, I. T., Ferrone, C., Thayer, S., Castillo, C., Sahani, D., Bounds, B. R., Forcione, D., et al. (2011) · Annals of Surgery · doi:10.1097/sla.0b013e3182383118 · Cited by 156 · see citing works
Clinical Validation of KRAS, BRAF, and EGFR Mutation Detection Using Next-Generation Sequencing
Lin, M., Mosier, S. L., Thiess, M., Beierl, K. F., Debeljak, M., Tseng, L., Chen, G., Yegnasubramanian, S., Ho, H., Cope, L., et al. (2014) · American Journal of Clinical Pathology · doi:10.1309/ajcpmwgwgo34egod · Cited by 152 · see citing works
IPMNs with co-occurring invasive cancers: neighbours but not always relatives
Felsenstein, M., Noë, M., Masica, D. L., Hosoda, W., Chianchiano, P. E., Fischer, C. G., Lionheart, G., Brosens, L. A. A., Pea, A., Yu, J., et al. (2018) · Gut · doi:10.1136/gutjnl-2017-315062 · Cited by 145 · see citing works
Self-citationHu, C.-M., Tien, S.-C., Hsieh, P.-K., Jeng, Y.-M., Chang, M.-C., Chang, Y.-T., Chen, Y.-J., Chen, Y.-J., Lee, E. Y.-H. P., & Lee, W.-H. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.02.005 · Cited by 123 · see citing works
Fischer, C. G., & Wood, L. D. (2018) · The Journal of Pathology · doi:10.1002/path.5154 · Cited by 92 · see citing works
Self-citationNiknafs, N., Guthrie, V. B., Naiman, D. Q., & Karchin, R. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004416 · Cited by 68 · see citing works
Self-citationSingle‐cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions
Kuboki, Y., Fischer, C. G., Guthrie, V. B., Huang, W., Yu, J., Chianchiano, P. E., Hosoda, W., Zhang, H., Zheng, L., Shao, X. M., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5194 · Cited by 62 · see citing works
Self-citationNew Developments in the Molecular Mechanisms of Pancreatic Tumorigenesis
Felsenstein, M., Hruban, R. H., & Wood, L. D. (2017) · Advances in Anatomic Pathology · doi:10.1097/pap.0000000000000172 · Cited by 54 · see citing works
Self-citationPittman, M. E., Rao, R. A., & Hruban, R. H. (2017) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2016-0426-ra · Cited by 49 · see citing works
Self-citationIntratumor Heterogeneity: Novel Approaches for Resolving Genomic Architecture and Clonal Evolution
Gupta, R. G., & Somer, R. A. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0070 · Cited by 48 · see citing works
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Self-citationFujikura, K., Hosoda, W., Felsenstein, M., Song, Q., Reiter, J. G., Zheng, L., Beleva Guthrie, V., Rincon, N., Dal Molin, M., Dudley, J., et al. (2021) · Gut · doi:10.1136/gutjnl-2020-321217 · Cited by 89 · see citing works
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- Authors
- Fischer, C. G., Beleva Guthrie, V., Braxton, A. M., Zheng, L., Wang, P., Song, Q., Griffin, J. F., Chianchiano, P. E., Hosoda, W., Niknafs, N., Springer, S., Dal Molin, M., Masica, D., Scharpf, R. B., Thompson, E. D., He, J., Wolfgang, C. L., Hruban, R. H., Roberts, N. J., Lennon, A. M., Jiao, Y., Karchin, R., & Wood, L. D.
- Affiliations
- Johns Hopkins University (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Karchin, Rachel
- Wood, Laura D.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 157
- Issue
- 4
- Pages
- 1123-1137.e22
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC6756950
- OpenAlex
- W2948414055
- Cited by
- 129
- References
- 44
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 17 · 2023: 19 · 2022: 21 · 2021: 20 · 2020: 18 · 2019: 2
- FWCI
- 6.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Gastroenterological Association
- American Association for Cancer Research
- Incyte
- American Cancer Society
- Gerald O. Mann Charitable Foundation
- National Cancer Institute (P50 CA62924)
- Rolfe Pancreatic Cancer Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK107781)
- Joseph C. Monastra Foundation for Pancreatic Cancer Research
- Lustgarten Foundation
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- intraductal papillary mucinous neoplasm, pancreatic cancer, polyclonal origin, clonal heterogeneity, somatic mutations, KRAS, GNAS, RNF43, TP53, convergent evolution, pancreatic carcinogenesis, dysplasia, microdissection, tumor evolution
- MeSH terms
- Pancreatic Intraductal Neoplasms, Aged, Aged, 80 and over, Cell Transformation, Neoplastic, Chromogranins, DNA Mutational Analysis, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Pancreatic Neoplasms, Phenotype, Retrospective Studies, Biomarkers, Tumor, Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Evolution, Molecular, GTP-Binding Protein alpha Subunits, Gs, Genetic Predisposition to Disease, Ubiquitin-Protein Ligases, Mutation Rate, Clonal Evolution
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