Whole genomes redefine the mutational landscape of pancreatic cancer
Open accessAbstract
Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
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Loss of PALB2 function is linked to BRCA-deficient signatures.
“supporting previous studies linking loss of PALB2 function with BRCA-deficient signatures [7, 10, 13].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [10]
Loss of BRCA1, BRCA2, or PALB2 function produces a high mutation burden and specific signatures indicating defective homologous recombination.
“Loss of function of BRCA1, BRCA2 and PALB2 yield a high mutation burden and specific signatures inferring defective HR [7, 9, 10, 13].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [10]
G12V is frequently identified in pancreatic ductal adenocarcinomas and is associated with aggressive disease biology.
“G12V is frequently identified in pancreatic ductal adenocarcinomas and is associated with aggressive disease biology [16,21].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [21]
Chromatin remodeling and SWI/SNF complex genes are among the most frequently altered classes of genes in PDAC and can occur via somatic deletions of associated chromosomal loci.
“Chromatin remodeling and SWI/SNF complex genes are one of the most frequently altered class of genes in PDAC45,48–50, and can occur via somatic deletions of the associated chromosomal loci94.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [49]
The PDAC genomic landscape is dominated by loss-of-function alterations in TP53, SMAD4, and CDKN2A.
“the genomic landscape of PDAC is also dominated by loss of function alterations of TP53, SMAD4 (also known as DPC4), and CDKN2A45,48–50.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [49]
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“These included amplifications of 1q (33%) along with deletions of 6p (41%), 6q (51%), 8p (28%), 9p (48%), 17p (64%), 17q (31%), 18p (32%), and 18q (71%) (Table S3), consistent with previous studies (Bailey et al., 2016; Iacobuzio-Donahue et al., 2004; Waddell et al., 2015).”
InfluentialSelf-citationKleeff, J., Korc, M., Apte, M., La Vecchia, C., Johnson, C. D., Biankin, A. V., Neale, R. E., Tempero, M., Tuveson, D. A., Hruban, R. H., et al. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.22 · Cited by 1,982 · see citing works
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Pancreatic cancer: Advances and challenges
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Self-citationCancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
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“In the recent whole-sequencing analysis [10], a significant proportion of tumours harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3, and PIK3CA), but at low prevalence among individual patients.”
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Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
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Therapeutic developments in pancreatic cancer: current and future perspectives
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Self-citationHRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures
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“Previously, base-substitution signature 3 was shown to distinguish germline BRCA1 / BRCA2 -null cancers from sporadic cancers in a small subset of breast cancers 29,30 and was subsequently extended to pancreatic 32,33 , ovarian 34 and stomach 35 cancers.”
BackgroundMethodOrganoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer
Tiriac, H., Belleau, P., Engle, D. D., Plenker, D., Deschênes, A., Somerville, T. D. D., Froeling, F. E. M., Burkhart, R. A., Denroche, R. E., Jang, G.-H., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0349 · Cited by 1,092 · see citing works
“To date, PDAC driver mutations have been hard to target in the clinical 109 setting, with the exception of microsatellite instability (8), BRCA2 mutations (9) and potentially targetable, 110 uncommon KRAS mutations (10).”
BackgroundSelf-citationWhole-genome landscape of pancreatic neuroendocrine tumours
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Self-citationWhole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma
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“These mutation counts are comparable to those previously observed in genomes from pancreatic cancer (9) (74 sSNVs and 5 indels per tumor), liver cancer with biliary phenotype (10) (79 sSNVs and 24 indels per tumor) and hepatocellular carcinoma (11) (70 sSNVs and 6 indels per tumor).”
Self-citationMolecular subtypes of pancreatic cancer
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Self-citationKRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer
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“Further, wholeexome deep-sequencing data of pancreatic cancer patients shows that 93% of the rare PIK3CA mutations co-occur with aKRASmutation, suggesting activated KRAS alone is not sufficient to effectively activate PI3K (Jones et al. 2008; Biankin et al. 2012; Sausen et al. 2015; Waddell et al. 2015; Witkiewicz et…”
BackgroundMethodInfluentialPancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment
Wood, L. D., Canto, M. I., Jaffee, E. M., & Simeone, D. M. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.03.056 · Cited by 875 · see citing works
Telomeres in cancer: tumour suppression and genome instability
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Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer
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Chromothripsis and Kataegis Induced by Telomere Crisis
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“Suchevents havebeenobserved in pancreatic cancer, esophageal cancer, breast cancer, and leukemias, among others (Bignell et al., 2007; Campbell et al., 2010; Waddell et al., 2015; Li et al., 2014; Nones et al., 2014).”
Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution
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Challenges and Opportunities for Pancreatic Cancer Immunotherapy
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“Consistent with previous large-scale deep-sequencing analyses (Waddell et al., 2015), PDAC organoids harbored common driver-gene alterations at the expected frequencies: KRAS (36/38); CDKN2A (31/38); TP53 (29/38); and SMAD4 (14/38; Table S2).”
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“Although tandem duplications have been observed in PDAC (8), a predominant duplicator phenotype has been described and studied more extensively in breast cancer especially within the context of HR deficiency (36–38) and platinum sensitivity (39).”
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Challenges in diagnosis of pancreatic cancer
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A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns
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Genetics and biology of pancreatic ductal adenocarcinoma
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“Correspondingly, PDACs harboring DDRmutations exhibit increased overall mutational burden and genomic instability (Waddell et al. 2015; Witkiewicz et al. 2015) and poorer prognosis (Witkiewicz et al. 2015).”
InfluentialUnderstanding and overcoming resistance to PARP inhibitors in cancer therapy
Dias, M. P., Moser, S. C., Ganesan, S., & Jonkers, J. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00532-x · Cited by 526 · see citing works
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“In conjunction, these studies showed that the gene encoding the proto-oncogenic GTPase KRAS as well as several tumor suppressor genes, including tumor suppressor protein 53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and mothers against decapentaplegic homologue 4 (SMAD4), exhibit the most frequent alterati…”
BackgroundInfluentialEnhancer Reprogramming Promotes Pancreatic Cancer Metastasis
Roe, J., Hwang, C., Somerville, T. D. D., Milazzo, J. P., Lee, E. J., Silva, B. D., Maiorino, L., Tiriac, H., Young, C. M., Miyabayashi, K., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.007 · Cited by 458 · see citing works
“Whole-genome sequencing studies have identified inactivating mutations of chromatin modifiers as frequent genetic events in PDA tumors (Waddell et al., 2015).”
Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics
Ding, L., Bailey, M. H., Porta-Pardo, E., Thorsson, V., Colaprico, A., Bertrand, D., Gibbs, D. L., Weerasinghe, A., Huang, K.-L., Tokheim, C., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.033 · Cited by 399 · see citing works
“…progress has been made in identifying driver mutations (Porta-Pardo et al., 2017), assessing their druggability (Niu et al., 2016), disease subtyping (Waddell et al., 2015), prognosis (Cancer Genome Atlas Research Network et al., 2015), and residual disease detection (Martinez-Lopez et al., 2014).”
Self-citationEvolutionary routes and KRAS dosage define pancreatic cancer phenotypes
Mueller, S., Engleitner, T., Maresch, R., Zukowska, M., Lange, S., Kaltenbacher, T., Konukiewitz, B., Öllinger, R., Zwiebel, M., Strong, A., et al. (2018) · Nature · doi:10.1038/nature25459 · Cited by 419 · see citing works
“…upregulation of genes in cluster 3 (containing MAPK signaling pathway and gene sets relevant during embryonic development or EMT) and (ii) downregulation of genes in clusters 2 and 5, which contain gene sets related to epithelial cell differentiation, embryonic development or metabolic signatures.”
Pancreatic cancer biology and genetics from an evolutionary perspective
Makohon-Moore, A. P., & Iacobuzio–Donahue, C. A. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.66 · Cited by 430 · see citing works
Self-citationSynthetic lethal therapies for cancer: what’s next after PARP inhibitors?
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Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair
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“The structural variant-based classification was used to annotate unstable, stable, locally rearranged and scattered genomes as previously described [11], but with different cut-offs for stable and unstable genomes, to account for the different genomic instability landscape in EAC compared to pancreatic cancer: genomes…”
Self-citationSurvival in Locally Advanced Pancreatic Cancer After Neoadjuvant Therapy and Surgical Resection
Gemenetzis, G., Groot, V. P., Blair, A. B., Laheru, D. A., Zheng, L., Narang, A. K., Fishman, E. K., Hruban, R. H., Yu, J., Burkhart, R. A., et al. (2018) · Annals of Surgery · doi:10.1097/sla.0000000000002753 · Cited by 403 · see citing works
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Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer
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Pancreatic Cancer: Yesterday, Today and Tomorrow
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Unravelling biology and shifting paradigms in cancer with single-cell sequencing
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Whole genome sequencing analysis for cancer genomics and precision medicine
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“WGS analysis for breast, ovarian and pancreatic cancers indicated that signatures were related with inactivation of DNA maintenance genes (BRCA1, BRCA2 and PALB2), and also related with high response to DNA-damaging agents and PARP inhibitors.(75,78) Recent studies have demonstrated that somatic substitution, insertio…”
BackgroundReal-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine
Aguirre, A. J., Nowak, J. A., Camarda, N. D., Moffitt, R. A., Ghazani, A. A., Hazar-Rethinam, M., Raghavan, S., Kim, J., Brais, L. K., Ragon, D., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0275 · Cited by 367 · see citing works
“As has been suggested in prior studies of primary PDAC resection specimens (7,9,12), we observed a striking prevalence of germline and somatic mutations in DDR genes in our cohort of advanced PDAC patients.”
BackgroundResultInfluentialEvaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations
Hu, Z. I., Shia, J., Stadler, Z. K., Varghese, A. M., Capanu, M., Salo‐Mullen, E. E., Lowery, M. A., Diaz, L. A., Mandelker, D. L., Yu, K. H., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3099 · Cited by 371 · see citing works
“NGShas alsobeenused to identify distinct mutational signatures, including a MMR-D subtype, in PDACs (4, 38).”
BackgroundSelf-citationWhole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer
Roberts, N. J., Norris, A. L., Petersen, G. M., Bondy, M. L., Brand, R., Gallinger, S., Kurtz, R. C., Olson, S. H., Rustgi, A. K., Schwartz, A. G., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0402 · Cited by 361 · see citing works
Self-citationLKB1 loss links serine metabolism to DNA methylation and tumorigenesis
Kottakis, F., Nicolay, B. N., Roumane, A., Karnik, R., Gu, H., Nagle, J. M., Boukhali, M., Hayward, M. C., Li, Y. Y., Chen, T., et al. (2016) · Nature · doi:10.1038/nature20132 · Cited by 348 · see citing works
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“In addition, ~31–38% of pancreatic cancers have mutations in SMAD4, which can occur in the late stages of pancreatic carcinogenesis.(23,25) In pancreatic cancer, the frequent loss of SMAD4 via homozygous deletion or mutation leads to decreasing SMAD4-dependent inhibition of transforming growth factor-β (TGF-β) and the…”
BackgroundPancreatic cancer evolution and heterogeneity: integrating omics and clinical data
Connor, A. A., & Gallinger, S. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-021-00418-1 · Cited by 369 · see citing works
Fibroblast growth factor receptors as treatment targets in clinical oncology
Katoh, M. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0115-y · Cited by 362 · see citing works
Stromal biology and therapy in pancreatic cancer: ready for clinical translation?
Neeße, A., Bauer, C. A., Öhlund, D., Lauth, M., Buchholz, M., Michl, P., Tuveson, D. A., & Gress, T. M. (2018) · Gut · doi:10.1136/gutjnl-2018-316451 · Cited by 348 · see citing works
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Self-citationAndricovich, J., Perkail, S., Kai, Y., Casasanta, N., Peng, W., & Tzatsos, A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.02.003 · Cited by 320 · see citing works
Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets
Newell, F., Kong, Y., Wilmott, J. S., Johansson, P. A., Ferguson, P. M., Cui, C., Li, Z., Kazakoff, S. H., Burke, H., Dodds, T. J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11107-x · Cited by 335 · see citing works
Self-citationSequencing thousands of single-cell genomes with combinatorial indexing
Vitak, S. A., Torkenczy, K. A., Rosenkrantz, J. L., Fields, A. J., Christiansen, L., Wong, M. H., Carbone, L., Steemers, F. J., & Adey, A. (2017) · Nature Methods · doi:10.1038/nmeth.4154 · Cited by 294 · see citing works
Micronucleus Assay: The State of Art, and Future Directions
Sommer, S., Buraczewska, I., & Kruszewski, M. K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041534 · Cited by 333 · see citing works
Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism
Biancur, D. E., Paulo, J. A., Małachowska, B., Quiles Del Rey, M., Sousa, C. M., Wang, X., Sohn, A. S. W., Chu, G. C., Gygi, S. P., Harper, J. W., et al. (2017) · Nature Communications · doi:10.1038/ncomms15965 · Cited by 315 · see citing works
“For combination studies with BSO, MPDAC-4 subcutaneous xenografts were generated as above in 8-week-old female NCr nude mice and were randomized to one of four treatment arms: (1) Vehicle oral gavage twice daily/Normal saline IP injection once daily, (2) CB-839 200 mg kg 1 oral gavage twice daily/normal saline IP inje…”
MethodDetecting the mutational signature of homologous recombination deficiency in clinical samples
Gulhan, D., Lee, J. J.-K., Melloni, G. E. M., Cortés‐Ciriano, I., & Park, P. J. (2019) · Nature Genetics · doi:10.1038/s41588-019-0390-2 · Cited by 316 · see citing works
CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer
Pereira, B., Vennin, C., Papanicolaou, M., Chambers, C. R., Herrmann, D., Morton, J. P., Cox, T. R., & Timpson, P. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.09.010 · Cited by 309 · see citing works
α-Ketoglutarate links p53 to cell fate during tumour suppression
Morris, J. P., Yashinskie, J. J., Koche, R., Chandwani, R., Tian, S., Chen, C.-C., Baslan, T., Marinkovic, Z. S., Sánchez-Rivera, F. J., Leach, S. D., et al. (2019) · Nature · doi:10.1038/s41586-019-1577-5 · Cited by 296 · see citing works
Therapeutic targeting of tumour myeloid cells
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“PDAC has been divided into four subtypes according to the structural rearrangements, and the unstable subtype is most sensitive to DNA-damaging agents [140].”
BackgroundCell-free DNA next-generation sequencing in pancreatobiliary carcinomas
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“As a result, most genomic research in PDA has centered around tumor-derived cell lines or xenografts in lieu of direct tumor sequencing(7), and expert bodies currently make no recommendations regarding molecular profiling for clinical decision-making in PDA(8), despite potentially sensitive subsets identified by seque…”
BackgroundPatient-centric trials for therapeutic development in precision oncology
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“This was consistent with the frequency of KRAS mutations in published studies (5, 6, 9).”
ResultVennin, C., Chin, V. T., Warren, S. C., Lucas, M. C., Herrmann, D., Magenau, A., Mélénec, P., Walters, S. N., del Monte‐Nieto, G., Conway, J. R. W., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aai8504 · Cited by 264 · see citing works
Self-citationPlasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker
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“Given the frequent down-regulation and genomic loss of LKB1/STK11 in human PDAC (Morton et al. 2010; Waddell et al. 2015), the predisposition of Peutz-Jeghers syndrome patients to develop pancreatic tumors (Su et al. 1999), and the impact of Lkb1 inactivation in other pancreatic tumor models (Hezel…”
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“This striking heterogeneity is not unexpected in light of the fact that there are numerous alterations in non-KRAS genes that are not widely shared among PDAC tumors (Waddell et al., 2015).”
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“High throughput sequencing and copy number studies of PDAC genome have identified and validated the known driver mutations in K-RAS, TP53, CDKN2A, and SMAD4, as well as novel gene mutations that may be involved in cell growth, DNA repair, invasiveness, angiogenesis and metabolism.(31) These studies can”
BackgroundTranslational advances in pancreatic ductal adenocarcinoma therapy
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Self-citationThe Immune Microenvironment in Pancreatic Cancer
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“PDAC driver mutations have proven difficult to target in the clinical setting, with the exception of microsatellite instability with immune check point inhibitors [17] or BRCA1/2 mutations with platinum-based chemotherapies and PARP-inhibitors [18,19]; however, these concern only a small number of patients.”
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Self-citationOrdered and deterministic cancer genome evolution after p53 loss
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Self-citation
- Authors
- Initiative, A. P. C. G., Waddell, N., Pajic, M., Patch, A.-M., Chang, D. K., Kassahn, K. S., Bailey, P., Johns, A. L., Miller, D., Nones, K., Quek, K., Quinn, M. C. J., Robertson, A. J., Fadlullah, M. Z. H., Bruxner, T. J. C., Christ, A. N., Harliwong, I., Idrisoglu, S., Manning, S., Nourse, C., Nourbakhsh, E., Wani, S., Wilson, P. J., Markham, E., Cloonan, N., Anderson, M. J., Fink, J. L., Holmes, O., Kazakoff, S. H., Leonard, C., Newell, F., Poudel, B., Song, S., Taylor, D., Waddell, N., Wood, S., Xu, Q., Wu, J., Pinese, M., Cowley, M. J., Lee, H. C., Jones, M. D., Nagrial, A. M., Humphris, J., Chantrill, L. A., Chin, V., Steinmann, A. M., Mawson, A., Humphrey, E. S., Colvin, E. K., Chou, A., Scarlett, C. J., Pinho, A. V., Giry-Laterriere, M., Rooman, I., Samra, J. S., Kench, J. G., Pettitt, J. A., Merrett, N. D., Toon, C., Epari, K., Nguyen, N. Q., Barbour, A., Zeps, N., Jamieson, N. B., Graham, J. S., Niclou, S. P., Bjerkvig, R., Grützmann, R., Aust, D., Hruban, R. H., Maitra, A., Iacobuzio-Donahue, C. A., Wolfgang, C. L., Morgan, R. A., Lawlor, R. T., Corbo, V., Bassi, C., Falconi, M., Zamboni, G., Tortora, G., Tempero, M. A., Gill, A. J., Eshleman, J. R., Pilarsky, C., Scarpa, A., Musgrove, E. A., Pearson, J. V., Biankin, A. V., & Grimmond, S. M.
- Affiliations
- The University of Queensland (AU)
- Garvan Institute of Medical Research (AU)
- The University of Sydney (AU)
- Royal Adelaide Hospital (AU)
- The University of Western Australia (AU)
- St John of God Subiaco Hospital (AU)
- Glasgow Royal Infirmary (GB)
- Beatson West of Scotland Cancer Centre (GB)
- Centre de Recherche Public de la Santé (LU)
- University of Bergen (NO)
- Technische Universität Dresden (DE)
- Johns Hopkins University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Verona (IT)
- QIMR Berghofer Medical Research Institute (AU)
- Corresponding author
- Grimmond, Sean M.
- ORCID
- Waddell, Nicola
- Pajic, Marina
- Patch, Ann-Marie
- Chang, David K.
- Kassahn, Karin S.
- Bailey, Peter
- Johns, Amber L.
- Quek, Kelly
- Quinn, Michael C. J.
- Robertson, Alan J.
- Fadlullah, Muhammad Z. H.
- Christ, Angelika N.
- Harliwong, Ivon
- Manning, Suzanne
- Nourbakhsh, Ehsan
- Wani, Shivangi
- Wilson, Peter J.
- Cloonan, Nicole
- Anderson, Matthew J.
- Fink, J. Lynn
- Holmes, Oliver
- Kazakoff, Stephen H.
- Leonard, Conrad
- Newell, Felicity
- Poudel, Barsha
- Song, Sarah
- Wood, Scott
- Wu, Jianmin
- Pinese, Mark
- Cowley, Mark J.
- Jones, Marc D.
- Nagrial, Adnan M.
- Chantrill, Lorraine A.
- Chin, Venessa
- Mawson, Amanda
- Colvin, Emily K.
- Chou, Angela
- Scarlett, Christopher J.
- Pinho, Andreia V.
- Rooman, Ilse
- Samra, Jaswinder S.
- Kench, James G.
- Pettitt, Jessica A.
- Merrett, Neil D.
- Toon, Christopher
- Nguyen, Nam Q.
- Barbour, Andrew
- Zeps, Nikolajs
- Jamieson, Nigel B.
- Graham, Janet S.
- Niclou, Simone P.
- Bjerkvig, Rolf
- Grützmann, Robert
- Aust, Daniela
- Hruban, Ralph H.
- Maitra, Anirban
- Wolfgang, Christopher L.
- Lawlor, Rita T.
- Corbo, Vincenzo
- Falconi, Massimo
- Zamboni, Giuseppe
- Tortora, Giampaolo
- Tempero, Margaret A.
- Gill, Anthony J.
- Eshleman, James R.
- Pilarsky, Christian
- Scarpa, Aldo
- Pearson, John V.
- Biankin, Andrew V.
- Grimmond, Sean M.
- Venue
- Nature
- Published
- 2015-02-25
- Volume
- 518
- Issue
- 7540
- Pages
- 495-501
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4523082
- OpenAlex
- W1987313243
- Cited by
- 2,642
- References
- 57
- Citations by year
- 2026: 118 · 2025: 171 · 2024: 185 · 2023: 234 · 2022: 259 · 2021: 301 · 2020: 292 · 2019: 251 · 2018: 260 · 2017: 242 · 2016: 226 · 2015: 96 · 2014: 1 · 2012: 1
- FWCI
- 120.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by)
- University of Southern Queensland ePrints (University of Southern Queensland) (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eSpace (Curtin University) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Funders
- American Association for Cancer Research
- Johns Hopkins University
- Royal College of Pathologists of Australasia
- Wellcome Trust (103721/Z/14/Z, 103721)
- Australian Government
- Cancer Research UK (C596/A18076, C29717/A17263, 17263, A18076, A17263)
- Academy of Medical Sciences (AMS-SGCL9-Jamieson)
- University of Glasgow (C596/A18076)
- Australian Cancer Research Foundation
- Cancer Institute NSW (11/REG/1-10, 09/CDF/2-40, 10/CRF/1-01, 10/TPG/1‐04, 06/ECF/1-24, 08/RSA/1-15, 10/CDF/2-26, 06/RSA/1-05, 11/CDF/3-26, 07/CDF/1-28, 07/CDF/1-03, 10/ECF/2-26, 09/RIG/1-02)
- Gastroenterological Society of Australia
- Royal Australasian College of Physicians
- Petre Foundation
- Queensland Government
- R.T. Hall Trust
- Università degli Studi di Verona
- National Institutes of Health (CA62924)
- Medical Research Council
- National Health and Medical Research Council (631701, 535903, 427601)
- Cancer Council NSW (SRP06-01)
- National Cancer Institute (P50CA-62924, P50CA062924, P30CA006973)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- pancreatic ductal adenocarcinoma, mutational landscape, chromosomal rearrangements, copy number variation, structural variants, tumor subtypes, focal amplification, genomic instability, DNA repair deficiency, TP53, SMAD4, CDKN2A, ARID1A, Robo2, KDM6A, PREX2, BRCA1, BRCA2, PALB2, platinum-based chemotherapy, therapeutic biomarkers
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Adenocarcinoma, Animals, DNA Mutational Analysis, DNA Repair, Female, Genetic Markers, Genotype, Humans, Mutation, Pancreatic Neoplasms, Platinum, Genome, Human, Point Mutation, Genes, BRCA1, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Genomics, Genes, BRCA2, Genomic Instability, Mice
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