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• W2904107848 abstract "•Higher cell cycle progression in PDAC metastases; increases with driver gene loss•Half of PDACs are hypoxic and are associated with subtypes and treatment response•Paired tumors show molecular conservation and Halstedian progression•Multiple PDACs arising in the same pancreas are intra-parenchymal metastases We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice. We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice. Pancreatic ductal adenocarcinoma has dismal prognosis due to rapid metastatic dissemination. This rigorous study of paired and unpaired tumors informs both progression mechanisms and therapy. First, there was no evidence of discrete metastases enabling genes. Second, greater CCP in metastases may explain aggressive behavior and correspond to treatment response. Third, hypoxia signature was associated with chemotherapy resistance. Fourth, comparing mutations in paired samples revealed sequential progression from primary to lymph node to distant metastases, and sequencing synchronous and metachronous lesions distinguished these as recurrences rather than separate primaries, resolving this clinical conundrum. Finally, clinical features outperformed and were independent of molecular alterations in survival analyses, implying greater insight is needed before molecular profiling broadly informs therapy. Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality within a decade (Rahib et al., 2014Rahib L. Smith B.D. Aizenberg R. Rosenzweig A.B. Fleshman J.M. Matrisian L.M. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.Cancer Res. 2014; 74: 2913-2921Crossref PubMed Scopus (4229) Google Scholar). Patients with localized, resectable disease have up to 30% survival at 5 years, whereas those with lymph node metastases and distant disease have only 10% and 3%, respectively (Ryan et al., 2014Ryan D.P. Hong T.S. Bardeesy N. Pancreatic adenocarcinoma.N. Engl. J. Med. 2014; 371: 1039-1049Crossref PubMed Scopus (1225) Google Scholar). Thus, extra-pancreatic metastases are a strong determinant of PDAC outcome. Yet, most genomic studies have characterized resectable disease only, which constitutes less than 20% of cases, as metastases are seldom removed or biopsied, hindering tissue collection. PDAC studies typically focus on primary tumors, which are often poorly cellular and challenging to sequence. This has been overcome by using samples obtained at rapid autopsy (Iacobuzio-Donahue et al., 2009Iacobuzio-Donahue C.A. Fu B. Yachida S. Luo M. Abe H. Henderson C.M. Vilardell F. Wang Z. Keller J.W. Banerjee P. et al.DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer.J. Clin. Oncol. 2009; 27: 1806-1813Crossref PubMed Scopus (832) Google Scholar), by using cell lines (Jones et al., 2008Jones S. Zhang X. Parsons D.W. Lin J.C. Leary R.J. Angenendt P. Mankoo P. Carter H. Kamiyama H. Jimeno A. et al.Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.Science. 2008; 321: 1801-1806Crossref PubMed Scopus (3102) Google Scholar) or xenografts (Yachida et al., 2010Yachida S. Jones S. Bozic I. Antal T. Leary R. Fu B. Kamiyama M. Hruban R.H. Eshleman J.R. Nowak M.A. et al.Distant metastasis occurs late during the genetic evolution of pancreatic cancer.Nature. 2010; 467: 1114-1117Crossref PubMed Scopus (1908) Google Scholar, Campbell et al., 2010Campbell P.J. Yachida S. Mudie L.J. Stephens P.J. Pleasance E.D. Stebbings L.A. Morsberger L.A. Latimer C. Mclaren S. Lin M. et al.The patterns and dynamics of genomic instability in metastatic pancreatic cancer.Nature. 2010; 467: 1109-1113Crossref PubMed Scopus (1034) Google Scholar) to enrich for tumor cells, by bulk sequencing of moderately cellular resected specimens (Biankin et al., 2012Biankin A.V. Waddell N. Kassahn K.S. Gingras M.C. Muthuswamy L.B. Johns A.L. Miller D.K. Wilson P.J. Patch A.M. Wu J. et al.Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.Nature. 2012; 491: 399-405Crossref PubMed Scopus (1513) Google Scholar, Waddell et al., 2015Waddell N. Pajic M. Patch A.M. Chang D.K. Kassahn K.S. Bailey P. Johns A.L. Miller D. Nones K. Quek K. et al.Whole genomes redefine the mutational landscape of pancreatic cancer.Nature. 2015; 518: 495-501Crossref PubMed Scopus (1688) Google Scholar, Bailey et al., 2016Bailey P. Chang D.K. Nones K. Johns A.L. Patch A.M. Gingras M.C. Miller D.K. Christ A.N. Bruxner T.J. Quinn M.C. et al.Genomic analyses identify molecular subtypes of pancreatic cancer.Nature. 2016; 531: 47-52Crossref PubMed Scopus (1976) Google Scholar, Witkiewicz et al., 2015Witkiewicz A.K. Mcmillan E.A. Balaji U. Baek G. Lin W.C. Mansour J. Mollaee M. Wagner K.U. Koduru P. Yopp A. et al.Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets.Nat. Commun. 2015; 6: 6744Crossref PubMed Scopus (722) Google Scholar), and by deep sequencing of either targeted panels (Cancer Genome Atlas Research Network, 2017Cancer Genome Atlas Research Network Integrated genomic characterization of pancreatic ductal adenocarcinoma.Cancer Cell. 2017; 32: 185-203.e13Abstract Full Text Full Text PDF PubMed Scopus (968) Google Scholar) or the exome (Zehir et al., 2017Zehir A. Benayed R. Shah R.H. Syed A. Middha S. Kim H.R. Srinivasan P. Gao J. Chakravarty D. Devlin S.M. et al.Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.Nat. Med. 2017; 23: 703-713Crossref PubMed Scopus (1805) Google Scholar). The recurrent theme across these studies is that PDAC is dominated by mutations in four driver genes: KRAS, SMAD4, CDKN2A, and TP53. Investigation of the roles of these genes in PDAC initiation and progression come largely from genetically engineered mouse models and early studies of human PDAC. KRAS mutations initiate pancreatic carcinogenesis (Almoguera et al., 1988Almoguera C. Shibata D. Forrester K. Martin J. Arnheim N. Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.Cell. 1988; 53: 549-554Abstract Full Text PDF PubMed Scopus (1903) Google Scholar, Hruban et al., 2000Hruban R.H. Goggins M. Parsons J. Kern S.E. Progression model for pancreatic cancer.Clin. Cancer Res. 2000; 6: 2969-2972PubMed Google Scholar, Hingorani et al., 2003Hingorani S.R. Petricoin E.F. Maitra A. Rajapakse V. King C. Jacobetz M.A. Ross S. Conrads T.P. Veenstra T.D. Hitt B.A. et al.Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.Cancer Cell. 2003; 4: 437-450Abstract Full Text Full Text PDF PubMed Scopus (1793) Google Scholar). Concomitant mutations in CDKN2A (Hruban et al., 2000Hruban R.H. Goggins M. Parsons J. Kern S.E. Progression model for pancreatic cancer.Clin. Cancer Res. 2000; 6: 2969-2972PubMed Google Scholar, Moskaluk et al., 1997Moskaluk C.A. Hruban R.H. Kern S.E. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma.Cancer Res. 1997; 57: 2140-2143PubMed Google Scholar, Aguirre et al., 2003Aguirre A.J. Bardeesy N. Sinha M. Lopez L. Tuveson D.A. Horner J. Redston M.S. Depinho R.A. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma.Genes Dev. 2003; 17: 3112-3126Crossref PubMed Scopus (800) Google Scholar) or TP53 (Hruban et al., 2000Hruban R.H. Goggins M. Parsons J. Kern S.E. Progression model for pancreatic cancer.Clin. Cancer Res. 2000; 6: 2969-2972PubMed Google Scholar, Hingorani et al., 2005Hingorani S.R. Wang L. Multani A.S. Combs C. Deramaudt T.B. Hruban R.H. Rustgi A.K. Chang S. Tuveson D.A. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.Cancer Cell. 2005; 7: 469-483Abstract Full Text Full Text PDF PubMed Scopus (1689) Google Scholar) hasten cancer progression. Inactivation of CDKN2A (Wilentz et al., 1998Wilentz R.E. Geradts J. Maynard R. Offerhaus G.J. Kang M. Goggins M. Yeo C.J. Kern S.E. Hruban R.H. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression.Cancer Res. 1998; 58: 4740-4744PubMed Google Scholar, Aguirre et al., 2003Aguirre A.J. Bardeesy N. Sinha M. Lopez L. Tuveson D.A. Horner J. Redston M.S. Depinho R.A. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma.Genes Dev. 2003; 17: 3112-3126Crossref PubMed Scopus (800) Google Scholar) or SMAD4 (Izeradjene et al., 2007Izeradjene K. Combs C. Best M. Gopinathan A. Wagner A. Grady W.M. Deng C.X. Hruban R.H. Adsay N.V. Tuveson D.A. et al.Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas.Cancer Cell. 2007; 11: 229-243Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, Whittle et al., 2015Whittle M.C. Izeradjene K. Rani P.G. Feng L. Carlson M.A. Delgiorno K.E. Wood L.D. Goggins M. Hruban R.H. Chang A.E. et al.RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma.Cell. 2015; 161: 1345-1360Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar) results in locally destructive disease, TP53 in miliary metastases (Wilentz et al., 2000Wilentz R.E. Goggins M. Redston M. Marcus V.A. Adsay N.V. Sohn T.A. Kadkol S.S. Yeo C.J. Choti M. Zahurak et al.Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity.Am. J. Pathol. 2000; 156: 1641-1651Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, Luttges et al., 2001Luttges J. Galehdari H. Brocker V. Schwarte-Waldhoff I. Henne-Bruns D. Kloppel G. Schmiegel W. Hahn S.A. Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis.Am. J. Pathol. 2001; 158: 1677-1683Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, Hingorani et al., 2005Hingorani S.R. Wang L. Multani A.S. Combs C. Deramaudt T.B. Hruban R.H. Rustgi A.K. Chang S. Tuveson D.A. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.Cancer Cell. 2005; 7: 469-483Abstract Full Text Full Text PDF PubMed Scopus (1689) Google Scholar), and concurrent SMAD4 and TP53 in either locally or metastatic dominant disease depending on the number of inactivated SMAD4 alleles (Hruban et al., 2000Hruban R.H. Goggins M. Parsons J. Kern S.E. Progression model for pancreatic cancer.Clin. Cancer Res. 2000; 6: 2969-2972PubMed Google Scholar, Whittle et al., 2015Whittle M.C. Izeradjene K. Rani P.G. Feng L. Carlson M.A. Delgiorno K.E. Wood L.D. Goggins M. Hruban R.H. Chang A.E. et al.RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma.Cell. 2015; 161: 1345-1360Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). Conversely, immunohistochemistry (IHC) of rapid autopsy specimens suggests that SMAD4 loss is associated with primary tumor constraint and metastatic proclivity (Iacobuzio-Donahue et al., 2009Iacobuzio-Donahue C.A. Fu B. Yachida S. Luo M. Abe H. Henderson C.M. Vilardell F. Wang Z. Keller J.W. Banerjee P. et al.DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer.J. Clin. Oncol. 2009; 27: 1806-1813Crossref PubMed Scopus (832) Google Scholar). Associations of KRAS activation and SMAD4 loss with clinical outcomes have also been observed (Wang et al., 2017Wang J.D. Jin K. Chen X.Y. Lv J.Q. Ji K.W. Clinicopathological significance of SMAD4 loss in pancreatic ductal adenocarcinomas: a systematic review and meta-analysis.Oncotarget. 2017; 8: 16704-16711Crossref PubMed Scopus (29) Google Scholar). Thus, there is consensus as to the four principal PDAC drivers, but their patterns of aberration and associations with tumor phenotypes in human primary and metastatic cancers remain ambiguous. Additional studies of gene expression profiles classify PDACs into two (Moffitt et al., 2015Moffitt R.A. Marayati R. Flate E.L. Volmar K.E. Loeza S.G. Hoadley K.A. Rashid N.U. Williams L.A. Eaton S.C. Chung A.H. et al.Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.Nat. Genet. 2015; 47: 1168-1178Crossref PubMed Scopus (998) Google Scholar), three (Collisson et al., 2011Collisson E.A. Sadanandam A. Olson P. Gibb W.J. Truitt M. Gu S. Cooc J. Weinkle J. Kim G.E. Jakkula L. et al.Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy.Nat. Med. 2011; 17: 500-503Crossref PubMed Scopus (1054) Google Scholar), or four (Bailey et al., 2016Bailey P. Chang D.K. Nones K. Johns A.L. Patch A.M. Gingras M.C. Miller D.K. Christ A.N. Bruxner T.J. Quinn M.C. et al.Genomic analyses identify molecular subtypes of pancreatic cancer.Nature. 2016; 531: 47-52Crossref PubMed Scopus (1976) Google Scholar) subtypes, and suggest that these may be prognostic for outcome and predictive of therapy response. There are few studies of PDAC metastases. A rapid autopsy series with serial radiologic evaluations of tumor progression premortem showed that growth rates of primaries and metastases are weakly correlated (Haeno et al., 2012Haeno H. Gonen M. Davis M.B. Herman J.M. Iacobuzio-Donahue C.A. Michor F. Computational modeling of pancreatic cancer reveals kinetics of metastasis suggesting optimum treatment strategies.Cell. 2012; 148: 362-375Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar). Exome (Yachida et al., 2010Yachida S. Jones S. Bozic I. Antal T. Leary R. Fu B. Kamiyama M. Hruban R.H. Eshleman J.R. Nowak M.A. et al.Distant metastasis occurs late during the genetic evolution of pancreatic cancer.Nature. 2010; 467: 1114-1117Crossref PubMed Scopus (1908) Google Scholar), genome (Campbell et al., 2010Campbell P.J. Yachida S. Mudie L.J. Stephens P.J. Pleasance E.D. Stebbings L.A. Morsberger L.A. Latimer C. Mclaren S. Lin M. et al.The patterns and dynamics of genomic instability in metastatic pancreatic cancer.Nature. 2010; 467: 1109-1113Crossref PubMed Scopus (1034) Google Scholar, Makohon-Moore et al., 2017Makohon-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.Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer.Nat. Genet. 2017; 49: 358-366Crossref PubMed Scopus (238) Google Scholar), and epigenome (McDonald et al., 2017McDonald O.G. Li X. Saunders T. Tryggvadottir R. Mentch S.J. Warmoes M.O. Word A.E. Carrer A. Salz T.H. Natsume S. et al.Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis.Nat. Genet. 2017; 49: 367-376Crossref PubMed Scopus (260) Google Scholar) sequencing of paired primary and metastatic samples from this series demonstrated that most somatic variation in metastases is present in primary subclones, driver gene alterations were concordant (Yachida et al., 2010Yachida S. Jones S. Bozic I. Antal T. Leary R. Fu B. Kamiyama M. Hruban R.H. Eshleman J.R. Nowak M.A. et al.Distant metastasis occurs late during the genetic evolution of pancreatic cancer.Nature. 2010; 467: 1114-1117Crossref PubMed Scopus (1908) Google Scholar, Makohon-Moore et al., 2017Makohon-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.Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer.Nat. Genet. 2017; 49: 358-366Crossref PubMed Scopus (238) Google Scholar), and metastasis-specific variation is often in genes of ambiguous functional importance (Makohon-Moore et al., 2017Makohon-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.Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer.Nat. Genet. 2017; 49: 358-366Crossref PubMed Scopus (238) Google Scholar). Yet, all of these studies included paired lesions from only a few patients, and often comprehensively sequenced only one index lesion per patient, followed by targeted sequencing of identified variants in paired tumors, likely underestimating tumor heterogeneity. Comparisons of large numbers of agnostically sequenced paired and unpaired PDAC primaries and metastases have not been performed, although it has proven informative in other malignancies (Yates et al., 2017Yates L.R. Knappskog S. Wedge D. Farmery J.H.R. Gonzalez S. Martincorena I. Alexandrov L.B. Van Loo P. Haugland H.K. Lilleng P.K. et al.Genomic evolution of breast cancer metastasis and relapse.Cancer Cell. 2017; 32: 169-184.e7Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar, Pectasides et al., 2018Pectasides E. Stachler M.D. Derks S. Liu Y. Maron S. Islam M. Alpert L. Kwak H. Kindler H. Polite B. et al.Genomic heterogeneity as a barrier to precision medicine in gastroesophageal adenocarcinoma.Cancer Discov. 2018; 8: 37-48Crossref PubMed Scopus (189) Google Scholar). Due to small sample sizes and limited tumor cellularity, previous studies of primary PDAC biology have left unanswered questions of how driver gene mutations, gene expression, and mutational-based subtypes are inter-related; whether these features are inherited by metastases; whether there are somatic alterations enriched in metastases; and whether heterogeneity between primary and metastatic samples is affected by timing and location of metastases. To address these questions, we characterized the whole genome and transcriptome of PDAC samples following tumor cell enrichment from fresh-frozen specimens with well-annotated clinicopathologic features. The study includes 319 PDAC tumors from 289 individuals, including one group of unpaired primary (n = 200) and metastatic (n = 70) tumors from 270 patients and a smaller group of paired primaries (n = 24) and metastases (n = 25) from 19 individuals (Figures 1 and 2A , Tables S1 and S2).Figure 2Mutational Signatures and Variants in Primaries and MetastasesShow full caption(A) Cohorts, (B) somatic mutational loads, (C) ploidy and cellularity, (D) Waddell class, (E) genomic complexity (the proportion of the tumor's genome with copy number deviating from its ploidy), (F) mutational signatures, (G) driver gene alterations, (H) copy number variation, (I) cell cycle progression, (J) hypoxia expression, (K) RNA subtypes.See also Figure S1.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) Cohorts, (B) somatic mutational loads, (C) ploidy and cellularity, (D) Waddell class, (E) genomic complexity (the proportion of the tumor's genome with copy number deviating from its ploidy), (F) mutational signatures, (G) driver gene alterations, (H) copy number variation, (I) cell cycle progression, (J) hypoxia expression, (K) RNA subtypes. See also Figure S1. We detected a median of 6,011 (range: 2,649–452,800) somatic single-nucleotide variants (SNVs) and indels in unpaired primaries and a median of 6,284 (3,439–75,930) in unpaired metastases. Sixty five (1–813) and 93 (7–652) structural variants (SVs) per genome were identified in unpaired primaries and metastases, respectively (Figure 2B). SNV and SV loads were consistent between paired samples (Figures S1A and S1B). We used MutSigCV and dNdScv to identify genes mutated more often than expected by non-silent SNVs or indels. We found KRAS (89%), TP53 (80%), CDKN2A (26%), SMAD4 (25%), ARID1A (9%), KDM6A (5%), RNF43 (5%), TGFBR2 (3%), and NRAS (1%) with both tools and GNAS (4%), MAP3K21 (3%), BRAF (3%), SMARCA4 (3%), ACVR2A (2%), ACVR1B (2%), FAM133A (<1%), and ZMAT2 (<1%) with either tool, largely concordant with previous work (Jones et al., 2008Jones S. Zhang X. Parsons D.W. Lin J.C. Leary R.J. Angenendt P. Mankoo P. Carter H. Kamiyama H. Jimeno A. et al.Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.Science. 2008; 321: 1801-1806Crossref PubMed Scopus (3102) Google Scholar, Biankin et al., 2012Biankin A.V. Waddell N. Kassahn K.S. Gingras M.C. Muthuswamy L.B. Johns A.L. Miller D.K. Wilson P.J. Patch A.M. Wu J. et al.Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.Nature. 2012; 491: 399-405Crossref PubMed Scopus (1513) Google Scholar) (Witkiewicz et al., 2015Witkiewicz A.K. Mcmillan E.A. Balaji U. Baek G. Lin W.C. Mansour J. Mollaee M. Wagner K.U. Koduru P. Yopp A. et al.Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets.Nat. Commun. 2015; 6: 6744Crossref PubMed Scopus (722) Google Scholar, Waddell et al., 2015Waddell N. Pajic M. Patch A.M. Chang D.K. Kassahn K.S. Bailey P. Johns A.L. Miller D. Nones K. Quek K. et al.Whole genomes redefine the mutational landscape of pancreatic cancer.Nature. 2015; 518: 495-501Crossref PubMed Scopus (1688) Google Scholar, Bailey et al., 2016Bailey P. Chang D.K. Nones K. Johns A.L. Patch A.M. Gingras M.C. Miller D.K. Christ A.N. Bruxner T.J. Quinn M.C. et al.Genomic analyses identify molecular subtypes of pancreatic cancer.Nature. 2016; 531: 47-52Crossref PubMed Scopus (1976) Google Scholar), and none more frequently in primaries or metastases. Most of the mutations in oncogenes were established gain-of-function variants, including KRAS (247 of 247), GNAS (11 of 11), BRAF (6 of 8), and NRAS (1 of 3). One additional NRAS variant (p.A146T) may also be activating. Notably, tumors bearing activating BRAF or NRAS variants did not possess KRAS mutations; this was also true in five of 11 GNAS-positive tumors. The BRAF and GNAS findings are concordant with previous work (Cancer Genome Atlas Research Network, 2017Cancer Genome Atlas Research Network Integrated genomic characterization of pancreatic ductal adenocarcinoma.Cancer Cell. 2017; 32: 185-203.e13Abstract Full Text Full Text PDF PubMed Scopus (968) Google Scholar). Ploidy was greater in metastases than in primaries (p = 0.00025; Figures 2C and 3), even when accounting for greater metastasis cellularity (p = 0.0003; Figures 2C and 3) in a linear model, but not qualitatively in paired samples (Figure S1C). Proportions of four SV classes previously described (Waddell et al., 2015Waddell N. Pajic M. Patch A.M. Chang D.K. Kassahn K.S. Bailey P. Johns A.L. Miller D. Nones K. Quek K. et al.Whole genomes redefine the mutational landscape of pancreatic cancer.Nature. 2015; 518: 495-501Crossref PubMed Scopus (1688) Google Scholar) did not differ in unpaired primaries and metastases (p = 0.6; Figures 2D and 3). Genomic complexity (the proportion of a tumor's genome with copy number deviating from its ploidy; Figure 2E) was found to be higher in metastatic polyploid tumors compared with polyploid primaries (p = 0.013, data not shown), which is likely a consequence of increased genomic instability in metastatic tumors, as they also display a non-significant trend toward increased SV burden (p = 0.078, data not shown). Consistent with our previous work (Connor et al., 2017Connor A.A. Denroche R.E. Jang G.H. Timms L. Kalimuthu S.N. Selander I. Mcpherson T. Wilson G.W. Chan-Seng-Yue M.A. Borozan I. et al.Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma.JAMA Oncol. 2017; 3: 774-783Crossref PubMed Scopus (181) Google Scholar, Grant et al., 2018Grant R.C. Denroche R.E. Borgida A. Virtanen C. Cook N. Smith A.L. Connor A.A. Wilson J.M. Peterson G. Roberts et al.Exome-wide association study of pancreatic cancer risk.Gastroenterology. 2018; 154: 719-722.e3Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar), we found 36 carriers of germline PDAC predisposition variants (Connor and Gallinger, 2015Connor A.A. Gallinger S. Hereditary pancreatic cancer syndromes.Surg. Oncol. Clin. N. Am. 2015; 24: 733-764Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar), representing 13% of the unpaired cohorts, including 1 APC, 2 ATM, 7 BRCA1, 18 BRCA2, 3 CDKN2A, 2 MLH1, 2 MSH6, and 1 PALB2, although these cohorts were not chosen with the intent of determining germline population frequencies. We applied non-negative least-squares linear models to deconvolute mutational signatures in primary and metastatic PDAC (Figure 2F) from base substitutions. Signatures 1 (“age-related”) and 3 (double-strand-break-repair [“DSBR”] deficient) were dominant. Proportions of signatures in unpaired primaries and metastases did not differ significantly (Figure 3) and were highly conserved in paired samples from the same individuals (Figure 2F). Thus, mutational processes in primaries are maintained in metastases, and each PDAC harnesses only a few mutational processes that contribute in equal proportions to genomic variation over time, as seen in breast cancer (Yates et al., 2017Yates L.R. Knappskog S. Wedge D. Farmery J.H.R. Gonzalez S. Martincorena I. Alexandrov L.B. Van Loo P. Haugland H.K. Lilleng P.K. et al.Genomic evolution of breast cancer metastasis and relapse.Cancer Cell. 2017; 32: 169-184.e7Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). Similarly, signatures did not vary in three pairs of liver metastases biopsied before and after receipt of systemic chemotherapy, implying treatment does not induce somatic mutations in distinct patterns. To compare driver gene events in primaries and metastases, we identified mono- and biallelic somatic mutations revealed by whole-genome sequencing (WGS), including point mutations, SVs, and copy number variation. In the unpaired cohort, TP53 biallelic loss was most common (∼65%), followed by CDKN2A (∼60%) and then SMAD4 (∼40%) (Figures 2G and 4). Frequencies of neither mono- nor biallelic somatic events differed significantly in primaries and metastases after excluding mismatch repair-deficient hypermutated tumors, although there was a trend toward increased TP53 loss in metastases (Figures 3, 4A, and 4B). GISTIC identified 109 copy number events in the unpaired cohort as recurrent (Figure 2H). Two amplifications (including KRAS) and four deletions were significantly more frequent in metastases (Figure 4C; Table S3). In 15 paired samples, a minority were discordant for biallelic inactivation of CDKN2A (n = 3 pairs), SMAD4 (n = 2 pairs), and TP53 (n = 1 pair), similar to what has been reported in multi-focal breast (Yates et al., 2015Yates L.R. Gerstung M. Knappskog S. Desmedt C. Gundem G. Van Loo P. Aas T. Alexandrov L.B. Larsimont D. Davies H. et al.Subclonal diversification of primary breast cancer revealed by multiregion sequencing.Nat. Med. 2015; 21: 751-759Crossref PubMed Scopus (544) Google Scholar) and renal (Gerlinger et al., 2012Gerlinger M. Rowan A.J. Horswell S. Math M. Larkin J. Endesfelder D. Gronroos E. Martinez P. Matthews N. Stewart et al.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.N. Engl. J. Med. 2012; 366: 883-892Crossref PubMed Scopus (5730) Google Scholar) cancers. The paired tumor retaining a copy of the driver gene was not consistently a primary or metastasis. Thus, driver gene events occur in approximately equal frequency in PDAC primaries and metastases, and differ in only a minority of paired cases, implying that they are acquired in primary tumors prior to and are not late drivers of metastases. Biallelic inactivation was strongly associated with reduced driver gene expression in the paired and unpaired cohorts (false discovery rate [FDR] <0.008), validating our two-hit approach. Primary and metastatic tumors with age-related signatures had biallelic inactivations occurring more frequently in combination than individually, whereas primary tumors with DSBR signatures more often bore single driver gene inactivation, or were wild-type (p = 0.02" @default.
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• W2904107848 date "2019-02-01" @default.
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• W2904107848 title "Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases" @default.
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