Genomic characterization of malignant progression in neoplastic pancreatic cysts

doi:10.1038/s41467-020-17917-8

. 2020 Aug 14;11(1):4085.

doi: 10.1038/s41467-020-17917-8.

Genomic characterization of malignant progression in neoplastic pancreatic cysts

Michaël Noë^{1

2}, Noushin Niknafs², Catherine G Fischer¹, Wenzel M Hackeng^{1

3}, Violeta Beleva Guthrie^{4

5}, Waki Hosoda^{1

6}, Marija Debeljak¹, Eniko Papp², Vilmos Adleff², James R White², Claudio Luchini⁷, Antonio Pea⁸, Aldo Scarpa^{7

9}, Giovanni Butturini¹⁰, Giuseppe Zamboni^{7

11}, Paola Castelli¹¹, Seung-Mo Hong^{1

12}, Shinichi Yachida¹³, Nobuyoshi Hiraoka¹⁴, Anthony J Gill^{15

16

17}, Jaswinder S Samra^{15

18

19}, G Johan A Offerhaus³, Anne Hoorens²⁰, Joanne Verheij²¹, Casper Jansen²², N Volkan Adsay²³, Wei Jiang²⁴, Jordan Winter^{25

26}, Jorge Albores-Saavedra²⁷, Benoit Terris²⁸, Elizabeth D Thompson¹, Nicholas J Roberts^{1

2}, Ralph H Hruban^{1

2}, Rachel Karchin^{2

4

5}, Robert B Scharpf², Lodewijk A A Brosens^{3

29}, Victor E Velculescu^{1

2

4}, Laura D Wood^{30

31}

Affiliations

¹ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Pathology, The University Medical Center Utrecht, Utrecht, The Netherlands.
⁴ Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁶ Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
⁷ Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.
⁸ Department of Surgery - The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy.
⁹ ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
¹⁰ Department of Surgery, Pederzoli Hospital, Peschiera del Garda, Italy.
¹¹ Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy.
¹² Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
¹³ Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.
¹⁴ Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
¹⁵ University of Sydney, Sydney, NSW, Australia.
¹⁶ NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia.
¹⁷ Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia.
¹⁸ Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, Sydney, NSW, Australia.
¹⁹ Faculty of Medical and Health Sciences, Macquarie University, Sydney, Australia.
²⁰ Department of Pathology, Ghent University Hospital, Ghent, Belgium.
²¹ Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
²² LABPON, Laboratory for Pathology Eastern Netherlands, Hengelo, The Netherlands.
²³ Koc University School of Medicine, Istanbul, Turkey.
²⁴ Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA.
²⁵ University Hospitals Cleveland Medical Center and Seidman Cancer Center, Cleveland, OH, USA.
²⁶ Case Comprehensive Cancer Center, Cleveland, OH, USA.
²⁷ Department of Pathology, Medica Sur Clinic and Foundation, Mexico City, Mexico.
²⁸ Service de Pathologie, AP-HP, Hôpital Cochin, Université Paris Descartes, Paris, France.
²⁹ Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
³⁰ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ldwood@jhmi.edu.
³¹ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ldwood@jhmi.edu.

PMID: 32796935
PMCID: PMC7428044
DOI: 10.1038/s41467-020-17917-8

Genomic characterization of malignant progression in neoplastic pancreatic cysts

Michaël Noë et al. Nat Commun. 2020.

. 2020 Aug 14;11(1):4085.

doi: 10.1038/s41467-020-17917-8.

Authors

Affiliations

¹ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Pathology, The University Medical Center Utrecht, Utrecht, The Netherlands.
⁴ Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁶ Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
⁷ Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.
⁸ Department of Surgery - The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy.
⁹ ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
¹⁰ Department of Surgery, Pederzoli Hospital, Peschiera del Garda, Italy.
¹¹ Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy.
¹² Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
¹³ Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.
¹⁴ Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
¹⁵ University of Sydney, Sydney, NSW, Australia.
¹⁶ NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia.
¹⁷ Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia.
¹⁸ Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, Sydney, NSW, Australia.
¹⁹ Faculty of Medical and Health Sciences, Macquarie University, Sydney, Australia.
²⁰ Department of Pathology, Ghent University Hospital, Ghent, Belgium.
²¹ Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
²² LABPON, Laboratory for Pathology Eastern Netherlands, Hengelo, The Netherlands.
²³ Koc University School of Medicine, Istanbul, Turkey.
²⁴ Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA.
²⁵ University Hospitals Cleveland Medical Center and Seidman Cancer Center, Cleveland, OH, USA.
²⁶ Case Comprehensive Cancer Center, Cleveland, OH, USA.
²⁷ Department of Pathology, Medica Sur Clinic and Foundation, Mexico City, Mexico.
²⁸ Service de Pathologie, AP-HP, Hôpital Cochin, Université Paris Descartes, Paris, France.
²⁹ Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
³⁰ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ldwood@jhmi.edu.
³¹ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ldwood@jhmi.edu.

PMID: 32796935
PMCID: PMC7428044
DOI: 10.1038/s41467-020-17917-8

Abstract

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.

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Conflict of interest statement

L.D.W. receives research funding from Applied Materials. V.E.V. is a founder of Personal Genome Diagnostics, a member of its Scientific Advisory Board and Board of Directors, and owns Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. V.E.V. is an advisor to Takeda Pharmaceuticals. Within the last five years, V.E.V. has been an advisor to Daiichi Sankyo, Janssen Diagnostics, and Ignyta. J.R.W. is founder and owner of Resphera Biosciences LLC, and is a consultant to Personal Genome Diagnostics Inc. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict of interest policies. The other authors declare no conflict of interest.

Figures

**Fig. 1. Somatic mutations identified in matched noninvasive and invasive cancer samples.**
a In each patient sample, multiple mutations were shared between the noninvasive and invasive cancer samples (gray). In addition, some mutations were limited to the noninvasive (blue/green), while others were limited to the cancer (red/pink). Darker colors indicate alterations that were likely restricted to one component but where sequencing coverage in the second component was limited. The proportions of shared and distinct mutations varied between different lesions. b Somatic mutations in the most frequently mutated genes are categorized as shared between noninvasive and cancer (gray), limited to noninvasive (blue), or limited to cancer (red). Mutations in some genes (such as *KRAS)* were always shared, while others were enriched in samples from noninvasive (*RNF43*) or cancer (*SMAD4*).

**Fig. 2. Copy number alterations identified in matched noninvasive and invasive cancer samples.**
Chromosomal gains (red) and losses (blue) are shown for each chromosome in each patient, with noninvasive samples on the left and cancer samples on the right.

**Fig. 3. Somatic mutations identified in MTP19 and MTP8 in targeted and whole exome sequencing.**
We show mutations identified in each sample, including low-grade IPMN (light blue), high-grade IPMN (dark blue), ductal cancer (red), mucinous cancer (pink), and cancerization (purple). The type of sequencing analysis (targeted or whole exome) performed for each sample is indicated in a track on the bottom. Representative images of neoplastic tissue stained by hematoxylin and eosin, as well as isolated regions before and after laser capture microdissection are shown for MTP19 and MTP8.

**Fig. 4. Evolutionary reconstruction of samples analyzed by whole exome and targeted sequencing.**
In all cases, noninvasive samples (blue/green) precede invasive samples (red/pink) in the evolutionary history. In MTP5, different invasive cancer samples are placed in different regions of the phylogeny, highlighting multiple independent invasion events in this lesion. In MTP19, a sample of cancerization (purple) has descended from invasive cancer samples.

See this image and copyright information in PMC

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References

1. Rahib L, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–2921. - PubMed
1. Basturk O, et al. A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am. J. Surg. Pathol. 2015;39:1730–1741. - PMC - PubMed
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[1] Rahib L, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–2921. - PubMed

[2] Rahib L, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–2921. - PubMed

[3] Basturk O, et al. A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am. J. Surg. Pathol. 2015;39:1730–1741. - PMC - PubMed

[4] Basturk O, et al. A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am. J. Surg. Pathol. 2015;39:1730–1741. - PMC - PubMed

[5] Lermite E, et al. Complications after pancreatic resection: diagnosis, prevention and management. Clin. Res. Hepatol. Gastroenterol. 2013;37:230–239. - PubMed

[6] Lermite E, et al. Complications after pancreatic resection: diagnosis, prevention and management. Clin. Res. Hepatol. Gastroenterol. 2013;37:230–239. - PubMed

[7] Wu J, et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc. Natl Acad. Sci. USA. 2011;108:21188–21193. - PMC - PubMed

[8] Wu J, et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc. Natl Acad. Sci. USA. 2011;108:21188–21193. - PMC - PubMed

[9] Furukawa T, et al. Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. Sci. Rep. 2011;1:161. - PMC - PubMed

[10] Furukawa T, et al. Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. Sci. Rep. 2011;1:161. - PMC - PubMed

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Genomic characterization of malignant progression in neoplastic pancreatic cysts

Affiliations

Genomic characterization of malignant progression in neoplastic pancreatic cysts

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Abstract

Conflict of interest statement

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Conflict of interest statement

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