. 2013 Dec;45(12):1470-1473.

doi: 10.1038/ng.2813. Epub 2013 Nov 3.

Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas

Yuchen Jiao^#^{1

2

3}, Timothy M Pawlik^#^{3

4}, Robert A Anders^#^{3

5}, Florin M Selaru⁶, Mirte M Streppel⁵, Donald J Lucas⁷, Noushin Niknafs⁸, Violeta Beleva Guthrie⁸, Anirban Maitra^{3

5}, Pedram Argani^{3

5}, G Johan A Offerhaus⁹, Juan Carlos Roa¹⁰, Lewis R Roberts¹¹, Gregory J Gores¹¹, Irinel Popescu¹², Sorin T Alexandrescu¹², Simona Dima¹², Matteo Fassan^{13

14}, Michele Simbolo^{13

14}, Andrea Mafficini¹³, Paola Capelli¹⁴, Rita T Lawlor^{13

14}, Andrea Ruzzenente¹⁵, Alfredo Guglielmi¹⁵, Giampaolo Tortora¹⁶, Filippo de Braud¹⁷, Aldo Scarpa^{13

14}, William Jarnagin¹⁸, David Klimstra¹⁹, Rachel Karchin⁸, Victor E Velculescu^{1

2

3}, Ralph H Hruban^{3

5}, Bert Vogelstein^{1

2

3}, Kenneth W Kinzler^{1

2

3}, Nickolas Papadopoulos^{1

2

3}, Laura D Wood⁵

Affiliations

¹ The Ludwig Center, Johns Hopkins University, Baltimore, Maryland, USA.
² Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland, USA.
³ Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
⁴ Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA.
⁵ Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
⁶ Department of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA.
⁷ Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
⁸ Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
⁹ Department of Pathology, University Medical Center, Utrecht, The Netherlands.
¹⁰ Department of Pathology, Universidad de La Frontera, Temuco, Chile.
¹¹ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
¹² Dan Setlacec Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
¹³ Applied Research on Cancer Network, Miriam Cherubini Research Centre, University of Verona, Verona, Italy.
¹⁴ Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
¹⁵ Department of Surgery, University of Verona, Verona, Italy.
¹⁶ Department of Medicine, Medical Oncology Unit, University of Verona, Verona, Italy.
¹⁷ Medical Oncology Unit 1, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy.
¹⁸ Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
¹⁹ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

^# Contributed equally.

PMID: 24185509
PMCID: PMC4013720
DOI: 10.1038/ng.2813

Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas

Yuchen Jiao et al. Nat Genet. 2013 Dec.

. 2013 Dec;45(12):1470-1473.

doi: 10.1038/ng.2813. Epub 2013 Nov 3.

Authors

Affiliations

¹ The Ludwig Center, Johns Hopkins University, Baltimore, Maryland, USA.
² Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland, USA.
³ Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
⁴ Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA.
⁵ Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
⁶ Department of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA.
⁷ Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
⁸ Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
⁹ Department of Pathology, University Medical Center, Utrecht, The Netherlands.
¹⁰ Department of Pathology, Universidad de La Frontera, Temuco, Chile.
¹¹ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
¹² Dan Setlacec Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
¹³ Applied Research on Cancer Network, Miriam Cherubini Research Centre, University of Verona, Verona, Italy.
¹⁴ Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
¹⁵ Department of Surgery, University of Verona, Verona, Italy.
¹⁶ Department of Medicine, Medical Oncology Unit, University of Verona, Verona, Italy.
¹⁷ Medical Oncology Unit 1, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy.
¹⁸ Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
¹⁹ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

^# Contributed equally.

PMID: 24185509
PMCID: PMC4013720
DOI: 10.1038/ng.2813

Abstract

Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.

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Figures

**Figure 1**
Genes with frequent inactivating mutations in intrahepatic cholangiocarcinoma. Inactivating mutations occurred throughout the coding sequences of *BAP1*, *ARID1A* and *PBRM1*. Rectangles, splice-site mutations; triangles, insertions and deletions; ovals, missense mutations; stars, nonsense mutations. H, HBM-like motif; BR, BRCA1-interacting domain; C, coiled-coil domain; N, nuclear localization signal; LXXLL, LXXLL domain; ARID, ARID domain; BD, bromodomain; BAH, BAH domain; HMG, HMG box.

See this image and copyright information in PMC

Comment in

Genetics: genetics of biliary tract cancer.
Ray K. Ray K. Nat Rev Gastroenterol Hepatol. 2013 Dec;10(12):692. doi: 10.1038/nrgastro.2013.219. Epub 2013 Nov 19. Nat Rev Gastroenterol Hepatol. 2013. PMID: 24247265 No abstract available.

References

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1. Blechacz B, et al. Clinical diagnosis and staging of cholangiocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 2011;8:512–522. - PMC - PubMed
1. Borger DR, et al. Frequent mutation of isocitrate dehydrogenase IDH1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17:72–79. - PMC - PubMed
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Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas

Affiliations

Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas

Authors

Affiliations

Abstract

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Comment in

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LinkOut - more resources

Full Text Sources

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