. 2018 Jul 26;174(3):758-769.e9.

doi: 10.1016/j.cell.2018.06.039. Epub 2018 Jul 19.

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

David A Quigley¹, Ha X Dang², Shuang G Zhao³, Paul Lloyd⁴, Rahul Aggarwal⁴, Joshi J Alumkal⁵, Adam Foye⁴, Vishal Kothari⁶, Marc D Perry⁶, Adina M Bailey⁴, Denise Playdle⁴, Travis J Barnard⁶, Li Zhang⁴, Jin Zhang⁷, Jack F Youngren⁴, Marcin P Cieslik⁸, Abhijit Parolia⁸, Tomasz M Beer⁹, George Thomas¹⁰, Kim N Chi¹¹, Martin Gleave¹², Nathan A Lack¹², Amina Zoubeidi¹², Robert E Reiter¹³, Matthew B Rettig¹⁴, Owen Witte¹⁵, Charles J Ryan¹⁶, Lawrence Fong⁴, Won Kim⁴, Terence Friedlander⁴, Jonathan Chou⁴, Haolong Li⁶, Rajdeep Das⁶, Hui Li⁶, Ruhollah Moussavi-Baygi⁶, Hani Goodarzi¹⁷, Luke A Gilbert¹⁸, Primo N Lara Jr¹⁹, Christopher P Evans²⁰, Theodore C Goldstein²¹, Joshua M Stuart²², Scott A Tomlins²³, Daniel E Spratt³, R Keira Cheetham²⁴, Donavan T Cheng²⁴, Kyle Farh²⁴, Julian S Gehring²⁴, Jörg Hakenberg²⁴, Arnold Liao²⁴, Philip G Febbo²⁴, John Shon²⁴, Brad Sickler²⁴, Serafim Batzoglou²⁴, Karen E Knudsen²⁵, Housheng H He²⁶, Jiaoti Huang²⁷, Alexander W Wyatt¹², Scott M Dehm²⁸, Alan Ashworth²⁹, Arul M Chinnaiyan³⁰, Christopher A Maher³¹, Eric J Small³², Felix Y Feng³³

Affiliations

¹ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Epidemiology and Biostatistics, UCSF, San Francisco, CA, USA.
² McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA; Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, USA.
³ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
⁴ Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.
⁵ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
⁶ Department of Radiation Oncology, UCSF, San Francisco, CA, USA.
⁷ Cancer Biology Division, Department of Radiation Oncology, Washington University in St. Louis, MO USA; Institute for Informatics (I(2)), Washington University in St. Louis, MO.
⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA.
⁹ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
¹⁰ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Department of Pathology, Oregon Health and Science University, Portland, OR, USA.
¹¹ Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; British Columbia Cancer Agency, Vancouver Centre, Vancouver, BC, Canada.
¹² Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
¹³ Jonsson Comprehensive Cancer Center, Department of Urology, UCLA, Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Department of Medicine, Los Angeles, CA, USA.
¹⁴ Jonsson Comprehensive Cancer Center, Department of Urology, UCLA, Los Angeles, CA, USA.
¹⁵ Department of Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
¹⁶ Division of Hematology, Oncology, and Transplant, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
¹⁷ Department of Biophysics and Biochemistry, UCSF, San Francisco, CA, USA; Department of Urology, UCSF, San Francisco, CA, USA.
¹⁸ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, UCSF, San Francisco, CA, USA.
¹⁹ Division of Hematology Oncology, Department of Internal Medicine, University of California Davis, Sacramento, CA, USA; Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA.
²⁰ Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA; Department of Urologic Surgery, University of California Davis, Sacramento, CA, USA.
²¹ Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA; UC Sant Cruz Genome Institute and Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
²² UC Sant Cruz Genome Institute and Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
²³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA.
²⁴ Illumina, Inc., San Diego, CA, USA.
²⁵ Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
²⁶ Princess Margaret Cancer Centre/University Health Network, Toronto, ON, Canada.
²⁷ Department of Pathology, Duke University, Durham, NC, USA.
²⁸ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
²⁹ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.
³⁰ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: arul@med.umich.edu.
³¹ McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA; Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: christophermaher@wustl.edu.
³² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA. Electronic address: eric.small@ucsf.edu.
³³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA; Department of Radiation Oncology, UCSF, San Francisco, CA, USA; Department of Urology, UCSF, San Francisco, CA, USA. Electronic address: felix.feng@ucsf.edu.

PMID: 30033370
PMCID: PMC6425931
DOI: 10.1016/j.cell.2018.06.039

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

David A Quigley et al. Cell. 2018.

. 2018 Jul 26;174(3):758-769.e9.

doi: 10.1016/j.cell.2018.06.039. Epub 2018 Jul 19.

Authors

Affiliations

¹ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Epidemiology and Biostatistics, UCSF, San Francisco, CA, USA.
² McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA; Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, USA.
³ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
⁴ Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.
⁵ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
⁶ Department of Radiation Oncology, UCSF, San Francisco, CA, USA.
⁷ Cancer Biology Division, Department of Radiation Oncology, Washington University in St. Louis, MO USA; Institute for Informatics (I(2)), Washington University in St. Louis, MO.
⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA.
⁹ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
¹⁰ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Department of Pathology, Oregon Health and Science University, Portland, OR, USA.
¹¹ Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; British Columbia Cancer Agency, Vancouver Centre, Vancouver, BC, Canada.
¹² Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
¹³ Jonsson Comprehensive Cancer Center, Department of Urology, UCLA, Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Department of Medicine, Los Angeles, CA, USA.
¹⁴ Jonsson Comprehensive Cancer Center, Department of Urology, UCLA, Los Angeles, CA, USA.
¹⁵ Department of Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
¹⁶ Division of Hematology, Oncology, and Transplant, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
¹⁷ Department of Biophysics and Biochemistry, UCSF, San Francisco, CA, USA; Department of Urology, UCSF, San Francisco, CA, USA.
¹⁸ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, UCSF, San Francisco, CA, USA.
¹⁹ Division of Hematology Oncology, Department of Internal Medicine, University of California Davis, Sacramento, CA, USA; Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA.
²⁰ Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA; Department of Urologic Surgery, University of California Davis, Sacramento, CA, USA.
²¹ Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA; UC Sant Cruz Genome Institute and Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
²² UC Sant Cruz Genome Institute and Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
²³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA.
²⁴ Illumina, Inc., San Diego, CA, USA.
²⁵ Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
²⁶ Princess Margaret Cancer Centre/University Health Network, Toronto, ON, Canada.
²⁷ Department of Pathology, Duke University, Durham, NC, USA.
²⁸ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
²⁹ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.
³⁰ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: arul@med.umich.edu.
³¹ McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA; Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: christophermaher@wustl.edu.
³² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA. Electronic address: eric.small@ucsf.edu.
³³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA; Department of Radiation Oncology, UCSF, San Francisco, CA, USA; Department of Urology, UCSF, San Francisco, CA, USA. Electronic address: felix.feng@ucsf.edu.

PMID: 30033370
PMCID: PMC6425931
DOI: 10.1016/j.cell.2018.06.039

Erratum in

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer.
Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal JJ, Foye A, Kothari V, Perry MD, Bailey AM, Playdle D, Barnard TJ, Zhang L, Zhang J, Youngren JF, Cieslik MP, Parolia A, Beer TM, Thomas G, Chi KN, Gleave M, Lack NA, Zoubeidi A, Reiter RE, Rettig MB, Witte O, Ryan CJ, Fong L, Kim W, Friedlander T, Chou J, Li H, Das R, Li H, Moussavi-Baygi R, Goodarzi H, Gilbert LA, Lara PN Jr, Evans CP, Goldstein TC, Stuart JM, Tomlins SA, Spratt DE, Cheetham RK, Cheng DT, Farh K, Gehring JS, Hakenberg J, Liao A, Febbo PG, Shon J, Sickler B, Batzoglou S, Knudsen KE, He HH, Huang J, Wyatt AW, Dehm SM, Ashworth A, Chinnaiyan AM, Maher CA, Small EJ, Feng FY. Quigley DA, et al. Cell. 2018 Oct 18;175(3):889. doi: 10.1016/j.cell.2018.10.019. Cell. 2018. PMID: 30340047 No abstract available.

Abstract

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

Keywords: BRCA2; androgen receptor; castration resistant prostate cancer; chromothripsis; gene fusion; genomics; metastases; structural variation; tandem duplication; whole-genome sequencing.

PubMed Disclaimer

Conflict of interest statement

DECLARATION OF INTERESTS

A.M.C. is on the scientific advisory board of Tempus. F.Y.F. is co-founder of PFS Genomics. R.K.C., D.T.C., K.F., J.S.G., J. H., A.L., J.S., S.B., and P.F. are employees of Illumina Inc and hold stock in the company. The University of Michigan has been issued a patent on ETS gene fusions in prostate cancer on which A.M.C. and S.A.T. are co-inventors. The diagnostic field of use has been licensed to Hologic/Gen-Probe, Inc., which has sublicensed rights to Roche/Ventana Medical Systems. S.A.T. has an unrelated sponsored research agreement with Astellas. S.A.T. has served as a consultant for and received honoraria from Almac Diagnostics, Janssen, and Astellas/Medivation. S.A.T. is a co-founder of, consultant for and Laboratory Director of Strata Oncology.

Figures

**Figure 1.**
Structural Variants Disrupt Tumor Suppressors and Activate Oncogenes (A) SV and copy number frequency plotted on scaled chromosomes. Wider green/blue bars indicate more frequent copy gain/loss. Darker black bars indicate more frequent SV. (B) Top: expression levels of *PTEN*, *TP53*, *RB1*, *CDKN1B*, and *CHD1* in individual samples reported as (*log*[1+(TPM × 10^{^6})]). Bottom: somatic events affecting each sample. Right: box and whisker plots showing expression for samples with 0, 1, or 2 alleles affected; horizontal bar indicates median. Each gene was sorted independently by expression level. See also Figure S3. (C) Schematic diagrams of ETS family fusions indicating previously observed and novel partners. See also Figure S3. (D) Schematic diagram of *ETV1* activation via RP11-35609.1 fusions. See also Figure S4. (E) Schematic diagrams of oncogene fusions showing previously observed and novel partners. See also Figure S2 and Tables S1, S2, S3, and S5.

**Figure 2.**
Tandem Duplication Target Enhancers near AR, *MYC*, and *FOXA1* (A) Aligned tracks showing the DNA amplification frequency (top), tandem duplication frequency (middle), tandem duplication bounds (middle), and H3K27ac average read coverage (bottom, from Kron et al., 2017) at the AR locus. (B) Box and whisker plot showing AR expression in the presence/absence of DNA amplification at AR or at the peak. (C) Samples with tandem duplication of the peak in (A) but not AR (red) more frequently had AR unamplified or amplified at low levels. (D and E) aligned tracks showing tandem duplications near *MYC* (D) and *FOXA1* (E) as in (A). See also Table S4.

**Figure 3.**
DNA Repair Alterations Are Associated with Structural Variation Frequency (A) Top: structural variant frequency by sample, sorted by deletion frequency. Bottom: presence of chromothripsis or biallelic inactivating alterations in *BRCA2*, *CDK12*, or *TP53*. (B) Circos plots illustrating *BRCA2* inactivation (left), *CDK12* inactivation (center), and chromothripsis (right). Colors as in (A). (C) Box and whiskers plots showing association between biallelic inactivating alterations in *BRCA2, CDK12*, or *TP53* and the frequencies of deletions, tandem duplications, and inverted rearrangements respectively. See also Figure S5. (D) Counts of inverted rearrangements and deletions per sample. Samples with biallelic *BRCA2* loss drawn in blue, samples bearing chromothripsis drawn in orange. (E) Box and whisker plots showing mutation frequency in the presence of biallelic loss of *BRCA2* and chromothripsis. See also Table S1.

**Figure 4.**
Mutational Signatures of DNA Damage in mCRPC (A) From top to bottom: the frequency of deletions bearing two or more nucleotides of microhomology; fit of mutation signatures COSMIC 3 and 8 and *de novo* 8; alterations associated with DNA repair by homologous recombination. See also Figure S6. (B) Box and whisker plots showing mutation frequency in samples bearing either biallelic loss of *BRCA2* or compound *BRCA1-BRCA2* heterozygosity, compared to samples lacking either of these alterations. (C) Box and whisker plots showing COSMIC signature 3 fit in tumors bearing biallelic loss of *BRCA2* and samples bearing compound *BRCA1-BRCA2* heterozygosity.

**Figure 5.**
Landscape of Somatic and Structural Alterations in mCRPC Mutation frequency (top) and germline or somatic alterations in key genes where such alterations were predicted to be functionally meaningful. Alteration frequency shown at right. See also Tables S3 and S5.

See this image and copyright information in PMC

Comment in

Sequence of events in prostate cancer.
Cotter KA, Rubin MA. Cotter KA, et al. Nature. 2018 Aug;560(7720):557-559. doi: 10.1038/d41586-018-06029-5. Nature. 2018. PMID: 30143757 No abstract available.

References

1. Abeshouse A, Ahn J, Akbani R, Ally A, Amin S, Andry, Christopher D, Annala M, Aprikian A, Armenia J, Arora A, et al. (2015). The Molecular Taxonomy of Primary Prostate Cancer. Cell 163, 1011–1025. - PMC - PubMed
1. Aggarwal R, Beer TM, Gleave M, Stuart JM, Rettig M, Evans CP, Youngren J, Alumkal JJ, Huang J, Thomas G, et al. (2016). Targeting Adaptive Pathways in Metastatic Treatment-Resistant Prostate Cancer: Update on the Stand Up 2 Cancer/Prostate Cancer Foundation-Supported West Coast Prostate Cancer Dream Team. European Urology Focus 2, 469–471. - PubMed
1. Alexandrov LB, Jones PH, Wedge DC, Sale JE, Campbell PJ, Nik-Zainal S, and Stratton MR (2015). Clock-like mutational processes in human somatic cells. Nat Genet 47, 1402–1407. - PMC - PubMed
1. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, et al. (2013). Signatures of mutational processes in human cancer. Nature 500, 415–421. - PMC - PubMed
1. Amundadottir LT, Sulem P, Gudmundsson J, Helgason A, Baker A, Agnarsson BA, Sigurdsson A, Benediktsdottir KR, Cazier JB, Sainz J, et al. (2006). A common variant associated with prostate cancer in European and African populations. Nat Genet 38, 652–658. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Affiliations

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous