- Integrated analysis of germline and somatic variants in ovarian cancer

http://www.nature.com/ncomms/2014/140122/ncomms4156/full/ncomms4156.html
:


  • Krishna L. Kanchi,
  • Kimberly J. Johnson,
  • Charles Lu,
  • Michael D. McLellan,
  • Mark D. M. Leiserson,
  • Michael C. Wendl,
  • Qunyuan Zhang,
  • Daniel C. Koboldt,
  • Mingchao Xie,
  • Cyriac Kandoth,
  • Joshua F. McMichael,
  • Matthew A. Wyczalkowski,
  • David E. Larson,
  • Heather K. Schmidt,
  • Christopher A. Miller,
  • Robert S. Fulton,
  • Paul T. Spellman,
  • Elaine R. Mardis,
  • Todd E. Druley,
  • Timothy A. Graubert

    • Nature Communications
     
    5,
     
    Article number:
     
    3156
     
    doi:10.1038/ncomms4156
    Received
     
    Accepted
     
    Published
     

    Abstract



    We report the first large-scale exome-wide analysis of the combined germline–somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2truncations, respectively. Germline–somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.

    Subject terms:

    At a glance

    Figures

    First | 1-4 of 5 | Last
    left
    1. Overview of the integrated analysis of germline and somatic variants in 429 TCGA serous ovarian cases.
      Figure 1
    2. Germline copy-number variants in BRCA1.
      Figure 2
    3. Lolliplots showing the distribution of germline truncation variants and somatic mutations.
      Figure 3
    4. LOH analysis in tumour samples.
      Figure 4
    5. Significant pathways and subnetworks in ovarian cancer.
      Figure 5
    right

    References



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    Author information



    1. These authors contributed equally to this work

      • Krishna L. Kanchi, 
      • Kimberly J. Johnson & 
      • Charles Lu

    Affiliations

    1. The Genome Institute, Washington University, St. Louis, Missouri 63108, USA

      • Krishna L. Kanchi,
        •  
      • Kimberly J. Johnson,
        •  
      • Charles Lu,
        •  
      • Michael D. McLellan,
        •  
      • Michael C. Wendl,
      • Qunyuan Zhang,
        •  
      • Daniel C. Koboldt,
        •  
      • Mingchao Xie,
        •  
      • Cyriac Kandoth,
        •  
      • Joshua F. McMichael,
        •  
      • Matthew A. Wyczalkowski,
        •  
      • David E. Larson,
        •  
      • Heather K. Schmidt,
        •  
      • Christopher A. Miller,
        •  
      • Robert S. Fulton,
      • Elaine R. Mardis,
        •  
      • Richard K. Wilson &
        •  
      • Li Ding

    2. Brown School, Washington University, St. Louis, Missouri 63130, USA

      • Kimberly J. Johnson

    3. Oregon Health and Science University, Portland, Oregon 97239, USA

      • Kimberly J. Johnson &
        •  
      • Paul T. Spellman

    4. Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA

      • Mark D. M. Leiserson &
        •  
      • Benjamin J. Raphael

    5. Department of Genetics, Washington University, St. Louis, Missouri 63108, USA

      • Michael C. Wendl,
        •  
      • Qunyuan Zhang,
        •  
      • David E. Larson,
        •  
      • Robert S. Fulton,
        •  
      • Elaine R. Mardis,
        •  
      • Todd E. Druley,
        •  
      • Richard K. Wilson &
        •  
      • Li Ding

    6. Department of Mathematics, Washington University, St. Louis, Missouri 63108, USA

      • Michael C. Wendl

    7. Siteman Cancer Center, Washington University, St. Louis, Missouri 63108, USA

      • Elaine R. Mardis,
        •  
      • Timothy A. Graubert,
        •  
      • Richard K. Wilson &
        •  
      • Li Ding

    8. Department of Pediatrics, Washington University, St. Louis, Missouri 63108, USA

      • Todd E. Druley

    9. Department of Medicine, Washington University, St. Louis, Missouri 63108, USA

      • Timothy A. Graubert &
        •  
      • Li Ding

    10. The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA

      • Paul J. Goodfellow

    Contributions

    L.D. and R.K.W. jointly supervised research. L.D., K.L.K., K.J.J., C.L., M.D.M., M.D.M.L., C.K., M.A.W., J.F.M., D.C.K., C.A.M., P.T.S. and B.J.R. analysed the data. M.C.W. and Q.Z. performed statistical analysis. K.L.K., C.L., J.F.M., M.D.M., M.A.W. and L.D. prepared figures and tables. R.S.F. performed experiments. E.R.M. and D.E.L. contributed analysis tools. L.D., K.J.J., T.A.G., P.J.G., T.E.D. and B.J.R conceived and designed the experiments. L.D. and K.J.J. wrote the manuscript. K.L.K., K.J.J., C.L. and M.D.M. contributed equally but due to restrictions on the number of first authors only K.L.K., K.J.J. and C.L. are denoted as such.

    Competing financial interests

    The authors declare no competing financial interests.

    Corresponding author

    Correspondence to: 

    Supplementary information



    PDF files

    1. Supplementary Figures and Tables (660 KB)
      Supplementary Figures S1-S5 and Supplementary Tables S1-S5

    Excel files

    1. Supplementary Data 1 (39 KB)
      Clinical Information For 557 WHI Cases
    2. Supplementary Data 2 (21 KB)
      429 TCGA Ovarian Cases Data Types and Clinical Information
    3. Supplementary Data 3 (3,642 KB)
      Somatic Mutations in 429 TCGA Ovarian cases
    4. Supplementary Data 4 (466 KB)
      All 3,635 high confidence, rare (<1% population variant allele frequency) germline truncations including 115 validated germline truncations in cancer
    5. Supplementary Data 5 (9 KB)
      Validated Truncation Variants in Cancer Genes
    6. Supplementary Data 6 (2,691 KB)
      All 22,953 missense variants (<1% population variant allele frequency), predicted to be functional by Condel in 387 Caucasians
    7. Supplementary Data 7 (575 KB)
      All truncation variants (<1% population variant allele frequency), in 557 Caucasians
    8. Supplementary Data 8 (2,434 KB)
      All 30335 missense variants (<1% population variant allele frequency), predicted to be functional by Condel in 557 Caucasians
    9. Supplementary Data 9 (331 KB)
      Burden Analysis results for the Missense variants
    10. Supplementary Data 10 (16 KB)
      Burden Analysis Results for the Missense and Truncation Variants in Cancer Genes
    11. Supplementary Data 11 (13 KB)
      Germline truncation and missense within close proximity (5 amino acid) to COSMIC/OMIM variants
    12. Supplementary Data 12 (67 KB)
      Germline truncations display LOH in corresponding tumor
    13. Supplementary Data 13 (14 KB)
      Germline missense variants in cancer genes display LOH in corresponding tumor
    14. Supplementary Data 14 (21 KB)
      High confidence, functional truncation and missense variants identified by integrated approaches
    15. Supplementary Data 15 (21 KB)
      Significant pathways identified by PathScan using germline truncations and somatic mutations
    16. Supplementary Data 16 (8 KB)
      Four significant subnetworks identified by HotNet using germline truncations and somatic mutations (P = 0.17)
    17. Supplementary Data 17 (17 KB)
      672 cancer genes
    18. Supplementary Data 18 (36 KB)
      Validated Missense Variants using 11 Whole Genome Sequencing BAMs
    19. Supplementary Data 19 (12 KB)
      Primers for TCGA Germline Validation using 3730 sequencing platform
    20. Supplementary Data 20 (49 KB)
      Primers for TCGA Germline Validation using miseq
    Update door d.d.
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    http://medicalxpress.com/news/2014-01-recurrent-ovarian-cancers-cancer-vaccine.html :


    Treatment with the drug decitabine prior to administration of chemotherapy and a cancer vaccine yielded clinical benefit for women with recurrent ovarian cancer, suggesting that this combinatorial chemoimmunotherapy may provide a new treatment option for patients with this disease, according to a study published in     Cancer Immunology Research, a journal of the American Association for Cancer Research.

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    This study was funded by the Ovarian Cancer Research Fund, the Roswell Park Alliance Foundation, a Cancer Vaccine Collaborative Grant, the Anna Maria Kellen Clinical Investigator Award, the National Cancer Institute, and Eisai Pharmaceuticals. Odunsi has declared no conflicts of interest.
    Update door d.d.
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    Update door d.d.
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    Uit: de Telegraaf 13.11.2013:

    UTRECHT - 
    Er zijn grote genetische verschillen tussen primaire tumoren aan de eierstokken en daaropvolgende uitzaaiingen. Deze nieuwe inzichten leiden wellicht tot een verbeterde behandeling van eierstokkanker.
      Foto: ANP
      Dit blijkt uit onderzoek van het UMC Utrecht en Life Technologies Corporation in Carlsbad CA (USA). De bevindingen zijn vandaag online gepubliceerd in het vakblad Genome Research.
      Eierstokkanker is een moeilijk te behandelen vorm van kanker en wordt ook wel de silent lady killer genoemd. Bij de meeste patiënten komt de ziekte terug na operatieve verwijdering van de tumor en chemotherapie. Om de groei van eierstokkanker beter te kunnen begrijpen bekeken de onderzoekers het DNA van tientallen stukjes (primaire- en uitgezaaide) tumor afkomstig van drie vrouwen met een vergevorderd stadium van eierstokkanker. Van alle stukjes tumor werd het DNA vergeleken met DNA uit gezond weefsel. Hieruit bleek dat vrijwel elk stukje eierstoktumor een unieke set van genetische veranderingen heeft.
      Verschilllen
      “Eierstokkanker wordt meestal pas in een laat stadium ontdekt, als de tumor al groot is en er in de buikholte uitzaaiingen zijn,” aldus dr. Wigard Kloosterman, een van de hoofdonderzoekers van de studie en verbonden aan het UMC Utrecht. “De extreme verschillen die we hebben gevonden tussen de tumormonsters van elke individuele patiënt zou een mogelijke verklaring kunnen zijn waarom deze vorm van kanker zo moeilijk te behandelen is.”
      De groei van de tumor was bij elk van de drie patiënten anders. Bij één patiënt kwamen er stapsgewijs steeds meer veranderingen bij. Bij twee andere patiënten ontstonden er al in een vroeg stadium twee verschillende groepen van uitzaaiingen met ieder unieke eigenschappen.
      Bij de huidige behandeling van eierstokkanker wordt zoveel mogelijk tumormateriaal weggesneden, waarna chemotherapie volgt. In principe krijgt elke patiënt de zelfde standaardbehandeling. De studie van het UMC Utrecht laat zien dat een grondige genetische analyse van eierstokkanker de basis kan vormen voor een meer verfijnde therapie met mogelijk een grotere succeskans.
      Update door d.d.
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