Next-generation sequencing of 487 esophageal adenocarcinomas reveals independently prognostic genomic driver alterations and pathways Journal Article


Authors: Sihag, S.; Nussenzweig, S. C.; Walch, H. S.; Hsu, M.; Tan, K. S.; Sanchez-Vega, F.; Chatila, W. K.; De La Torre, S. A.; Patel, A.; Janjigian, Y. Y.; Maron, S.; Ku, G. Y.; Tang, L. H.; Hechtman, J.; Shah, P. M.; Wu, A. J.; Jones, D. R.; Molena, D.; Solit, D. B.; Schultz, N.; Berger, M. F.
Article Title: Next-generation sequencing of 487 esophageal adenocarcinomas reveals independently prognostic genomic driver alterations and pathways
Abstract: Purpose: To delineate recurrent oncogenic driver alterations and dysregulated pathways in esophageal adenocarcinoma and to assess their prognostic value. Experimental Design: We analyzed a large cohort of patients with lower esophageal and junctional adenocarcinoma, prospectively sequenced by MSK-IMPACT with high-quality clinical annotation. Patients were subdivided according to treatment intent, curative versus palliative, which closely mirrored clinical staging. Genomic features, alterations, and pathways were examined for association with overall survival using Cox proportional hazard models, adjusted for relevant clinicopathologic factors knowable at the time of diagnosis. Results: Analysis of 487 patients revealed 16 oncogenic driver alterations,mostlyamplifications, present in ≥ 5% of patients. Patients in the palliative-intent cohort, compared with those in the curativeintent cohort, were more likely to have metastatic disease, ERBB2 amplifications, Cell-cycle and RTK-RAS pathway alterations, as well as a higher fraction of genome altered and rate of whole-genome doubling. In multivariable analyses, CDKN2A alterations, SMAD4 alterations,KRAS amplifications,Cell-cycle andTGFβ pathways, and overall number of oncogenic drivers were independently associated with worse overall survival. ERBB2 amplification was associated with improved survival, presumably due to trastuzumab therapy. Conclusions: Our study suggests that higher levels of genomic instability are associated with more advanced disease in esophageal adenocarcinoma. Furthermore, CDKN2A, KRAS, and SMAD4 represent prognostic biomarkers, given their strong association with poor survival. © 2021 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 27
Issue: 12
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2021-06-15
Start Page: 3491
End Page: 3498
Language: English
DOI: 10.1158/1078-0432.Ccr-20-4707
PUBMED: 33795256
PROVIDER: scopus
PMCID: PMC8228505
DOI/URL:
Notes: Article -- Export Date: 1 July 2021 -- Source: Scopus
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Citation Impact
MSK Authors
  1. Meier Hsu
    139 Hsu
  2. David Solit
    628 Solit
  3. Geoffrey Yuyat Ku
    151 Ku
  4. Yelena Yuriy Janjigian
    243 Janjigian
  5. Abraham Jing-Ching Wu
    280 Wu
  6. Laura Hong Tang
    382 Tang
  7. Michael Forman Berger
    569 Berger
  8. Nikolaus D Schultz
    317 Schultz
  9. Pari Mayank Shah
    30 Shah
  10. Jaclyn Frances Hechtman
    195 Hechtman
  11. David Randolph Jones
    258 Jones
  12. Daniela   Molena
    130 Molena
  13. Kay See   Tan
    149 Tan
  14. Smita Sihag
    37 Sihag
  15. Walid Khaled Chatila
    47 Chatila
  16. Steven Maron
    27 Maron
  17. Henry Stuart Walch
    13 Walch
  18. Assem Manoj Patel
    1 Patel