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Common germline-somatic variant interactions in advanced urothelial cancer

Author

Listed:
  • Aram Vosoughi

    (Weill Cornell Medicine)

  • Tuo Zhang

    (Weill Cornell Medicine-New York-Presbyterian Hospital
    Weill Cornell Medicine)

  • Kyrillus S. Shohdy

    (Weill Cornell Medicine
    Cairo University)

  • Panagiotis J. Vlachostergios

    (Weill Cornell Medicine)

  • David C. Wilkes

    (Weill Cornell Medicine-New York-Presbyterian Hospital)

  • Bhavneet Bhinder

    (Weill Cornell Medicine-New York-Presbyterian Hospital
    Weill Cornell Medicine, New York)

  • Scott T. Tagawa

    (Weill Cornell Medicine)

  • David M. Nanus

    (Weill Cornell Medicine)

  • Ana M. Molina

    (Weill Cornell Medicine)

  • Himisha Beltran

    (Dana Farber Cancer Institute)

  • Cora N. Sternberg

    (Weill Cornell Medicine)

  • Samaneh Motanagh

    (Dartmouth–Hitchcock Medical Center)

  • Brian D. Robinson

    (Weill Cornell Medicine)

  • Jenny Xiang

    (Weill Cornell Medicine)

  • Xiao Fan

    (Columbia University, NY)

  • Wendy K. Chung

    (Columbia University, NY)

  • Mark A. Rubin

    (University of Bern)

  • Olivier Elemento

    (Weill Cornell Medicine-New York-Presbyterian Hospital
    Weill Cornell Medicine, New York)

  • Andrea Sboner

    (Weill Cornell Medicine
    Weill Cornell Medicine-New York-Presbyterian Hospital
    Weill Cornell Medicine, New York)

  • Juan Miguel Mosquera

    (Weill Cornell Medicine
    Weill Cornell Medicine-New York-Presbyterian Hospital)

  • Bishoy M. Faltas

    (Weill Cornell Medicine-New York-Presbyterian Hospital
    Weill Cornell Medicine
    Weill Cornell Medicine)

Abstract

The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifying putative deleterious germline variants (pDGVs) from WES data. Here, we show that UC patients harbor a high prevalence of pDGVs that truncate tumor suppressor proteins. Deepening somatic loss of heterozygosity in serial tumor samples is observed, suggesting a critical role for these pDGVs in tumor progression. Significant intra-patient heterogeneity in germline-somatic variant interactions results in divergent biological pathway alterations between primary and metastatic tumors. Our results characterize the spectrum of germline variants in UC and highlight their roles in shaping the natural history of the disease. These findings could have broad clinical implications for cancer patients.

Suggested Citation

  • Aram Vosoughi & Tuo Zhang & Kyrillus S. Shohdy & Panagiotis J. Vlachostergios & David C. Wilkes & Bhavneet Bhinder & Scott T. Tagawa & David M. Nanus & Ana M. Molina & Himisha Beltran & Cora N. Sternb, 2020. "Common germline-somatic variant interactions in advanced urothelial cancer," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19971-8
    DOI: 10.1038/s41467-020-19971-8
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