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Common Germline-Somatic Variant Interactions in Advanced Urothelial Cancer

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.

Aram Vosoughi,1,12 Tuo Zhang,2,3,12 Kyrillus S. Shohdy,4,5 Panagiotis J. Vlachostergios,4 David C. Wilkes,2 Bhavneet Bhinder,2,6 Scott T. Tagawa,4 David M. Nanus,4 Ana M. Molina,4 Himisha Beltran,7 Cora N. Sternberg,4 Samaneh Motanagh,8 Brian D. Robinson,1 Jenny Xiang,3 Xiao Fan,9 Wendy K. Chung,9 Mark A. Rubin,10 Olivier Elemento,2,6 Andrea Sboner,1,2,6,13 Juan Miguel Mosquera1,2,13 & Bishoy M. Faltas2,4,11,13

1. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. 2. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine-New York-Presbyterian Hospital, New York, NY, USA. 3. Genomic Resources Core Facility, Weill Cornell Medicine, New York, NY, USA. 4. Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA. 5. Department of Clinical Oncology, Kasr Alainy School of Medicine, Cairo University, Cairo, Egypt. 6. Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, NY, USA. 7. Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA. 8. Department of Pathology, Dartmouth–Hitchcock Medical Center, Lebanon, NH, USA. 9. Departments of Pediatrics and Medicine, Columbia University, NY, Columbia, NY, USA. 10. Department for Biomedical Research, University of Bern, Bern, Switzerland. 11. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. 12. These authors contributed equally: Aram Vosoughi, Tuo Zhang. 13. These authors jointly supervised this work: Andrea Sboner, Juan Miguel Mosquera, Bishoy M. Faltas. 

Source: Vosoughi, A., Zhang, T., Shohdy, K.S. et al. Common germline-somatic variant interactions in advanced urothelial cancer. Nat Commun 11, 6195 (2020). https://doi.org/10.1038/s41467-020-19971-8