Common germline-somatic variant interactions in advanced urothelial cancer

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. Sternberg, Samaneh Motanagh, Brian D. Robinson, Jenny Xiang, Xiao Fan, Wendy K. Chung, Mark A. Rubin, Olivier Elemento, Andrea Sboner, Juan Miguel Mosquera and Bishoy M. Faltas ()
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Aram Vosoughi: Weill Cornell Medicine
Tuo Zhang: Weill Cornell Medicine-New York-Presbyterian Hospital
Kyrillus S. Shohdy: Weill Cornell Medicine
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
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
Andrea Sboner: Weill Cornell Medicine
Juan Miguel Mosquera: Weill Cornell Medicine
Bishoy M. Faltas: Weill Cornell Medicine-New York-Presbyterian Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19971-8

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