Common germline-somatic variant interactions in advanced urothelial cancer

• Published in: Nature communications Vol. 11; no. 1; pp. 6195 - 13
• Main Authors: Vosoughi, Aram, Zhang, Tuo, Shohdy, Kyrillus S., Vlachostergios, Panagiotis J., Wilkes, David C., Bhinder, Bhavneet, Tagawa, Scott T., Nanus, David M., Molina, Ana M., Beltran, Himisha, Sternberg, Cora N., Motanagh, Samaneh, Robinson, Brian D., Xiang, Jenny, Fan, Xiao, Chung, Wendy K., Rubin, Mark A., Elemento, Olivier, Sboner, Andrea, Mosquera, Juan Miguel, Faltas, Bishoy M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.12.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 49; 49/23; 49/91; 631/67/69; 692/4028/67/589/1336; Biological effects; Biological Evolution; Bladder cancer; Cancer; Cohort Studies; Computer applications; DNA sequencing; Genome, Human; Germ-Line Mutation - genetics; Heterogeneity; Heterozygosity; Humanities and Social Sciences; Humans; Loss of heterozygosity; Loss of Heterozygosity - genetics; Metastases; Metastasis; multidisciplinary; Neoplasm Staging; Protein Domains; Proteins; Proteins - chemistry; Proteins - genetics; Science; Science (multidisciplinary); Tumor suppressor genes; Tumors; Urologic Neoplasms - genetics; Urologic Neoplasms - pathology; Urothelial cancer
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19971-8

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. The role of germline variation in human cancers is not fully understood. Here, the authors define the landscape of putative deleterious germline variants that abrogate tumor suppressor proteins in advanced urothelial cancer patients.