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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,
  • Bishoy M. Faltas

Publication: Nature Communications, December 2020

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.

Commentary by Dr. Benjamin Pradere

This month, an important article for the future of precision medicine has been published by Vosoughi et al. in Nature Communications.

The team led by BM. Faltas provided an atlas of putative deleterious germline variants (pDGVs) and define the spectrum of germline-somatic interactions (GSIs) in urothelial carcinoma (UC) patients.

Germline genomic integrity is safeguarded against high mutation rates. When deleterious germline variants occur, they can have profound effects throughout an organism’s lifespan. It is known that first-degree relatives of UC patients have a higher risk of developing UC.

Germline variants transmit genetic information that determines the heritability of complex disorders. A large epidemiological study of 203,691 individual twins estimated a 33% heritable component. There is a 14–24% prevalence of germline variants in UC patients.

The objective of the study was to define the spectrum of germline variants affecting protein-coding genes and germline-somatic interactions (GSIs) in UC patients.

The authors performed a Whole Exome Sequencing (WES) of prospectively collected germline DNA samples and 157 tumors from 80 UC patients. They created a stepwise computational framework (DGVar) to distinguish putative deleterious germline variants (pDGVs) from a large number of background germline variants in each UC patient. They decided to identify and prioritize germline variants that truncate tumor suppressor proteins.

Then, they investigated the biological impact of pDGVs in UC tumors and examined the loss of heterozygosity (LOH) events to identify pDGVs undergoing positive. To dissect the effects of pDGVs on UC throughout its lifetime, they also examined LOH events in matched primary and metastatic tumors within the same patient.

The authors identified 61 germline pDGVs in 45 (56%) of patients in the WCM-UC cohort. All pDGVs occurred in genes annotated as Tumor Suppressor Genes (TSG). The EPHB6, ARL11, KLK6, ITGA7, and POLQ genes harbored the most recurrent pDGVs.

Deepening loss of heterozygosity (LOH) occurs under evolutionary pressure.

They discovered that 79% (23/29) of the paired comparisons showed significant VAF increases in the metastatic tumors compared to the primary tumors. That suggests that the evolutionary pressure on pDGVs drives progressive LOH in metastatic UC and pDGVs play a critical role in tumor progression.

Their findings suggest that pDGVs are individually rare but collectively common, occurring in approximately half of UC patients. The analysis suggests that targeted sequencing, which is frequently used for clinical testing approaches, significantly underestimates the prevalence of pDGVs in UC patients. They demonstrated the feasibility of using whole-exome sequencing to interrogate a broader range of pDGVs in cancer patients. The majority of the pDGVs they identified clustered with known somatic variants within functional protein domains. Moreover, deepening LOH affecting the majority of pDGVs was observed during cancer progression, supporting their functional relevance.

They also identified significant intra-patient heterogeneity arising from private GSIs in individual tumors. These interactions involve divergent biological processes. The findings highlight how germline-somatic variant interactions contribute to cancer heterogeneity. The functional consequences of these interactions warrant additional studies.

The study highlights that the WES expands the repertoire of germline variants beyond commonly used targeted sequencing approaches.

These recurrent pDGVs in DNA damage repair pathways are potential therapeutic targets.

By expanding the repertoire of pDGVs in DNA damage repair genes, their results open the door to trials of these targeted therapeutic strategies in properly selected UC patients.