In a study reported in Nature Communications, Bishoy M. Faltas, MD, of the Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, and colleagues identified common germline-somatic variant interactions in advanced urothelial cancer, with these interactions appearing to play a central role in disease progression.¹

As stated by the investigators: “The prevalence and the biological consequences of deleterious germline variants in urothelial cancer are not fully characterized…. We reasoned that variants that truncate tumor suppressor proteins would increase predisposition to cancer and potentially play an important role in tumor progression in the context of the classical two-hit model.”

“Patients with urothelial cancer harbor a high prevalence of putative deleterious germline variants that truncate tumor suppressor proteins.”

— Bishoy M. Faltas, MD

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Study Details

The study involved whole-exome sequencing of germline DNA and 157 primary and metastatic tumors from 80 patients with urothelial cancer at Weill Cornell Medicine. A computational framework was developed for identifying putative deleterious germline variants from whole-exome sequencing data.

Overall, 66 patients (82.5%) had metastatic disease during the study period, 61 (76%) had a history of smoking, 39 (49%) had a history of a second non–urothelial cancer primary, 40 (50%) had a family history of cancer in at least one first-degree relative. Most patients had European ancestry.

Key Findings

A total of 61 germline putative deleterious germline variants were identified in 45 patients (56%). The most frequent genes harboring recurrent putative deleterious germline variants were ITGA7, POLQ, KLK6, EPHB6, and CNDP2, occurring in 11 of the 45 patients (24%). Pathway analysis showed an enrichment of putative deleterious germline variants involving genes in the DNA repair pathway, including POLQ, POLK, FANCA, XPA, ASCC1, and BRCA2.

Of 28 putative deleterious germline variants with available structural information for the encoded protein, 27 (96%) clustered with previously reported somatic variants (P < .001). The clusters harbored a median of five variants and frequently involved domains that were important for protein function.

The potential functional role of putative deleterious germline variants in urothelial cancer progression was assessed by determining whether these loss-of-function putative deleterious germline variants in tumor-suppressor genes undergo positive selection in urothelial cancer, as manifest by somatic loss of heterozygosity. It was found that 53% of putative deleterious germline variants showed evidence of loss of heterozygosity.

Assessment of longitudinal putative deleterious germline variants loss of heterozygosity changes in 29 primary and metastatic urothelial cancer pairs showed that 23 paired comparisons (79%) exhibited significant variant allele frequency increases in the metastatic tumors (P = .004), suggestive of deepening loss of heterozygosity. These findings suggest that evolutionary pressure on putative deleterious germline variants may be associated with progressive loss of heterozygosity in metastatic urothelial cancer and that putative deleterious germline variants have a central role in tumor progression consistent with the Knudson two-hit model.

Analysis of germline-somatic interactions in the same gene or other genes in the same biologic pathway showed somatic copy number losses in 8 of 45 patients (18%) involving KLK6, HTRA3, DLG1, PTPN13, CCDC136, PINX1, RNASEL, and TRIM32. Additional analysis showed that 14 patients had at least one pathway-level germline-somatic interaction (P < .05), including interactions in DNA repair, TP53 regulation, Hippo signaling, T-cell receptor signaling, and WNT signaling pathways.

In analyses to determine whether the observed somatic heterogeneity was associated with divergent germline-somatic interactions in tumors within the same patient, it was found that 60% of the tumor samples in the matched primary-advanced tumor pairs had unique pathways not shared by other tumor samples within the same patient. As stated by the investigators: “These data collectively suggest that germline-somatic interactions should be taken into consideration to fully understand the functional consequences of somatic alterations in cancer genomes.”

The investigators concluded: “Here, we show that patients with urothelial cancer harbor a high prevalence of putative deleterious germline variants that truncate tumor suppressor proteins. Deepening somatic loss of heterozygosity in serial tumor samples is observed, suggesting a critical role for these putative deleterious germline variants in tumor progression…. Our results characterize the spectrum of germline variants in urothelial cancer and highlight their roles in shaping the natural history of the disease. These findings could have broad clinical implications for patients with cancer.” 

DISCLOSURE: The investigators were supported by the Conquer Cancer Foundation, John and Elizabeth Leonard Family Foundation, Department of Defense, and others. Dr. Faltas has served as a consultant or advisor to Immunomedics, QED Therapeutics, and Merck & Co and has received research funding from Eli Lilly. For full disclosures of the other study authors, visit nature.com.

REFERENCE

1. Vosoughi A, Zhang T, Shohdy KS, et al: Common germline-somatic variant interactions in advanced urothelial cancer. Nat Commun 11:6195, 2020.