1. Genomic changes in Kaposi Sarcoma-associated Herpesvirus and their clinical correlates.
- Author
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Santiago, Jan Clement, Adams, Scott V., Towlerton, Andrea, Okuku, Fred, Phipps, Warren, and Mullins, James I.
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HERPESVIRUSES , *VIRAL mutation , *WHOLE genome sequencing , *GENETIC variation , *KAPOSI'S sarcoma-associated herpesvirus , *VIRAL variation , *GENE silencing , *PHENOTYPES , *GENETIC mutation - Abstract
Kaposi sarcoma (KS), a common HIV-associated malignancy, presents a range of clinicopathological features. Kaposi sarcoma-associated herpesvirus (KSHV) is its etiologic agent, but the contribution of viral genomic variation to KS development is poorly understood. To identify potentially influential viral polymorphisms, we characterized KSHV genetic variation in 67 tumors from 1–4 distinct sites from 29 adults with advanced KS in Kampala, Uganda. Whole KSHV genomes were sequenced from 20 tumors with the highest viral load, whereas only polymorphic genes were screened by PCR and sequenced from 47 other tumors. Nine individuals harbored ≥1 tumors with a median 6-fold over-coverage of a region centering on K5 and K6 genes. K8.1 gene was inactivated in 8 individuals, while 5 had mutations in the miR-K10 microRNA coding sequence. Recurring inter-host polymorphisms were detected in K4.2 and K11.2. The K5-K6 region rearrangement breakpoints and K8.1 mutations were all unique, indicating that they arise frequently de novo. Rearrangement breakpoints were associated with potential G-quadruplex and Z-DNA forming sequences. Exploratory evaluations of viral mutations with clinical and tumor traits were conducted by logistic regression without multiple test corrections. K5-K6 over-coverage and K8.1 inactivation were tentatively correlated (p<0.001 and p = 0.005, respectively) with nodular rather than macular tumors, and with individuals that had lesions in ≤4 anatomic areas (both p≤0.01). Additionally, a trend was noted for miR-K10 point mutations and lower survival rates (HR = 4.11, p = 0.053). Two instances were found of distinct tumors within an individual sharing the same viral mutation, suggesting metastases or transmission of the aberrant viruses within the host. To summarize, KSHV genomes in tumors frequently have over-representation of the K5-K6 region, as well as K8.1 and miR-K10 mutations, and each might be associated with clinical phenotypes. Studying their possible effects may be useful for understanding KS tumorigenesis and disease progression. Author summary: How chronic KSHV infection leads to the development of KS is poorly understood, however, evaluation of KSHV mutations found in vivo may assist this understanding. Here, targeted and whole genome sequencing of KSHV in multiple tumors from individuals in Uganda revealed an increase in copy number of the region of the genome encompassing the K5 and K6 genes or inactivation of the K8.1 gene in at least a third of the individuals. In an exploratory analysis these mutations were found more in tumors of nodular than macular morphotype and in individuals with fewer lesions. These mutations were unique across individuals, indicating that they arise frequently de novo. Point mutations in the miR-K10 micro-RNA sequence were weakly associated with lower survival. Occasionally, distinct tumors within an individual shared the same viral mutation, suggesting metastases or transmission of the aberrant viruses within the host. Clustering of genome rearrangement breakpoints were associated with potential G-quadruplex and Z-DNA forming regions in the viral DNA. The viral genetic differences uncovered and their associated clinical phenotypes call for targeted surveys of these genes to potentially establish a prognostic or treatment-selective biomarker and more studies into their roles in tumorigenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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