Oncogenome of Kaposi Sarcoma

Kaposi Sarcoma (KS) is an aggressive cancer caused by the Kaposi Sarcoma Herpesvirus (KSHV/HHV-8). Individuals with immunodeficiencies, exemplified by HIV, have an elevated risk of developing KS. However, understanding of the genetic factors contributing to KS progression is still limited. To explore potential genetic alterations in KS that could offer biological or therapeutic insights, whole exome sequencing was performed on 78 KS tumors and matching normal skin samples from 59 adults with KS (46 with HIV-associated KS and 13 with HIV-negative KS) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. Results showed a very low mutational burden in all samples except one (median = 11 mutations), which is the smallest number of mutations found across all 33 cancer types in The Cancer Genome Atlas (TCGA). No recurrent mutations were identified. Mutational signatures included impaired DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from a single clone. The number of genome copy alterations per genome was higher in tumors from individuals without HIV and those with advanced-stage disease. This suggests that lesions that take longer to develop may accumulate more alterations, although the overall number of alterations remains low compared to other cancers. These findings suggest that KS pathogenesis differs from other cancers, with KSHV viral infection and the expression of viral oncogenes being the primary drivers of carcinogenesis, rather than clonal oncogenic transformation arising from genetic alterations of cancer-related cellular genes.]]>
Specimens were obtained from participants enrolled in the “HIPPOS” Study, a prospective cohort study, begun in 2012, of adults with KS initiating treatment at the Uganda Cancer Institute (UCI) in Kampala, Uganda. Participants were eligible for the HIPPOS study if they were >18 years of age with biopsy-proven KS and naïve to antiretroviral therapy (ART) and chemotherapy at enrollment. Participants attended 12 study visits over a one-year period and received treatment for KS consisting of ART if HIV-infected and chemotherapy (a combination of bleomycin and vincristine or paclitaxel) per standard protocols by UCI physicians. At each visit, participants received a detailed physical exam to assess clinical response using the AIDS Clinical Trials Group (ACTG) KS response criteria]]>
This study was initiated as a collaboration between Dr. Waren Phipps and Ethel Cesarman, and funded by the NIH/NCI grant R21 R21 CA206851, which included Dr. Olivier Elemento as a co-investigator. It was based on the prior establishment of a cohort of participats with KS in Kampala, Uganda by Dr. Warren Phipps, called HIPPOS, and NIH/NCI grants K23 CA 150931, R01 CA217138, and R01 CA239287. The study entailed exome sequencing which was performed at both Weill Cornell Medicine or the Fred Hutch Genomics Shared Resource. B. Bhinder performed computational analysis and preparation of manuscript figures. ]]>