OVARIAN ADENOCARCINOMA IN JAGUARS ( PANTHERA ONCA ): A NATURALLY-OCCURRING MODEL OF HUMAN INHERITED OVARIAN CANCER?

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Jaguars are an endangered species and represent the only felid in the Americas from the genus Panthera. Wild jaguars continue to be threatened by habitat loss and other human impacts; therefore, maintaining a healthy breeding population in zoological institutions is critical to jaguar survival. Ovarian adenocarcinoma (OC) commonly occurs in adult jaguars housed in North American zoological institutions, and is an important cause of mortality in this population. This neoplasm is very rare in domestic cats and has not been reported in other zoo felids. Archived, formalin-fixed, paraffin embedded (FFPE) reproductive tissues from 55 female jaguars were examined. OC was confirmed histologically in 22 (40%) jaguars originating from 17 zoological institutions. Seven jaguars with OC were traced back to one breeding pair, and pedigree analysis shows an autosomal dominant pattern of inheritance. The purpose of this study is to investigate the genetic pathogenesis of ovarian adenocarcinoma in jaguars by identifying an inherited germline mutation in BRCA1, BRCA2 or other cancer genes with known involvement in human ovarian and breast cancer.A candidate gene approach was used for investigation, as minimal wild type gene sequences are available for the jaguar, and no previous studies have been undertaken to investigate genetic mechanisms of disease in this species. By utilizing genomic information available from closely related species, a targeted library preparation and next-generation sequencing approach was used to evaluate exon sequences of multiple cancer genes (n=276) in paired OC and normal FFPE tissues from each jaguar. Probes designed in this assay captured the majority of target regions, covering 92% of total base pairs within the 1.4 Mbp target region. Average depth across FFPE samples was 114x. Multiple variants were detected in jaguar candidate genes. One variant of interest in BRCA2 exon 11 includes a single nucleotide variant in the jaguar sequence that corresponds to position c.3732 in humans. The c.3732C>G variant gives rise to the substitution p.Ser1252Arg which is predicted to be potentially deleterious. This variant was present in all jaguar samples, but demonstrates loss of heterozygosity in the jaguar ovarian adenocarcinomas compared to paired normal tissues. This variant is in the region of exon 11 containing several amino acid (BRC) repeats essential for RAD51 binding.Maintaining genetic diversity in endangered animals, such as the jaguar, while preserving the species in zoological institutions by captive breeding is an important aspect of their conservation. Identifying a germline mutation associated with OC in jaguars will enable the identification of mutation carriers and will allow for educated breeding decisions, better disease monitoring, and earlier intervention. Jaguars may also be a naturally-occurring animal model that parallels hereditary breast and ovarian cancer syndrome in humans.
Original languageEnglish
Article numberTMEM-020
JournalClinical Cancer Research
Volume23
Issue number11 Suppl
Publication statusPublished - 31 May 2017

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