Abstract 6715: Cross-species investigation of gene copy number and cancer resistance

Low cancer incidence rates are observed in large mammals such as elephants and whales, despite their mass and long lifespan hypothetically contributing to a higher lifetime probability of acquiring oncogenic mutations. Few studies have investigated cancer-related genes in these animals. One reported that bowhead whales possess two functional copies of PCNA. Multiple studies have investigated the presence of multiple retrogene copies of TP53 in elephants. Extra copies of genes involved in DNA damage detection and repair could contribute to cancer resistance. Droplet digital PCR (ddPCR) was used to quantify gene copy number for TP53, PCNA, HER2, DLG1, and DLG2 in genomic DNA extracted from frozen skin samples of beluga, narwhal and bowhead whales (n=20 each). Results showed that all 3 whale species had more than one copy of PCNA. Agarose gel PCR showed the simultaneous presence of wild-type PCNA (possessing introns) and variable numbers of pseudogene sequences (lacking introns) within individuals for belugas, narwhals, and bowheads. ddPCR found that elephants did not have increased PCNA copy number, but agarose gel PCR showed the presence of PCNA pseudogenes. Similar patterns were also observed in rhinos, horses, cows and other ungulate species. To investigate copy number loss in cancer, ddPCR was performed on formalin-fixed, paraffin embedded normal and matched tumor tissue of 7 individual belugas from the St. Lawrence estuary, an area that was historically contaminated with industrial carcinogens. Copy number loss was not observed for any investigated tumor suppressor gene in tumor tissue compared to normal tissue. Our results show that bowhead whales are not unique in having multiple copies of PCNA. The presence of incomplete copies with unknown function may influence copy number quantification. Further study is required to understand the significance of the variable PCNA pseudogene copies. Understanding natural copy number variation in tumor suppressor genes may provide insight into risk factors and prevention methods across species. Citation Format: Morla Phan, Thompson Worden, Sarah Adamowicz, Stéphane Lair, Mauricio Seguel, Claire Jardine, Geoffrey Wood, Dirk Steinke. Cross-species investigation of gene copy number and cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6715.