According to the National Institutes of Health (NIH), “A copy number variation (CNV) is when the number of copies of a particular gene varies from one individual to the next. Following the completion of the Human Genome Project, it became apparent that the genome experiences gains and losses of genetic material.” We know that the genome, both human and canine, are not as stable as once believed. Indeed, the genomic instability that characterizes cancer cells, makes this process quite likely in cancer.
By convention, CNV is used for germline events, and Copy Number Alteration (CNA) is used for somatic events. But for this blog post, I will be using the terms interchangeably.
CNVs are defined as structural variations in the genome larger than 1 kilobase (kb) in size and can involve gains or losses of genomic DNA. Additional copies of oncogenes or losses of tumor suppressor genes are particularly important as it relates to cancer pathogenesis.
Knowing which genes are associated with CNVs is only the first step. Scientists must then try and determine which of these genes are dosage-sensitive and which tissues that contain these oncogene or tumor suppressor gene CNVs will undergo malignant transformation.
In veterinary medicine, a recent article by Heather Gardner et al, showed that CNVs were both common and important in canine osteosarcoma, similar to what is seen in human osteosarcomas. CNVs were seen in both oncogenes and tumor suppressor genes (MYC, CDKN2A/B, RB1, PTEN). They also found that CNVs, predominantly copy number losses, of the DMD gene were seen very frequently in canine osteosarcoma samples.
We know that CNV is important for a multitude of cancers in people, with a large percentage of the following cancers having CNVs: uterine carcinomas, sarcomas, esophageal carcinomas ovarian carcinomas, adrenocortical carcinomas, cutaneous melanomas, bladder carcinomas, gastric carcinomas, renal carcinomas, hepatocellular carcinomas, lung squamous cell carcinomas, breast carcinomas, head and neck squamous cell carcinomas, cholangiocarcinomas, prostate carcinomas, lung adenocarcinomas, mesotheliomas, colon adenocarcinomas, glioblastomas, gliomas, pancreatic carcinomas, pheochromocytomas, thymomas, thyroid carcinomas, and diffuse large B-cell lymphomas.
As we gather more and more clinico-genomic data from canine tumors, the importance of CNVs will likely become more and more apparent.
Shlien, A., Malkin, D. Copy number variations and cancer. Genome Med 1, 62 (2009). https://doi.org/10.1186/gm62
Gardner, H.L., Sivaprakasam, K., Briones, N. et al. Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2. Commun Biol 2, 266 (2019). https://doi.org/10.1038/s42003-019-0487-2
Harbers, L., Agostini, F., Nicos, M. et al. Somatic Copy Number Alterations in Human Cancers: An Analysis of Publicly Available Data From The Cancer Genome Atlas
Front. Oncol., 28 July 2021 | https://doi.org/10.3389/fonc.2021.700568